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Sample records for endocannabinoids selectively enhance

  1. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    International Nuclear Information System (INIS)

    Vilela, Luciano R.; Gobira, Pedro H.; Viana, Thercia G.; Medeiros, Daniel C.; Ferreira-Vieira, Talita H.; Doria, Juliana G.; Rodrigues, Flávia; Aguiar, Daniele C.; Pereira, Grace S.; Massessini, André R.; Ribeiro, Fabíola M.; Oliveira, Antonio Carlos P. de; Moraes, Marcio F.D.; Moreira, Fabricio A.

    2015-01-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB 1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB 1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis attenuates

  2. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Vilela, Luciano R. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Gobira, Pedro H.; Viana, Thercia G. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Medeiros, Daniel C.; Ferreira-Vieira, Talita H. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Doria, Juliana G. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Rodrigues, Flávia [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Aguiar, Daniele C. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Pereira, Grace S.; Massessini, André R. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Ribeiro, Fabíola M. [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Oliveira, Antonio Carlos P. de [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis

  3. Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses

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    María-Paz Viveros

    2007-01-01

    Full Text Available The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long- term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.

  4. Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment-Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats

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    Hai-Jing Sun

    2017-01-01

    Full Text Available Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA and 2-arachidonoylglycerol (2-AG detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS, malonaldehyde (MDA, and MPO (myeloperoxidase and increased superoxide dismutase (SOD production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.

  5. Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex.

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    Scheggia, D; Zamberletti, E; Realini, N; Mereu, M; Contarini, G; Ferretti, V; Managò, F; Margiani, G; Brunoro, R; Rubino, T; De Luca, M A; Piomelli, D; Parolaro, D; Papaleo, F

    2018-04-01

    The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC.

  6. Endocannabinoids and the processing of value-related signals

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    Miriam eMelis

    2012-02-01

    Full Text Available Endocannabinoids serve as retrograde signaling molecules at many synapses within the CNS, particularly GABAergic and glutamatergic synapses. Synapses onto midbrain dopamine (DA neurons in the ventral tegmental area (VTA make no exception to this rule. In fact, the effects of cannabinoids on dopamine transmission as well as DA-related behaviors are generally exerted through the modulation of inhibitory and excitatory afferents impinging onto DA neurons. Endocannabinoids, by regulating different forms of synaptic plasticity in the VTA, provide a critical modulation of the DA neuron output and, ultimately, of the systems driving and regulating motivated behaviors. Because DA cells exhibit diverse states of activity, which crucially depend on their intrinsic properties and afferent drive, the understanding of the role played by endocannabinoids in synaptic modulations is critical for their overall functions. Particularly, endocannabinoids by selectively inhibiting afferent activity may alter the functional states of DA neurons and potentiate the responsiveness of the reward system to phasic DA.

  7. Endocannabinoids as Guardians of Metastasis

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    Irmgard Tegeder

    2016-02-01

    Full Text Available Endocannabinoids including anandamide and 2-arachidonoylglycerol are involved in cancer pathophysiology in several ways, including tumor growth and progression, peritumoral inflammation, nausea and cancer pain. Recently we showed that the endocannabinoid profiles are deranged during cancer to an extent that this manifests in alterations of plasma endocannabinoids in cancer patients, which was mimicked by similar changes in rodent models of local and metastatic cancer. The present topical review summarizes the complexity of endocannabinoid signaling in the context of tumor growth and metastasis.

  8. Endocannabinoid signaling in reward and addiction

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    Parsons, Loren H.; Hurd, Yasmin L.

    2015-01-01

    Brain endocannabinoid signaling influences the motivation for natural rewards (such as palatable food, sexual activity and social interaction) and modulates the rewarding effects of addictive drugs. Pathological forms of natural and drug-induced reward are associated with dysregulated endocannabinoid signaling that may derive from pre-existing genetic factors or from prolonged drug exposure. Impaired endocannabinoid signaling contributes to dysregulated synaptic plasticity, increased stress responsivity, negative emotional states, and craving that propel addiction. Understanding the contributions of endocannabinoid disruptions to behavioral and physiological traits provides insight into the endocannabinoid influence on addiction vulnerability. PMID:26373473

  9. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

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    Grant, Igor; Cahn, B. Rael

    2008-01-01

    The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control. PMID:18806886

  10. Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation.

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    András Iring

    Full Text Available Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1 receptor blockade and inhibition of cannabinoid reuptake, respectively on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H.In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v. failed to influence blood pressure (BP, cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v. induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the

  11. Endocannabinoid system and drug addiction: new insights from mutant mice approaches.

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    Maldonado, Rafael; Robledo, Patricia; Berrendero, Fernando

    2013-08-01

    The involvement of the endocannabinoid system in drug addiction was initially studied by the use of compounds with different affinities for each cannabinoid receptor or for the proteins involved in endocannabinoids inactivation. The generation of genetically modified mice with selective mutations in these endocannabinoid system components has now provided important advances in establishing their specific contribution to drug addiction. These genetic tools have identified the particular interest of CB1 cannabinoid receptor and endogenous anandamide as potential targets for drug addiction treatment. Novel genetic tools will allow determining if the modulation of CB2 cannabinoid receptor activity and 2-arachidonoylglycerol tone can also have an important therapeutic relevance for drug addiction. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Motion sickness, stress and the endocannabinoid system.

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    Alexander Choukèr

    Full Text Available BACKGROUND: A substantial number of individuals are at risk for the development of motion sickness induced nausea and vomiting (N&V during road, air or sea travel. Motion sickness can be extremely stressful but the neurobiologic mechanisms leading to motion sickness are not clear. The endocannabinoid system (ECS represents an important neuromodulator of stress and N&V. Inhibitory effects of the ECS on N&V are mediated by endocannabinoid-receptor activation. METHODOLOGY/PRINCIPAL FINDINGS: We studied the activity of the ECS in human volunteers (n = 21 during parabolic flight maneuvers (PFs. During PFs, microgravity conditions (<10(-2 g are generated for approximately 22 s which results in a profound kinetic stimulus. Blood endocannabinoids (anandamide and 2-arachidonoylglycerol, 2-AG were measured from blood samples taken in-flight before start of the parabolic maneuvers, after 10, 20, and 30 parabolas, in-flight after termination of PFs and 24 h later. Volunteers who developed acute motion sickness (n = 7 showed significantly higher stress scores but lower endocannabinoid levels during PFs. After 20 parabolas, blood anandamide levels had dropped significantly in volunteers with motion sickness (from 0.39+/-0.40 to 0.22+/-0.25 ng/ml but increased in participants without the condition (from 0.43+/-0.23 to 0.60+/-0.38 ng/ml resulting in significantly higher anandamide levels in participants without motion sickness (p = 0.02. 2-AG levels in individuals with motion sickness were low and almost unchanged throughout the experiment but showed a robust increase in participants without motion sickness. Cannabinoid-receptor 1 (CB1 but not cannabinoid-receptor 2 (CB2 mRNA expression in leucocytes 4 h after the experiment was significantly lower in volunteers with motion sickness than in participants without N&V. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that stress and motion sickness in humans are associated with impaired endocannabinoid

  13. Endocannabinoid involvement in reward and impulsivity in addiction

    NARCIS (Netherlands)

    van Hell, H.H.

    2011-01-01

    Addiction is one of the most disabling diseases in the world. An important neurotransmitter system that has recently been implicated in addiction is the endocannabinoid system. The endocannabinoid system consists of cannabinoid receptors and endocannabinoid ligands that work on these receptors.

  14. Endocannabinoids

    DEFF Research Database (Denmark)

    Hansen, Harald S.; Petersen, G.; Artmann, A.

    2006-01-01

    The endocannabinoid system embraces a group of lipid molecules, enzymes and receptor proteins. This system appears to be involved in the modulation of neurotransmitter release thereby modifying learning and memory, in the regulation of food intake, and in the modulation of inflammation and pain...

  15. Endocannabinoids, Related Compounds and Their Metabolic Routes

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    Filomena Fezza

    2014-10-01

    Full Text Available Endocannabinoids are lipid mediators able to bind to and activate cannabinoid receptors, the primary molecular targets responsible for the pharmacological effects of the Δ9-tetrahydrocannabinol. These bioactive lipids belong mainly to two classes of compounds: N-acylethanolamines and acylesters, being N-arachidonoylethanolamine (AEA and 2-arachidonoylglycerol (2-AG, respectively, their main representatives. During the last twenty years, an ever growing number of fatty acid derivatives (endocannabinoids and endocannabinoid-like compounds have been discovered and their activities biological is the subject of intense investigations. Here, the most recent advances, from a therapeutic point of view, on endocannabinoids, related compounds, and their metabolic routes will be reviewed.

  16. The Endocannabinoid System and Sex Steroid Hormone-Dependent Cancers

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    Thangesweran Ayakannu

    2013-01-01

    Full Text Available The “endocannabinoid system (ECS” comprises the endocannabinoids, the enzymes that regulate their synthesis and degradation, the prototypical cannabinoid receptors (CB1 and CB2, some noncannabinoid receptors, and an, as yet, uncharacterised transport system. Recent evidence suggests that both cannabinoid receptors are present in sex steroid hormone-dependent cancer tissues and potentially play an important role in those malignancies. Sex steroid hormones regulate the endocannabinoid system and the endocannabinoids prevent tumour development through putative protective mechanisms that prevent cell growth and migration, suggesting an important role for endocannabinoids in the regulation of sex hormone-dependent tumours and metastasis. Here, the role of the endocannabinoid system in sex steroid hormone-dependent cancers is described and the potential for novel therapies assessed.

  17. Peripheral endocannabinoids regulate skeletal muscle development and maintenance

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    Dongjiao Zhao

    2010-12-01

    Full Text Available As a principal tissue responsible for insulin-mediated glucose uptake, skeletal muscle is important for whole-body health. The role of peripheral endocannabinoids as regulators of skeletal muscle metabolism has recently gained a lot of interest, as endocannabinoid system disorders could cause peripheral insulin resistance. We investigated the role of the peripheral endocannabinoid system in skeletal muscle development and maintenance. Cultures of C2C12 cells, primary satellite cells and mouse skeletal muscle single fibers were used as model systems for our studies. We found an increase in cannabinoid receptor type 1 (CB1 mRNA and endocannabinoid synthetic enzyme mRNA skeletal muscle cells during differentiation. We also found that activation of CB1 inhibited myoblast differentiation, expanded the number of satellite cells, and stimulated the fast-muscle oxidative phenotype. Our findings contribute to understanding of the role of the endocannabinoid system in skeletal muscle metabolism and muscle oxygen consumption, and also help to explain the effects of the peripheral endocannabinoid system on whole-body energy balance.

  18. Endocannabinoid System: A Multi-Facet Therapeutic Target.

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    Kaur, Rimplejeet; Ambwani, Sneha R; Singh, Surjit

    2016-01-01

    the therapeutic targets for both cannabinoid receptor agonists and antagonists. One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that act selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted. Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids. In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as "protective" and "disease inducing substance", time-dependent changes in the expression of cannabinoid receptors.

  19. Involvement of the endocannabinoid system in periodontal healing

    Energy Technology Data Exchange (ETDEWEB)

    Kozono, Sayaka [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Matsuyama, Takashi, E-mail: takashi@dent.kagoshima-u.ac.jp [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Biwasa, Kamal Krishna [Department of Biochemistry and Molecular Biology, Rajshahi University, Rajshahi 6205 (Bangladesh); Kawahara, Ko-ichi [Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Nakajima, Yumiko; Yoshimoto, Takehiko; Yonamine, Yutaka; Kadomatsu, Hideshi [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Tancharoen, Salunya [Department of Pharmacology, Faculty of Dentistry, Mahidol University, Bangkok 10400 (Thailand); Hashiguchi, Teruto [Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Noguchi, Kazuyuki [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Maruyama, Ikuro [Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

    2010-04-16

    Endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are important lipid mediators for immunosuppressive effects and for appropriate homeostasis via their G-protein-coupled cannabinoid (CB) receptors in mammalian organs and tissues, and may be involved in wound healing in some organs. The physiological roles of endocannabinoids in periodontal healing remain unknown. We observed upregulation of the expression of CB1/CB2 receptors localized on fibroblasts and macrophage-like cells in granulation tissue during wound healing in a wound-healing model in rats, as well as an increase in AEA levels in gingival crevicular fluid after periodontal surgery in human patients with periodontitis. In-vitro, the proliferation of human gingival fibroblasts (HGFs) by AEA was significantly attenuated by AM251 and AM630, which are selective antagonists of CB1 and CB2, respectively. CP55940 (CB1/CB2 agonist) induced phosphorylation of the extracellular-regulated kinases (ERK) 1/2, p38 mitogen-activated protein kinase (p38MAPK), and Akt in HGFs. Wound closure by CP55940 in an in-vitro scratch assay was significantly suppressed by inhibitors of MAP kinase kinase (MEK), p38MAPK, and phosphoinositol 3-kinase (PI3-K). These findings suggest that endocannabinoid system may have an important role in periodontal healing.

  20. Involvement of the endocannabinoid system in periodontal healing

    International Nuclear Information System (INIS)

    Kozono, Sayaka; Matsuyama, Takashi; Biwasa, Kamal Krishna; Kawahara, Ko-ichi; Nakajima, Yumiko; Yoshimoto, Takehiko; Yonamine, Yutaka; Kadomatsu, Hideshi; Tancharoen, Salunya; Hashiguchi, Teruto; Noguchi, Kazuyuki; Maruyama, Ikuro

    2010-01-01

    Endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are important lipid mediators for immunosuppressive effects and for appropriate homeostasis via their G-protein-coupled cannabinoid (CB) receptors in mammalian organs and tissues, and may be involved in wound healing in some organs. The physiological roles of endocannabinoids in periodontal healing remain unknown. We observed upregulation of the expression of CB1/CB2 receptors localized on fibroblasts and macrophage-like cells in granulation tissue during wound healing in a wound-healing model in rats, as well as an increase in AEA levels in gingival crevicular fluid after periodontal surgery in human patients with periodontitis. In-vitro, the proliferation of human gingival fibroblasts (HGFs) by AEA was significantly attenuated by AM251 and AM630, which are selective antagonists of CB1 and CB2, respectively. CP55940 (CB1/CB2 agonist) induced phosphorylation of the extracellular-regulated kinases (ERK) 1/2, p38 mitogen-activated protein kinase (p38MAPK), and Akt in HGFs. Wound closure by CP55940 in an in-vitro scratch assay was significantly suppressed by inhibitors of MAP kinase kinase (MEK), p38MAPK, and phosphoinositol 3-kinase (PI3-K). These findings suggest that endocannabinoid system may have an important role in periodontal healing.

  1. Endocannabinoids and the Cardiovascular System in Health and Disease.

    Science.gov (United States)

    O'Sullivan, Saoirse Elizabeth

    2015-01-01

    The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.

  2. The skeletal endocannabinoid system: clinical and experimental insights.

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    Raphael, Bitya; Gabet, Yankel

    2016-05-01

    Recently, there has been a rapidly growing interest in the role of cannabinoids in the regulation of skeletal remodeling and bone mass, addressed in basic, translational and clinical research. Since the first publications in 2005, there are more than 1000 publications addressing the skeletal endocannabinoid system. This review focuses on the roles of the endocannabinoid system in skeletal biology via the cannabinoid receptors CB1, CB2 and others. Endocannabinoids play important roles in bone formation, bone resorption and skeletal growth, and are sometimes age, gender, species and strain dependent. Controversies in the literature and potential therapeutic approaches targeting the endocannabinoid system in skeletal disorders are also discussed.

  3. Endocannabinoid antagonism: blocking the excess in the treatment of high-risk abdominal obesity.

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    Duffy, Danielle; Rader, Daniel

    2007-02-01

    Abdominal obesity is a prevalent, worldwide problem linked to cardiometabolic comorbidities and an increased risk of coronary heart disease. First-line therapy to reduce such risk revolves around diet and exercise; however, such changes are often difficult to implement and unsuccessful. Understanding the underlying pathophysiology of underlying metabolic derangements could provide new targets for pharmacologic therapy. One system that has gained recent attention is the endocannabinoid system. The endocannabinoid system has a significant role in central appetite control and peripheral lipogenesis and is up-regulated in diet-induced obesity. Rimonabant is a selective cannabinoid-1 receptor antagonist and is the first compound of its type to test the hypothesis that down-regulating an overactive endocannabinoid system could have therapeutic benefit not only for weight loss but also for the atherogenic dyslipidemia and insulin resistance that cluster with abdominal obesity in particular. Animal models have been critical for elucidating the role of the endocannabinoid system in obesity and in demonstrating that antagonism with rimonabant can induce loss of visceral fat and improve insulin sensitivity. Early human trials with rimonabant have confirmed significant reductions in weight, as well as favorable changes in atherogenic dyslipidemia, insulin resistance, and markers of inflammation. Interestingly, some of these beneficial metabolic effects are partially weight-loss-independent, confirming the importance of peripheral endocannabinoid system effects in addition to central effects.

  4. Role of endocannabinoids in regulating drug dependence

    Directory of Open Access Journals (Sweden)

    Daniela Parolaro

    2007-01-01

    Full Text Available Daniela Parolaro, Daniela Vigano’, Natalia Realini, Tiziana RubinoNeuroscience Center, DBSF, University of Insubria, Busto Arsizio, ItalyAbstract: This review will discuss the latest knowledge of how the endocannabinoid system might be involved in treating addiction to the most common illicit drugs. Experimental models are providing increasing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also for preventing relapse to the various drugs of abuse, including opioids, cocaine, nicotine, alcohol and metamphetamine. Preclinical and clinical studies suggest that the endocannabinoid system can be manipulated by the CB1 receptor antagonist SR141716A, that might constitute a new generation of compounds for treating addiction across different classes of abused drugs.Keywords: Endocannabinoids, drug dependence, opioids, nicotine, alcohol, psychostimulants

  5. Endocannabinoids in the Dentate Gyrus

    OpenAIRE

    Frazier, Charles J.

    2007-01-01

    Recent years have produced rapid and enormous growth in our understanding of endocannabinoid-mediated signalling in the CNS. While much of the recent progress has focused on other areas of the brain, a significant body of evidence has developed that indicates the presence of a robust system for endocannabinoid-mediated signalling in the dentate gyrus. This chapter will provide an overview of our current understanding of that system based on available anatomical and physiological data.

  6. THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

    Science.gov (United States)

    Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

    2016-02-01

    Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. © The Author(s) 2015.

  7. Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits.

    Science.gov (United States)

    Lau, Benjamin K; Cota, Daniela; Cristino, Luigia; Borgland, Stephanie L

    2017-09-15

    The endocannabinoid system has emerged as a key player in the control of eating. Endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide (AEA), modulate neuronal activity via cannabinoid 1 receptors (CB1Rs) in multiple nuclei of the hypothalamus to induce or inhibit food intake depending on nutritional and hormonal status, suggesting that endocannabinoids may act in the hypothalamus to integrate different types of signals informing about the animal's energy needs. In the mesocorticolimbic system, (endo)cannabinoids modulate synaptic transmission to promote dopamine release in response to palatable food. In addition, (endo)cannabinoids act within the nucleus accumbens to increase food's hedonic impact; although this effect depends on activation of CB1Rs at excitatory, but not inhibitory inputs in the nucleus accumbens. While hyperactivation of the endocannabinoid system is typically associated with overeating and obesity, much evidence has emerged in recent years suggesting a more complicated system than first thought - endocannabinoids promote or suppress feeding depending on cell and input type, or modulation by various neuronal or hormonal signals. This review presents our latest knowledge of the endocannabinoid system in non-homeostatic and homeostatic feeding circuits. In particular, we discuss the functional role and cellular mechanism of action by endocannabinoids within the hypothalamus and mesocorticolimbic system, and how these are modulated by neuropeptide signals related to feeding. In light of recent advances and complexity in the field, we review cannabinoid-based therapeutic strategies for the treatment of obesity and how peripheral restriction of CB1R antagonists may provide a different mechanism of weight loss without the central adverse effects. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

    International Nuclear Information System (INIS)

    Sanson, Benoît; Wang, Tao; Sun, Jing; Wang, Liqun; Kaczocha, Martin; Ojima, Iwao; Deutsch, Dale; Li, Huilin

    2014-01-01

    FABP5 was recently found to intracellularly transport endocannabinoid signaling lipids. The structures of FABP5 complexed with two endocannabinoids and an inhibitor were solved. Human FABP5 was found to dimerize via a domain-swapping mechanism. This work will help in the development of inhibitors to raise endocannabinoid levels. In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocket via hydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels

  9. Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

    Energy Technology Data Exchange (ETDEWEB)

    Sanson, Benoît; Wang, Tao [Brookhaven National Laboratory, Upton, NY 11973-5000 (United States); Sun, Jing; Wang, Liqun; Kaczocha, Martin [Stony Brook University, Stony Brook, NY 11794-5213 (United States); Ojima, Iwao [Stony Brook University, Stony Brook, NY 1794-3400 (United States); Stony Brook University, Stony Brook, NY 11794-3400 (United States); Deutsch, Dale, E-mail: dale.deutsch@stonybrook.edu [Stony Brook University, Stony Brook, NY 11794-5213 (United States); Stony Brook University, Stony Brook, NY 11794-3400 (United States); Li, Huilin, E-mail: dale.deutsch@stonybrook.edu [Brookhaven National Laboratory, Upton, NY 11973-5000 (United States); Stony Brook University, Stony Brook, NY 11794-5213 (United States); Stony Brook University, Stony Brook, NY 11794-3400 (United States)

    2014-02-01

    FABP5 was recently found to intracellularly transport endocannabinoid signaling lipids. The structures of FABP5 complexed with two endocannabinoids and an inhibitor were solved. Human FABP5 was found to dimerize via a domain-swapping mechanism. This work will help in the development of inhibitors to raise endocannabinoid levels. In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocket via hydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels.

  10. Emerging Role of (EndoCannabinoids in Migraine

    Directory of Open Access Journals (Sweden)

    Pinja Leimuranta

    2018-04-01

    Full Text Available In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain. Individual sections of this review cover key aspects of this topic, such as: (i the current knowledge on the endocannabinoid system (ECS with emphasis on expression of its components in migraine related structures; (ii distinguishing peripheral from central site of action of cannabinoids, (iii proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v dual (possibly opposing actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors. We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD underlying the migraine aura. Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components or novel endocannabinoid therapeutics in migraine treatment.

  11. Responses of peripheral endocannabinoids and endocannabinoid-related compounds to hedonic eating in obesity.

    Science.gov (United States)

    Monteleone, A M; Di Marzo, V; Monteleone, P; Dalle Grave, R; Aveta, T; Ghoch, M El; Piscitelli, F; Volpe, U; Calugi, S; Maj, M

    2016-06-01

    Hedonic eating occurs independently from homeostatic needs prompting the ingestion of pleasurable foods that are typically rich in fat, sugar and/or salt content. In normal weight healthy subjects, we found that before hedonic eating, plasma levels of 2-arachidonoylglycerol (2-AG) were higher than before nonhedonic eating, and although they progressively decreased after food ingestion in both eating conditions, they were significantly higher in hedonic eating. Plasma levels of anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), instead, progressively decreased in both eating conditions without significant differences. In this study, we investigated the responses of AEA, 2-AG, OEA and PEA to hedonic eating in obese individuals. Peripheral levels of AEA, 2-AG, OEA and PEA were measured in 14 obese patients after eating favourite (hedonic eating) and non-favourite (nonhedonic eating) foods in conditions of no homeostatic needs. Plasma levels of 2-AG increased after eating the favourite food, whereas they decreased after eating the non-favourite food, with the production of the endocannabinoid being significantly enhanced in hedonic eating. Plasma levels of AEA decreased progressively in nonhedonic eating, whereas they showed a decrease after the exposure to the favourite food followed by a return to baseline values after eating it. No significant differences emerged in plasma OEA and PEA responses to favourite and non-favourite food. Present findings compared with those obtained in our previously studied normal weight healthy subjects suggest deranged responses of endocannabinoids to food-related reward in obesity.

  12. Endocannabinoids mediate neuron-astrocyte communication.

    Science.gov (United States)

    Navarrete, Marta; Araque, Alfonso

    2008-03-27

    Cannabinoid receptors play key roles in brain function, and cannabinoid effects in brain physiology and drug-related behavior are thought to be mediated by receptors present in neurons. Neuron-astrocyte communication relies on the expression by astrocytes of neurotransmitter receptors. Yet, the expression of cannabinoid receptors by astrocytes in situ and their involvement in the neuron-astrocyte communication remain largely unknown. We show that hippocampal astrocytes express CB1 receptors that upon activation lead to phospholipase C-dependent Ca2+ mobilization from internal stores. These receptors are activated by endocannabinoids released by neurons, increasing astrocyte Ca2+ levels, which stimulate glutamate release that activates NMDA receptors in pyramidal neurons. These results demonstrate the existence of endocannabinoid-mediated neuron-astrocyte communication, revealing that astrocytes are targets of cannabinoids and might therefore participate in the physiology of cannabinoid-related addiction. They also reveal the existence of an endocannabinoid-glutamate signaling pathway where astrocytes serve as a bridge for nonsynaptic interneuronal communication.

  13. The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents.

    Science.gov (United States)

    Murillo-Rodriguez, Eric; Pastrana-Trejo, Jose Carlos; Salas-Crisóstomo, Mireille; de-la-Cruz, Miriel

    2017-01-01

    indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. The endocannabinoid system and associative learning and memory in zebrafish.

    Science.gov (United States)

    Ruhl, Tim; Moesbauer, Kirstin; Oellers, Nadine; von der Emde, Gerhard

    2015-09-01

    In zebrafish the medial pallium of the dorsal telencephalon represents an amygdala homolog structure, which is crucially involved in emotional associative learning and memory. Similar to the mammalian amygdala, the medial pallium contains a high density of endocannabinoid receptor CB1. To elucidate the role of the zebrafish endocannabinoid system in associative learning, we tested the influence of acute and chronic administration of receptor agonists (THC, WIN55,212-2) and antagonists (Rimonabant, AM-281) on two different learning paradigms. In an appetitively motivated two-alternative choice paradigm, animals learned to associate a certain color with a food reward. In a second set-up, a fish shuttle-box, animals associated the onset of a light stimulus with the occurrence of a subsequent electric shock (avoidance conditioning). Once fish successfully had learned to solve these behavioral tasks, acute receptor activation or inactivation had no effect on memory retrieval, suggesting that established associative memories were stable and not alterable by the endocannabinoid system. In both learning tasks, chronic treatment with receptor antagonists improved acquisition learning, and additionally facilitated reversal learning during color discrimination. In contrast, chronic CB1 activation prevented aversively motivated acquisition learning, while different effects were found on appetitively motivated acquisition learning. While THC significantly improved behavioral performance, WIN55,212-2 significantly impaired color association. Our findings suggest that the zebrafish endocannabinoid system can modulate associative learning and memory. Stimulation of the CB1 receptor might play a more specific role in acquisition and storage of aversive learning and memory, while CB1 blocking induces general enhancement of cognitive functions. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

    Directory of Open Access Journals (Sweden)

    Ahmet Ulugöl

    2014-06-01

    Full Text Available Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH and monoacylglycerol lipase (MAGL, the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targets is the endocannabinoid degrading enzyme. In this review, I provide an overview of the current understanding about the processes accounting for the biosynthesis, transport and metabolism of endocannabinoids, and pharmacological approaches and potential therapeutic applications in this area, regarding the use of drugs elevating endocannabinoid levels in pain conditions.

  16. Classical endocannabinoid-like compounds and their regulation by nutrients

    DEFF Research Database (Denmark)

    Kleberg, Karen; Hassing, Helle A.; Hansen, Harald S.

    2014-01-01

    Endocannabinoid-like compounds are structurally related to the true endocannabinoids but do not contain highly unsaturated fatty acids, and they do not bind the cannabinoid receptors. The classical endocannabinoid-like compounds include N-acylethanolamines and 2-monoacylglycerols......, which are particularly interesting in a nutritional and metabolic context. Exogenously supplied oleoylethanolamide, palmitoylethanolamide, and linoleoylethanolamide have anorexic effects, and the endogenous formation of these N-acylethanolamines in the small intestine may serve an important role...

  17. Neuroprotective Properties of Endocannabinoids N-Arachidonoyl Dopamine and N-Docosahexaenoyl Dopamine Examined in Neuronal Precursors Derived from Human Pluripotent Stem Cells.

    Science.gov (United States)

    Novosadova, E V; Arsenyeva, E L; Manuilova, E S; Khaspekov, L G; Bobrov, M Yu; Bezuglov, V V; Illarioshkin, S N; Grivennikov, I A

    2017-11-01

    Neuroprotective properties of endocannabinoids N-arachidonoyl dopamine (NADA) and N-docosahexaenoyl dopamine (DHDA) were examined in neuronal precursor cells differentiated from human induced pluripotent stem cells and subjected to oxidative stress. Both compounds exerted neuroprotective activity, which was enhanced by elevating the concentration of the endocannabinoids within the 0.1-10 µM range. However, both agents at 10 µM concentration showed a marked toxic effect resulting in death of ~30% of the cells. Finally, antagonists of cannabinoid receptors as well as the receptor of the TRPV1 endovanilloid system did not hamper the neuroprotective effects of these endocannabinoids.

  18. Behavioral and electrophysiological effects of endocannabinoid and dopaminergic systems on salient stimuli

    Directory of Open Access Journals (Sweden)

    Daniela eLaricchiuta

    2014-05-01

    Full Text Available Rewarding effects have been related to enhanced dopamine (DA release in corticolimbic and basal ganglia structures. The DAergic and endocannabinoid interaction in the responses to reward is described. This study investigated the link between endocannabinoid and DAergic transmission in the processes that are related to response to two types of reward, palatable food and novelty. Mice treated with drugs acting on endocannabinoid system (ECS (URB597, AM251 or DAergic system (haloperidol were submitted to approach-avoidance conflict tasks with palatable food or novelty. In the same mice, the cannabinoid type-1 (CB1-mediated GABAergic transmission in medium spiny neurons of the dorsomedial striatum was analyzed. The endocannabinoid potentiation by URB597 magnified approach behavior for reward (food and novelty and in parallel inhibited dorsostriatal GABAergic neurotransmission. The decreased activity of CB1 receptor by AM251 (alone or with URB597 or of DAergic D2 receptor by haloperidol had inhibitory effects toward the reward and did not permit the inhibition of dorsostriatal GABAergic transmission. When haloperidol was coadministered with URB597, a restoration effect on reward and reward-dependent motor activity was observed, only if the reward was the palatable food. In parallel, the coadministration led to restoring inhibition of CB1-mediated GABAergic transmission. Thus, in the presence of simultaneous ECS activation and inhibition of DAergic system the response to reward appears to be a stimulus-dependent manner.

  19. The endocannabinoid system and spermatogenesis

    Directory of Open Access Journals (Sweden)

    Paola eGrimaldi

    2013-12-01

    Full Text Available AbstractSpermatogenesis is a complex process in which male germ cells undergo a mitotic phase followed by meiosis and by a morphogenetic process to form mature spermatozoa. Spermatogenesis is under the control of gonadotropins, steroid hormones and it is modulated by a complex network of autocrine and paracrine factors. These modulators ensure the correct progression of germ cell differentiation to form mature spermatozoa. Recently, it has been pointed out the relevance of endocannabinoids as critical modulators of male reproduction. Endocannabinoids are natural lipids able to bind to cannabinoid receptors and whose levels are regulated by specific biosynthetic and degradative enzymes. Together with their receptors and metabolic enzymes, they form the endocannabinoid system (ECS. In male reproductive tracts, they affect Sertoli cell activities, Leydig cell proliferation, germ cell differentiation, sperm motility, capacitation and acrosome reaction. The ECS interferes with the pituitary-gonadal axis, and an intricate crosstalk between ECS and steroid hormones has been highlighted. This mini-review will focus on the involvement of the ECS in the control of spermatogenesis and on the interaction between ECS and steroid hormones.

  20. The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.

    Directory of Open Access Journals (Sweden)

    Jessica Freundt-Revilla

    Full Text Available Endocannabinoids (ECs are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS. Activation of cannabinoid type 2 receptors (CB2 is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The aim of the current study was to investigate the influence of the endocannabinoid system in two different CNS inflammatory diseases of the dog, i.e. Steroid-Responsive Meningitis-Arteritis (SRMA and Intraspinal Spirocercosis (IS. The two main endocannabinoids, anandamide (AEA and 2-AG, were quantified by mass spectrometry in CSF and serum samples of dogs affected with Steroid- Responsive Meningitis-Arteritis in the acute phase (SRMA A, SRMA under treatment with prednisolone (SRMA Tr, intraspinal Spirocercosis and healthy dogs. Moreover, expression of the CB2 receptor was evaluated in inflammatory lesions of SRMA and IS and compared to healthy controls using immunohistochemistry (IHC. Dogs with SRMA A showed significantly higher concentrations of total AG and AEA in serum in comparison to healthy controls and in CSF compared to SRMA Tr (p<0.05. Furthermore, dogs with IS displayed the highest ECs concentrations in CSF, being significantly higher than in CSF samples of dogs with SRMA A (p<0.05. CSF samples that demonstrated an eosinophilic pleocytosis had the highest levels of ECs, exceeding those with neutrophilic pleocytosis, suggesting that ECs have a major effect on migration of eosinophils in the CSF. Furthermore, CB2 receptor expression was found in glial cells in the spinal cord of healthy dogs, whereas in dogs with SRMA and IS, CB2 was strongly expressed not only in glial cells but also on the cellular

  1. The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.

    Science.gov (United States)

    Freundt-Revilla, Jessica; Heinrich, Franciska; Zoerner, Alexander; Gesell, Felix; Beyerbach, Martin; Shamir, Merav; Oevermann, Anna; Baumgärtner, Wolfgang; Tipold, Andrea

    2018-01-01

    Endocannabinoids (ECs) are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS). Activation of cannabinoid type 2 receptors (CB2) is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG) has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The aim of the current study was to investigate the influence of the endocannabinoid system in two different CNS inflammatory diseases of the dog, i.e. Steroid-Responsive Meningitis-Arteritis (SRMA) and Intraspinal Spirocercosis (IS). The two main endocannabinoids, anandamide (AEA) and 2-AG, were quantified by mass spectrometry in CSF and serum samples of dogs affected with Steroid- Responsive Meningitis-Arteritis in the acute phase (SRMA A), SRMA under treatment with prednisolone (SRMA Tr), intraspinal Spirocercosis and healthy dogs. Moreover, expression of the CB2 receptor was evaluated in inflammatory lesions of SRMA and IS and compared to healthy controls using immunohistochemistry (IHC). Dogs with SRMA A showed significantly higher concentrations of total AG and AEA in serum in comparison to healthy controls and in CSF compared to SRMA Tr (p<0.05). Furthermore, dogs with IS displayed the highest ECs concentrations in CSF, being significantly higher than in CSF samples of dogs with SRMA A (p<0.05). CSF samples that demonstrated an eosinophilic pleocytosis had the highest levels of ECs, exceeding those with neutrophilic pleocytosis, suggesting that ECs have a major effect on migration of eosinophils in the CSF. Furthermore, CB2 receptor expression was found in glial cells in the spinal cord of healthy dogs, whereas in dogs with SRMA and IS, CB2 was strongly expressed not only in glial cells but also on the cellular surface of

  2. Effect of blockage of the endocannabinoid system by CB(1) antagonism on cardiovascular risk.

    Science.gov (United States)

    Mach, François; Montecucco, Fabrizio; Steffens, Sabine

    2009-01-01

    The endocannabinoid system is a crucial player in the inflammatory processes underlying atherosclerosis. Recently, basic research studies and animal models have strongly supported the role of the endocannabinoid system not only in the regulation of classical cardiovascular risk factors (including lipid profile and glucose homeostasis), but also in the activation of immune cells and inflammatory mediators. Clinical trials investigating treatment with rimonabant (a selective antagonist of the cannabinoid type 1 receptor) have suggested a beneficial effect of this drug in the management of obesity. Further studies are needed to explore a possible use for rimonabant in treating type 2 diabetes and acute and chronic cardiovascular disease. Despite the slight increase in adverse events (mainly psychiatric), which has led to the recent withdrawal of rimonabant from the market, CB(1) receptor antagonism might represent a very promising therapeutic strategy to reduce the cardiovascular risk. In the present review, we focused on the most important experimental investigations into the role of the endocannabinoid system in atherosclerosis and cardiovascular risk.

  3. Endocannabinoid Signaling in Motivation, Reward, and Addiction: Influences on Mesocorticolimbic Dopamine Function.

    Science.gov (United States)

    Sagheddu, Claudia; Muntoni, Anna Lisa; Pistis, Marco; Melis, Miriam

    2015-01-01

    Evidence suggests that the endocannabinoid system has been conserved in the animal kingdom for 500 million years, and this system influences many critical behavioral processes including associative learning, reward signaling, goal-directed behavior, motor skill learning, and action-habit transformation. Additionally, the neurotransmitter dopamine has long been recognized to play a critical role in the processing of natural rewards, as well as of motivation that regulates approach and avoidance behavior. This motivational role of dopamine neurons is also based upon the evidence provided by several studies investigating disorders of dopamine pathways such as drug addiction and Parkinson's disease. From an evolutionary point of view, individuals engage in behaviors aimed at maximizing and minimizing positive and aversive consequences, respectively. Accordingly, those with the greatest fitness have a better potential to survival. Hence, deviations from fitness can be viewed as a part of the evolutionary process by means of natural selection. Given the long evolutionary history of both the endocannabinoid and dopaminergic systems, it is plausible that they must serve as fundamental and basic modulators of physiological functions and needs. Notably, endocannabinoids regulate dopamine neuronal activity and its influence on behavioral output. The goal of this chapter is to examine the endocannabinoid influence on dopamine signaling specifically related to (i) those behavioral processes that allow us to successfully adapt to ever-changing environments (i.e., reward signaling and motivational processes) and (ii) derangements from behavioral flexibility that underpin drug addiction. © 2015 Elsevier Inc. All rights reserved.

  4. The endocannabinoid system in brain reward processes.

    Science.gov (United States)

    Solinas, M; Goldberg, S R; Piomelli, D

    2008-05-01

    Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.

  5. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agnieszka [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland); Toczek, Marek [Department of Experimental Physiology and Pathophysiology Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok (Poland); Bielawska, Katarzyna [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland); Skrzydlewska, Elżbieta, E-mail: elzbieta.skrzydlewska@umb.edu.pl [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland)

    2016-06-15

    Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB{sub 1} receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB{sub 1} receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance in the

  6. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

    International Nuclear Information System (INIS)

    Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agnieszka; Toczek, Marek; Bielawska, Katarzyna; Skrzydlewska, Elżbieta

    2016-01-01

    Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB 1 receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB 1 receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance in the liver of

  7. The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder

    Directory of Open Access Journals (Sweden)

    Viviana eTrezza

    2013-08-01

    Full Text Available Posttraumatic stress disorder (PTSD is a psychiatric disorder of significant prevalence and morbidity, whose pathogenesis relies on paradoxical changes of emotional memory processing. An ideal treatment would be a drug able to block the pathological over-consolidation and continuous retrieval of the traumatic event, while enhancing its extinction and reducing the anxiety symptoms. While the latter benefit from antidepressant medications, no drug is available to control the cognitive symptomatology. Endocannabinoids regulate affective states and participate in memory consolidation, retrieval and extinction. Clinical findings showing a relationship between Cannabis use and PTSD, as well as changes in endocannabinoid activity in PTSD patients, further suggest the existence of a link between endocannabinoids and maladaptive brain changes after trauma exposure. Along these lines, we suggest that endocannabinoid degradation inhibitors may be an ideal therapeutic approach to simultaneously treat the emotional and cognitive features of PTSD, avoiding the unwanted psychotropic effects of compounds directly binding cannabinoid receptors.

  8. “Redundancy” of Endocannabinoid Inactivation: New Challenges and Opportunities for Pain Control

    Science.gov (United States)

    2012-01-01

    Redundancy of metabolic pathways and molecular targets is a typical feature of all lipid mediators, and endocannabinoids, which were originally defined as endogenous agonists at cannabinoid CB1 and CB2 receptors, are no exception. In particular, the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, are inactivated through alternative biochemical routes, including hydrolysis and oxidation, and more than one enzyme might be used even for the same type of inactivating reaction. These enzymes also recognize as substrates other concurrent lipid mediators, whereas, in turn, endocannabinoids might interact with noncannabinoid receptors with subcellular distribution and ultimate biological actions either similar to or completely different from those of cannabinoid receptors. Even splicing variants of endocannabinoid hydrolyzing enzymes, such as FAAH-1, might play distinct roles in endocannabinoid inactivation. Finally, the products of endocannabinoid catabolism may have their own targets, with biological roles different from those of cannabinoid receptors. These peculiarities of endocannabinoid signaling have complicated the use of inhibitors of its inactivation mechanisms as a safer and more efficacious alternative to the direct targeting of cannabinoid receptors for the treatment of several pathological conditions, including pain. However, new strategies, including the rediscovery of “dirty drugs”, and the use of certain natural products (including non-THC cannabis constituents), are emerging that might allow us to make a virtue of necessity and exploit endocannabinoid redundancy to develop new analgesics. PMID:22860203

  9. The endocannabinoid system: emotion, learning and addiction.

    Science.gov (United States)

    Moreira, Fabrício A; Lutz, Beat

    2008-06-01

    The identification of the cannabinoid receptor type 1 (CB1 receptor) was the milestone discovery in the elucidation of the behavioural and emotional responses induced by the Cannabis sativa constituent Delta(9)-tetrahydrocannabinol. The subsequent years have established the existence of the endocannabinoid system. The early view relating this system to emotional responses is reflected by the fact that N-arachidonoyl ethanolamine, the pioneer endocannabinoid, was named anandamide after the Sanskrit word 'ananda', meaning 'bliss'. However, the emotional responses to cannabinoids are not always pleasant and delightful. Rather, anxiety and panic may also occur after activation of CB1 receptors. The present review discusses three properties of the endocannabinoid system as an attempt to understand these diverse effects. First, this system typically functions 'on-demand', depending on environmental stimuli and on the emotional state of the organism. Second, it has a wide neuro-anatomical distribution, modulating brain regions with different functions in responses to aversive stimuli. Third, endocannabinoids regulate the release of other neurotransmitters that may have even opposing functions, such as GABA and glutamate. Further understanding of the temporal, spatial and functional characteristics of this system is necessary to clarify its role in emotional responses and will promote advances in its therapeutic exploitation.

  10. The endocannabinoid system and nondrug rewarding behaviours.

    Science.gov (United States)

    Fattore, Liana; Melis, Miriam; Fadda, Paola; Pistis, Marco; Fratta, Walter

    2010-07-01

    Rewarding behaviours such as sexual activity, eating, nursing, parenting, social interactions, and play activity are conserved strongly in evolution, and they are essential for development and survival. All of these behaviours are enjoyable and represent pleasant experiences with a high reward value. Remarkably, rewarding behaviours activate the same brain circuits that mediate the positive reinforcing effects of drugs of abuse and of other forms of addiction, such as gambling and food addiction. Given the involvement of the endocannabinoid system in a variety of physiological functions of the nervous system, it is not surprising that it takes part in the complex machinery that regulates gratification and perception of pleasure. In this review, we focus first on the role of the endocannabinoid system in the modulation of neural activity and synaptic functions in brain regions that are involved in natural and nonnatural rewards (namely, the ventral tegmental area, striatum, amygdala, and prefrontal cortex). Then, we examine the role of the endocannabinoid system in modulating behaviours that directly or indirectly activate these brain reward pathways. More specifically, current knowledge of the effects of the pharmacological manipulation of the endocannabinoid system on natural (eating, sexual behaviour, parenting, and social play) and pathological (gambling) rewarding behaviours is summarised and discussed. Copyright 2010 Elsevier Inc. All rights reserved.

  11. Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex.

    Directory of Open Access Journals (Sweden)

    Mathieu Lafourcade

    2007-08-01

    Full Text Available Cannabinoids have deleterious effects on prefrontal cortex (PFC-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown.Here, using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v/vi of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R faced postsynaptic mGluR5 while diacylglycerol lipase alpha (DGL-alpha, the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca(2+ as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602 but not of anandamide (with URB 597 converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, our data show that 2-AG mediates LTD at these synapses.Our data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of PFC-related pathologies.

  12. Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats

    International Nuclear Information System (INIS)

    Ito, Yuki; Tomizawa, Motohiro; Suzuki, Himiko; Okamura, Ai; Ohtani, Katsumi; Nunome, Mari; Noro, Yuki; Wang, Dong; Nakajima, Tamie; Kamijima, Michihiro

    2014-01-01

    Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10 mg/kg FNT for 9 weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement. - Highlights: • Subchronic exposure to fenitrothion induces spermatotoxicity in rats. • The fatty acid amide hydrolase is a potential target for the spermatotoxicity. • Overstimulation of the endocannabinoid signal possibly leads to the spermatotoxicity

  13. Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Yuki, E-mail: yukey@med.nagoya-cu.ac.jp [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Tomizawa, Motohiro [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502 (Japan); Suzuki, Himiko [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Okamura, Ai [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Ohtani, Katsumi [National Institute of Occupational Safety and Health, Kanagawa 214-8585 (Japan); Nunome, Mari; Noro, Yuki [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Wang, Dong; Nakajima, Tamie [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Kamijima, Michihiro, E-mail: kamijima@med.nagoya-cu.ac.jp [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan)

    2014-09-15

    Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10 mg/kg FNT for 9 weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement. - Highlights: • Subchronic exposure to fenitrothion induces spermatotoxicity in rats. • The fatty acid amide hydrolase is a potential target for the spermatotoxicity. • Overstimulation of the endocannabinoid signal possibly leads to the spermatotoxicity.

  14. The dual FAAH/MAGL inhibitor JZL195 has enhanced effects on endocannabinoid transmission and motor behavior in rats as compared to those of the MAGL inhibitor JZL184

    OpenAIRE

    Seillier, Alexandre; Aguilar, David Dominguez; Giuffrida, Andrea

    2014-01-01

    The biological actions of the endocannabinoids anandamide and 2-arachidonoyl glycerol (2-AG) are terminated by enzymatic hydrolysis of these lipids via fatty acid amide hydrolase (FAAH ) and monoacylglycerol lipase (MAGL), respectively. While several selective FAAH inhibitors have been developed and characterized in vitro and in vivo, none of the initial MAGL blockers have shown adequate potency and specificity for in vivo applications. More recently, a selective MAGL inhibitor, JZL184, has b...

  15. Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes.

    Science.gov (United States)

    Thompson, Zoe; Argueta, Donovan; Garland, Theodore; DiPatrizio, Nicholas

    2017-03-01

    The endocannabinoid system serves many physiological roles, including in the regulation of energy balance, food reward, and voluntary locomotion. Signaling at the cannabinoid type 1 receptor has been specifically implicated in motivation for rodent voluntary exercise on wheels. We studied four replicate lines of high runner (HR) mice that have been selectively bred for 81 generations based on average number of wheel revolutions on days five and six of a six-day period of wheel access. Four additional replicate lines are bred without regard to wheel running, and serve as controls (C) for random genetic effects that may cause divergence among lines. On average, mice from HR lines voluntarily run on wheels three times more than C mice on a daily basis. We tested the general hypothesis that circulating levels of endocannabinoids (i.e., 2-arachidonoylglycerol [2-AG] and anandamide [AEA]) differ between HR and C mice in a sex-specific manner. Fifty male and 50 female mice were allowed access to wheels for six days, while another 50 males and 50 females were kept without access to wheels (half HR, half C for all groups). Blood was collected by cardiac puncture during the time of peak running on the sixth night of wheel access or no wheel access, and later analyzed for 2-AG and AEA content by ultra-performance liquid chromatography coupled to tandem mass spectrometry. We observed a significant three-way interaction among sex, linetype, and wheel access for 2-AG concentrations, with females generally having lower levels than males and wheel access lowering 2-AG levels in some but not all subgroups. The number of wheel revolutions in the minutes or hours immediately prior to sampling did not quantitatively predict plasma 2-AG levels within groups. We also observed a trend for a linetype-by-wheel access interaction for AEA levels, with wheel access lowering plasma concentrations of AEA in HR mice, while raising them in C mice. In addition, females tended to have higher AEA

  16. Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans.

    Science.gov (United States)

    Fuss, Johannes; Bindila, Laura; Wiedemann, Klaus; Auer, Matthias K; Briken, Peer; Biedermann, Sarah V

    2017-11-01

    Endocannabinoids are critical for rewarding behaviors such as eating, physical exercise, and social interaction. The role of endocannabinoids in mammalian sexual behavior has been suggested because of the influence of cannabinoid receptor agonists and antagonists on rodent sexual activity. However, the involvement of endocannabinoids in human sexual behavior has not been studied. To investigate plasma endocannabinoid levels before and after masturbation in healthy male and female volunteers. Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide, the endocannabinoid-like lipids oleoyl ethanolamide and palmitoyl ethanolamide, arachidonic acid, and cortisol before and after masturbation to orgasm. In study 1, endocannabinoid and cortisol levels were measured before and after masturbation to orgasm. In study 2, masturbation to orgasm was compared with a control condition using a single-blinded, randomized, 2-session crossover design. In study 1, masturbation to orgasm significantly increased plasma levels of the endocannabinoid 2-AG, whereas anandamide, oleoyl ethanolamide, palmitoyl ethanolamide, arachidonic acid, and cortisol levels were not altered. In study 2, only masturbation to orgasm, not the control condition, led to a significant increase in 2-AG levels. Interestingly, we also found a significant increase of oleoyl ethanolamide after masturbation to orgasm in study 2. Endocannabinoids might play an important role in the sexual response cycle, leading to possible implications for the understanding and treatment of sexual dysfunctions. We found an increase of 2-AG through masturbation to orgasm in 2 studies including a single-blinded randomized design. The exact role of endocannabinoid release as part of the sexual response cycle and the biological significance of the finding should be studied further. Cannabis and other drug use and the attainment of orgasm were self-reported in the present study. Our data indicate that the

  17. Dynamic regulation of the endocannabinoid system: implications for analgesia

    Directory of Open Access Journals (Sweden)

    Wong Amy

    2009-10-01

    Full Text Available Abstract The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics.

  18. Effects of activation of endocannabinoid system on myocardial metabolism

    Directory of Open Access Journals (Sweden)

    Agnieszka Polak

    2016-05-01

    Full Text Available Endocannabinoids exert their effect on the regulation of energy homeostasis via activation of specific receptors. They control food intake, secretion of insulin, lipids and glucose metabolism, lipid storage. Long chain fatty acids are the main myocardial energy substrate. However, the heart exerts enormous metabolic flexibility emphasized by its ability to utilzation not only fatty acids, but also glucose, lactate and ketone bodies. Endocannabinoids can directly act on the cardiomyocytes through the CB1 and CB2 receptors present in cardiomyocytes. It appears that direct activation of CB1 receptors promotes increased lipogenesis, pericardial steatosis and bioelectrical dysfunction of the heart. In contrast, stimulation of CB2 receptors exhibits cardioprotective properties, helping to maintain appropriate amount of ATP in cardiomyocytes. Furthermore, the effects of endocannabinoids at both the central nervous system and peripheral tissues, such as liver, pancreas, or adipose tissue, resulting indirectly in plasma availability of energy substrates and affects myocardial metabolism. To date, there is little evidence that describes effects of activation of the endocannabinoid system in the cardiovascular system under physiological conditions. In the present paper the impact of metabolic diseases, i. e. obesity and diabetes, as well as the cardiovascular diseases - hypertension, myocardial ischemia and myocardial infarction on the deregulation of the endocannabinoid system and its effect on the metabolism are described.

  19. The endocannabinoid system and its relevance for nutrition

    DEFF Research Database (Denmark)

    Maccarrone, Mauro; Gasperi, Valeria; Catani, Maria Valeria

    2010-01-01

    Endocannabinoids bind to cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. The biological actions of these polyunsaturated lipids are controlled by key agents responsible for their synthesis, transport and degradation, which together form an endocannabinoid system (ECS......). In the past few years, evidence has been accumulated for a role of the ECS in regulating food intake and energy balance, both centrally and peripherally. In addition, up-regulation of the ECS in the gastrointestinal tract has a potential impact on inflammatory bowel diseases. In this review, the main features...... of the ECS are summarized in order to put in better focus our current knowledge of the nutritional relevance of endocannabinoid signaling and of its role in obesity, cardiovascular pathologies, and gastrointestinal diseases. The central and peripheral pathways that underlie these effects are discussed...

  20. Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Elphick Maurice R

    2009-07-01

    Full Text Available Abstract Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG, and the related compound N-palmitoylethanolamine (PEA, in neuropathic spinal cord. Selective spinal nerve ligation (SNL in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P P P P P

  1. Neuromodulatory effects of the dorsal hippocampal endocannabinoid system in dextromethorphan/morphine-induced amnesia.

    Science.gov (United States)

    Ghasemzadeh, Zahra; Rezayof, Ameneh

    2017-01-05

    Dextromethorphan which is an active ingredient in many cough medicines has been previously shown to potentiate amnesic effect of morphine in rats. However, the effect of dextromethorphan, that is also a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, in combination with morphine on hippocampus-based long term memory has not been well characterized. The aim of the present study was to assess the possible role of endocannabinoid system of the dorsal hippocampus in dextromethorphan /morphine-induced amnesia. Our results showed that intraperitoneal (i.p.) injection of morphine (5mg/kg) or dextromethorphan (5-15mg/kg) before testing the passive avoidance learning induced amnesia. Combination of ineffective doses of dextromethorphan (7.5mg/kg, i.p.) and morphine (2mg/kg, i.p.) also produced amnesia, suggesting the enhancing effects of the drugs. To assess the effect of the activation or inhibition of the dorsal hippocampal cannabinoid CB 1 receptors on this amnesia, ACPA or AM251 as selective receptor agonists or antagonists were respectively injected into the CA1 regions before systemic injection of dextromethorphan and morphine. Interestingly, intra-CA1 microinjection of ACPA (0.5-1ng/rat) improved the amnesic effect of dextromethorphan /morphine combination. The microinjection of AM251 into the CA1 region enhanced the response of the combination of dextromethorphan /morphine in inducing amnesia. Moreover, Intra-CA1 microinjection of AM251 inhibited the improving effect of ACPA on dextromethorphan /morphine-induced amnesia. It is important to note that intra-CA1 microinjection of the same doses of the agonist or antagonist by itself had no effects on memory formation. Thus, it can be concluded that the dorsal hippocampal endocannabinoid system, via CB 1 receptor-dependent mechanism, may be involved in morphine/dextromethorphan -induced amnesia. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation.

    Science.gov (United States)

    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; Fornari, Raquel V; Roozendaal, Benno

    2015-05-01

    Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory-enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation.

  3. Endocannabinoid release modulates electrical coupling between CCK cells connected via chemical and electrical synapses in CA1

    Directory of Open Access Journals (Sweden)

    Jonathan eIball

    2011-11-01

    Full Text Available Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholesystokinin (CCK interneurons which co-express cannbinoid type-1 (CB1 receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labelling in acute slices of rat hippocampus at P18-20 days. CA1 stratum radiatum CCK Schaffer collateral associated (SCA cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released IPSPs that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5M resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI, maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization.

  4. An endocannabinoid hypothesis of drug reward and drug addiction.

    Science.gov (United States)

    Onaivi, Emmanuel S

    2008-10-01

    Pharmacologic treatment of drug and alcohol dependency has largely been disappointing, and new therapeutic targets and hypotheses are needed. There is accumulating evidence indicating a central role for the previously unknown but ubiquitous endocannabinoid physiological control system (EPCS) in the regulation of the rewarding effects of abused substances. Thus an endocannabinoid hypothesis of drug reward is postulated. Endocannabinoids mediate retrograde signaling in neuronal tissues and are involved in the regulation of synaptic transmission to suppress neurotransmitter release by the presynaptic cannabinoid receptors (CB-Rs). This powerful modulatory action on synaptic transmission has significant functional implications and interactions with the effects of abused substances. Our data, along with those from other investigators, provide strong new evidence for a role for EPCS modulation in the effects of drugs of abuse, and specifically for involvement of cannabinoid receptors in the neural basis of addiction. Cannabinoids and endocannabinoids appear to be involved in adding to the rewarding effects of addictive substances, including, nicotine, opiates, alcohol, cocaine, and BDZs. The results suggest that the EPCS may be an important natural regulatory mechanism for drug reward and a target for the treatment of addictive disorders.

  5. Peripheral Endocannabinoid System Activity in Patients Treated With Sibutramine

    Science.gov (United States)

    Engeli, Stefan; Heusser, Karsten; Janke, Jürgen; Gorzelniak, Kerstin; Bátkai, Sándor; Pacher, Pál; Harvey-White, Judith; Luft, Friedrich C.; Jordan, Jens

    2008-01-01

    Objective The endocannabinoid system (ECS) promotes weight gain and obesity-associated metabolic changes. Weight loss interventions may influence obesity-associated risk indirectly through modulation of the peripheral ECS. We investigated the effect of acute and chronic treatment with sibutramine on components of the peripheral ECS. Methods and Procedures Twenty obese otherwise healthy patients received randomized, double-blind, crossover treatment with placebo and 15 mg/day sibutramine for 5 days each, followed by 12 weeks open-label sibutramine treatment. We determined circulating anandamide and 2-arachidonoylglycerol and expression levels of endocannabinoid genes in subcutaneous abdominal adipose tissue biopsies. Results Body weight was stable during the acute treatment period and decreased by 6.0 ± 0.8 kg in those patients completing 3 months of sibutramine treatment (P sibutramine treatment. Discussion The ECS is activated in obesity. We did not find any influence of 5% body weight loss induced by sibutramine on circulating levels of endocannabinoids and adipose-tissue expression of endocannabinoid genes in obese subjects. These data confirm our previous findings on dietary weight loss and suggest that the dysregulation of the ECS may be a cause rather than a consequence of obesity. PMID:18356837

  6. The cannabinoid transporter inhibitor OMDM-2 reduces social interaction: Further evidence for transporter-mediated endocannabinoid release.

    Science.gov (United States)

    Seillier, Alexandre; Giuffrida, Andrea

    2018-03-01

    Experimental evidence suggests that the transport of endocannabinoids might work bi-directionally. Accordingly, it is possible that pharmacological blockade of the latter affects not only the re-uptake, but also the release of endocannabinoids, thus preventing them from stimulating CB 1 receptors. We used biochemical, pharmacological, and behavioral approaches to investigate the effects of the transporter inhibitor OMDM-2 on social interaction, a behavioral assay that requires activation of CB 1 receptors. The underlying mechanisms of OMDM-2 were compared with those of the Fatty Acid Amide Hydrolase (FAAH) inhibitor URB597. Systemic administration of OMDM-2 reduced social interaction, but in contrast to URB597-induced social deficit, this effect was not reversed by the TRPV1 antagonist capsazepine. The CB 1 antagonist AM251, which did not affect URB597-induced social withdrawal, exacerbated OMDM-2 effect. In addition, the potent CB 1 agonist CP55,940 reversed OMDM-2-, but not URB597-, induced social withdrawal. Blockade of CB 1 receptor by AM251 reduced social interaction and the cholecystokinin CCK2 antagonist LY225910 reversed this effect. Similarly, OMDM-2-induced social withdrawal was reversed by LY225910, whereas URB597 effect was not. Elevation of endocannabinoid levels by URB597 or JZL184, an inhibitor of 2-AG degradation, failed to reverse OMDM-2-induced social withdrawal, and did not show additive effects on cannabinoid measurements when co-administered with OMDM-2. Taken together, these findings indicate that OMDM-2 impaired social interaction in a manner that is consistent with reduced activation of presynaptic CB 1 receptors. As cannabinoid reuptake inhibitors may impair endocannabinoid release, caution should be taken when using these drugs to enhance endocannabinoid tone in vivo. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification

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    Jantana Keereetaweep

    2016-01-01

    Full Text Available The endocannabinoids N-arachidonoylethanolamide (or anandamide, AEA and 2-arachidonoylglycerol (2-AG belong to the larger groups of N-acylethanolamines (NAEs and monoacylglycerol (MAG lipid classes, respectively. They are biologically active lipid molecules that activate G-protein-coupled cannabinoid receptors found in various organisms. After AEA and 2-AG were discovered in the 1990s, they have been extensively documented to have a broad range of physiological functions. Along with AEA, several NAEs, for example, N-palmitoylethanolamine (PEA, N-stearoylethanolamine (SEA, and N-oleoylethanolamine (OEA are also present in tissues, usually at much larger concentrations than AEA. Any perturbation that involves the endocannabinoid pathway may subsequently alter basal level or metabolism of these lipid mediators. Further, the altered levels of these molecules often reflect pathological conditions associated with tissue damage. Robust and sensitive methodologies to analyze these lipid mediators are essential to understanding how they act as endocannabinoids. The recent advances in mass spectrometry allow researchers to develop lipidomics approaches and several methodologies have been proposed to quantify endocannabinoids in various biological systems.

  8. Endocannabinoid Release Modulates Electrical Coupling between CCK Cells Connected via Chemical and Electrical Synapses in CA1

    Science.gov (United States)

    Iball, Jonathan; Ali, Afia B.

    2011-01-01

    Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholecystokinin (CCK) interneurons which co-express cannabinoid type-1 (CB1) receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of rat hippocampus at P18–20 days. CA1 stratum radiatum CCK Schaffer collateral-associated cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released inhibitory postsynaptic potential (IPSPs) that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5 μM) resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI), maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization. PMID

  9. The Role of the Brain's Endocannabinoid System in Pain and Its Modulation by Stress.

    Science.gov (United States)

    Corcoran, Louise; Roche, Michelle; Finn, David P

    2015-01-01

    Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor. The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli. The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein. We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain's endocannabinoid system modulates pain. We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia. Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders. © 2015 Elsevier Inc. All rights reserved.

  10. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

    OpenAIRE

    Campolongo, Patrizia; Roozendaal, Benno; Trezza, Viviana; Hauer, Daniela; Schelling, Gustav; McGaugh, James L.; Cuomo, Vincenzo

    2009-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN5...

  11. ENDOCANNABINOIDS AND EICOSAMOIDS: BIOSYNTHESIS AND INTERACTIONS WITH IMMUNE RESPONSE

    Directory of Open Access Journals (Sweden)

    Yu. K. Karaman

    2013-01-01

    Full Text Available The review is dedicated to modern concepts of arachidonic acid metabolites, i.e., endocannabinoids and eicosanoids, their biosynthetic pathways, cross-talk mechanisms and participation in immune response. New information from literature and own results include data concerning overlapping enzymatic pathways controlling biosynthesis of endocannabinoids and eicosanoids. Impact of synthetic cannabinoid receptor ligands upon production rates of proinflammatory cytokines and eicosanoids is discussed, as like as relationships among immune system reactivity and expression levels of cannabinoid receptors.

  12. Gestation Related Gene Expression of the Endocannabinoid Pathway in Rat Placenta

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    Kanchan Vaswani

    2015-01-01

    Full Text Available Mammalian placentation is a vital facet of the development of a healthy and viable offspring. Throughout gestation the placenta changes to accommodate, provide for, and meet the demands of a growing fetus. Gestational gene expression is a crucial part of placenta development. The endocannabinoid pathway is activated in the placenta and decidual tissues throughout pregnancy and aberrant endocannabinoid signaling during the period of placental development has been associated with pregnancy disorders. In this study, the gene expression of eight endocannabinoid system enzymes was investigated throughout gestation. Rat placentae were obtained at E14.25, E15.25, E17.25, and E20, RNA was extracted, and microarray was performed. Gene expression of enzymes Faah, Mgll, Plcd4, Pld1, Nat1, Daglα, and Ptgs2 was studied (cohort 1, microarray. Biological replication of the results was performed by qPCR (cohort 2. Four genes showed differential expression (Mgll, Plcd4, Ptgs2, and Pld1, from mid to late gestation. Genes positively associated with gestational age were Ptgs2, Mgll, and Pld1, while Plcd4 was downregulated. This is the first comprehensive study that has investigated endocannabinoid pathway gene expression during rat pregnancy. This study provides the framework for future studies that investigate the role of endocannabinoid system during pregnancy.

  13. Endocannabinoids modulate apoptosis in endometriosis and adenomyosis.

    Science.gov (United States)

    Bilgic, Elif; Guzel, Elif; Kose, Sevil; Aydin, Makbule Cisel; Karaismailoglu, Eda; Akar, Irem; Usubutun, Alp; Korkusuz, Petek

    2017-06-01

    Adenomyosis that is a form of endometriosis is the growth of ectopic endometrial tissue within the muscular wall of the uterus (myometrium), which may cause dysmenorrhea and infertility. Endocannabinoid mediated apoptotic mechanisms of endometriosis and adenomyosis are not known. We hypothesized that the down regulation of endocannabinoid receptors and/or alteration in their regulatory enzymes may have a direct role in the pathogenesis of endometriosis and adenomyosis through apoptosis. Endocannabinoid receptors CB1 and CB2, their synthesizing and catabolizing enzymes (FAAH, NAPE-PLD, DAGL, MAGL) and the apoptotic indexes were immunohistochemically assessed in endometriotic and adenomyotic tissues. Findings were compared to normal endometrium and myometrium. Endometrial adenocarcinoma (Ishikawa) and ovarian endometriosis cyst wall stromal (CRL-7566) cell lines were furthermore cultured with or without cannabinoid receptor agonists. The IC50 value for CB1 and CB2 receptor agonists was quantified. Cannabinoid agonists on cell death were investigated by Annexin-V/Propidium iodide labeling with flow cytometry. CB1 and CB2 receptor levels decreased in endometriotic and adenomyotic tissues compared to the control group (p=0,001 and p=0,001). FAAH, NAPE-PLD, MAGL and DAGL enzyme levels decreased in endometriotic and adenomyotic tissues compared to control (p=0,001, p=0,001, p=0,001 and p=0,002 respectively). Apoptotic cell indexes both in endometriotic and adenomyotic tissues also decreased significantly, compared to the control group (p=0,001 and p=0,001). CB1 and CB2 receptor agonist mediated dose dependent fast anti-proliferative and pro-apoptotic effects were detected in Ishikawa and ovarian endometriosis cyst wall stromal cell lines (CRL-7566). Endocannabinoids are suggested to increase apoptosis mechanisms in endometriosis and adenomyosis. CB1 and CB2 antagonists can be considered as potential medical therapeutic agents for endometriosis and adenomyosis. Copyright

  14. The Endocannabinoid System across Postnatal Development in Transmembrane Domain Neuregulin 1 Mutant Mice

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    Rose Chesworth

    2018-02-01

    Full Text Available The use of cannabis is a well-established component risk factor for schizophrenia, particularly in adolescent individuals with genetic predisposition for the disorder. Alterations to the endocannabinoid system have been found in the prefrontal cortex of patients with schizophrenia. Thus, we assessed whether molecular alterations exist in the endocannabinoid signalling pathway during brain development in a mouse model for the schizophrenia risk gene neuregulin 1 (Nrg1. We analysed transcripts encoding key molecules of the endocannabinoid system in heterozygous transmembrane domain Nrg1 mutant mice (Nrg1 TM HET, which is known to have increased sensitivity to cannabis exposure. Tissue from the prelimbic cortex and hippocampus of male and female Nrg1 TM HET mice and wild type-like littermates was collected at postnatal days (PNDs 7, 10, 14, 21, 28, 35, 49, and 161. Quantitative polymerase chain reaction was conducted to assess mRNA levels of cannabinoid receptor 1 (CB1R and enzymes for the synthesis and breakdown of the endocannabinoid 2-arachidonoylglycerol [i.e., diacylglycerol lipase alpha (DAGLα, monoglyceride lipase (MGLL, and α/β-hydrolase domain-containing 6 (ABHD6]. No sex differences were found for any transcripts in either brain region; thus, male and female data were pooled. Hippocampal and cortical mRNA expression of DAGLα, MGLL, and ABHD6 increased until PND 21–35 and then decreased and stabilised for the rest of postnatal development. Hippocampal CB1R mRNA expression increased until PND 21 and decreased after this age. Expression levels of these endocannabinoid markers did not differ in Nrg1 TM HET compared to control mice at any time point. Here, we demonstrate dynamic changes in the developmental trajectory of several key endocannabinoid system transcripts in the mouse brain, which may correspond with periods of endocannabinoid system maturation. Nrg1 TM HET mutation did not alter the developmental trajectory of the

  15. Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol.

    Science.gov (United States)

    Hanlon, Erin C; Tasali, Esra; Leproult, Rachel; Stuhr, Kara L; Doncheck, Elizabeth; de Wit, Harriet; Hillard, Cecilia J; Van Cauter, Eve

    2016-03-01

    Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake. In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions. A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks. Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep. A commentary on this article appears in this issue on page 495. © 2016 Associated Professional Sleep Societies, LLC.

  16. A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

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    Justin R. Piro

    2012-06-01

    Full Text Available Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD. Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid β levels and plaques in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine-lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology and put forth MAGL inhibitors as a potential next-generation strategy for combating AD.

  17. Endocannabinoid system: Role in depression, reward and pain control (Review).

    Science.gov (United States)

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-10-01

    Depression and pain co-exist in almost 80% of patients and are associated with impaired health-related quality of life, often contributing to high mortality. However, the majority of patients who suffer from the comorbid depression and pain are not responsive to pharmacological treatments that address either pain or depression, making this comorbidity disorder a heavy burden on patients and society. In ancient times, this depression-pain comorbidity was treated using extracts of the Cannabis sativa plant, known now as marijuana and the mode of action of Δ9‑tetrahydrocannabinol, the active cannabinoid ingredient of marijuana, has only recently become known, with the identification of cannabinoid receptor type 1 (CB1) and CB2. Subsequent investigations led to the identification of endocannabinoids, anandamide and 2-arachidonoylglycerol, which exert cannabinomimetic effects through the CB1 and CB2 receptors, which are located on presynaptic membranes in the central nervous system and in peripheral tissues, respectively. These endocannabinoids are produced from membrane lipids and are lipohilic molecules that are synthesized on demand and are eliminated rapidly after their usage by hydrolyzing enzymes. Clinical studies revealed altered endocannabinoid signaling in patients with chronic pain. Considerable evidence suggested the involvement of the endocannabinoid system in eliciting potent effects on neurotransmission, neuroendocrine, and inflammatory processes, which are known to be deranged in depression and chronic pain. Several synthetic cannabinomimetic drugs are being developed to treat pain and depression. However, the precise mode of action of endocannabinoids on different targets in the body and whether their effects on pain and depression follow the same or different pathways, remains to be determined.

  18. The Endocannabinoid System in the Postimplantation Period: A Role during Decidualization and Placentation

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    B. M. Fonseca

    2013-01-01

    Full Text Available Although the detrimental effects of cannabis consumption during gestation are known for years, the vast majority of studies established a link between cannabis consumption and foetal development. The complex maternal-foetal interrelationships within the placental bed are essential for normal pregnancy, and decidua definitively contributes to the success of this process. Nevertheless, the molecular signalling network that coordinates strategies for successful decidualization and placentation are not well understood. The discovery of the endocannabinoid system highlighted new signalling mediators in various physiological processes, including reproduction. It is known that endocannabinoids present regulatory functions during blastocyst development, oviductal transport, and implantation. In addition, all the endocannabinoid machinery was found to be expressed in decidual and placental tissues. Additionally, endocannabinoid’s plasmatic levels were found to fluctuate during normal gestation and to induce decidual cell death and disturb normal placental development. Moreover, aberrant endocannabinoid signalling during the period of placental development has been associated with pregnancy disorders. It indicates the existence of a possible regulatory role for these molecules during decidualization and placentation processes, which are known to be particularly vulnerable. In this review, the influence of the endocannabinoid system in these critical processes is explored and discussed.

  19. Comparative effects of parathion and chlorpyrifos on endocannabinoid and endocannabinoid-like lipid metabolites in rat striatum.

    Science.gov (United States)

    Liu, Jing; Parsons, Loren; Pope, Carey

    2015-09-01

    Parathion and chlorpyrifos are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). The endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) are endogenous neuromodulators that regulate presynaptic neurotransmitter release in neurons throughout the central and peripheral nervous systems. While substantial information is known about the eCBs, less is known about a number of endocannabinoid-like metabolites (eCBLs, e.g., N-palmitoylethanolamine, PEA; N-oleoylethanolamine, OEA). We report the comparative effects of parathion and chlorpyrifos on AChE and enzymes responsible for inactivation of the eCBs, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and changes in the eCBs AEA and 2AG and eCBLs PEA and OEA, in rat striatum. Adult, male rats were treated with vehicle (peanut oil, 2 ml/kg, sc), parathion (27 mg/kg) or chlorpyrifos (280 mg/kg) 6-7 days after surgical implantation of microdialysis cannulae into the right striatum, followed by microdialysis two or four days later. Additional rats were similarly treated and sacrificed for evaluation of tissue levels of eCBs and eCBLs. Dialysates and tissue extracts were analyzed by LC-MS/MS. AChE and FAAH were extensively inhibited at both time-points (85-96%), while MAGL activity was significantly but lesser affected (37-62% inhibition) by parathion and chlorpyrifos. Signs of toxicity were noted only in parathion-treated rats. In general, chlorpyrifos increased eCB levels while parathion had no or lesser effects. Early changes in extracellular AEA, 2AG and PEA levels were significantly different between parathion and chlorpyrifos exposures. Differential changes in extracellular and/or tissue levels of eCBs and eCBLs could potentially influence a number of signaling pathways and contribute to selective neurological changes following acute OP intoxications. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Dissociating the role of endocannabinoids in the pleasurable and motivational properties of social play behaviour in rats.

    Science.gov (United States)

    Achterberg, E J Marijke; van Swieten, Maaike M H; Driel, Nina V; Trezza, Viviana; Vanderschuren, Louk J M J

    2016-08-01

    Social play behaviour is a vigorous form of social interaction, abundant during the juvenile and adolescent phases of life in many mammalian species, including humans. Social play is highly rewarding and it is important for social and cognitive development. Being a rewarding activity, social play can be dissociated in its pleasurable and motivational components. We have previously shown that endocannabinoids modulate the expression of social play behaviour in rats. In the present study, we investigated whether endocannabinoids modulate the motivational and pleasurable properties of social play behaviour, using operant and place conditioning paradigms, respectively. Treatment with the anandamide hydrolysis inhibitor URB597 did not affect operant responding or social play-induced conditioned place preference (CPP) when administered at a dose (0.1mg/kg) known to increase the expression of social play behaviour, while it modestly reduced operant responding at a higher dose (0.2mg/kg). The cannabinoid-1 (CB1) receptor antagonist rimonabant reduced operant responding when administered at a dose (1mg/kg) known to decrease the expression of social play behaviour, although this effect may be secondary to concurrent drug-induced stereotypic behaviours (i.e., grooming and scratching). These data demonstrate that enhancing endocannabinoid levels does not differentially affect the motivational and pleasurable aspects of social play behaviour, whereas CB1 receptor blockade reduces the motivational aspects of social play behaviour, possibly due to response competition. Thus, endocannabinoids likely drive the expression of social play behaviour as a whole, without differentially affecting its motivational or pleasurable properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Beyond Cannabis: Plants and the Endocannabinoid System.

    Science.gov (United States)

    Russo, Ethan B

    2016-07-01

    Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies. One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Expression and Function of the Endocannabinoid System in the Retina and the Visual Brain

    Directory of Open Access Journals (Sweden)

    Jean-François Bouchard

    2016-01-01

    Full Text Available Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system. Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoring Gi/o protein. They are known to play an important role in various processes, including metabolic regulation, craving, pain, anxiety, and immune function. In the last decade, there has been a growing interest for endocannabinoids in the retina and their role in visual processing. The purpose of this review is to characterize the expression and physiological functions of the endocannabinoid system in the visual system, from the retina to the primary visual cortex, with a main interest regarding the retina, which is the best-described area in this system so far. It will show that the endocannabinoid system is widely present in the retina, mostly in the through pathway where it can modulate neurotransmitter release and ion channel activity, although some evidence also indicates possible mechanisms via amacrine, horizontal, and Müller cells. The presence of multiple endocannabinoid ligands, synthesizing and catabolizing enzymes, and receptors highlights various pharmacological targets for novel therapeutic application to retinal diseases.

  3. A role for the endocannabinoid 2-arachidonoyl-sn-glycerol for social and high-fat food reward in male mice.

    Science.gov (United States)

    Wei, Don; Lee, DaYeon; Li, Dandan; Daglian, Jennifer; Jung, Kwang-Mook; Piomelli, Daniele

    2016-05-01

    The endocannabinoid system is an important modulator of brain reward signaling. Investigations have focused on cannabinoid (CB1) receptors, because dissection of specific contributions of individual endocannabinoids has been limited by the available toolset. While we recently described an important role for the endocannabinoid anandamide in the regulation of social reward, it remains to be determined whether the other major endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), serves a similar or different function. To study the role of 2-AG in natural reward, we used a transgenic mouse model (MGL-Tg mice) in which forebrain 2-AG levels are selectively reduced. We complemented behavioral analysis with measurements of brain 2-AG levels. We tested male MGL-Tg mice in conditioned place preference (CPP) tasks for high-fat food, social contact, and cocaine. We measured 2-AG content in the brain regions of interest by liquid chromatography/mass spectrometry. Male MGL-Tg mice are impaired in developing CPP for high-fat food and social interaction, but do develop CPP for cocaine. Furthermore, compared to isolated mice, levels of 2-AG in socially stimulated wild-type mice are higher in the nucleus accumbens and ventral hippocampus (183 and 140 % of controls, respectively), but unchanged in the medial prefrontal cortex. The results suggest that reducing 2-AG-mediated endocannabinoid signaling impairs social and high-fat food reward in male mice, and that social stimulation mobilizes 2-AG in key brain regions implicated in the control of motivated behavior. The time course of this response differentiates 2-AG from anandamide, whose role in mediating social reward was previously documented.

  4. Mustard vesicants alter expression of the endocannabinoid system in mouse skin

    International Nuclear Information System (INIS)

    Wohlman, Irene M.; Composto, Gabriella M.; Heck, Diane E.; Heindel, Ned D.; Lacey, C. Jeffrey; Guillon, Christophe D.; Casillas, Robert P.; Croutch, Claire R.; Gerecke, Donald R.; Laskin, Debra L.; Joseph, Laurie B.; Laskin, Jeffrey D.

    2016-01-01

    Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.

  5. Mustard vesicants alter expression of the endocannabinoid system in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Wohlman, Irene M.; Composto, Gabriella M. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Environmental Health Science, New York Medical College, Valhalla, NY (United States); Heindel, Ned D.; Lacey, C. Jeffrey; Guillon, Christophe D. [Department of Chemistry, Lehigh University, Bethlehem, PA (United States); Casillas, Robert P.; Croutch, Claire R. [MRIGlobal, Kansas City, MO (United States); Gerecke, Donald R.; Laskin, Debra L.; Joseph, Laurie B. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, NJ (United States)

    2016-07-15

    Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.

  6. Biomarkers of endocannabinoid system activation in severe obesity.

    Directory of Open Access Journals (Sweden)

    Jack C Sipe

    2010-01-01

    Full Text Available Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs, combined with genotyping for mutations in fatty acid amide hydrolase (FAAH would identify circulating biomarkers of ECS activation in severe obesity.Plasma samples were obtained from 96 severely obese subjects with body mass index (BMI of > or = 40 kg/m(2, and 48 normal weight subjects with BMI of A (P129T mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1+/-1.4 pmol/ml and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3+/-1.0 pmol/ml with wild-type FAAH genotype (p = 0.04, and significance was maintained after controlling for BMI.Significantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.

  7. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System

    Science.gov (United States)

    Gomes, Felipe V.; Silva, Andréia L.; Uliana, Daniela L.; Camargo, Laura H. A.; Guimarães, Francisco S.; Cunha, Fernando Q.; Joca, Sâmia R. L.; Resstel, Leonardo B. M.

    2015-01-01

    Background: Inducible or neuronal nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since nitric oxide and endocannabinoids interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain nitric oxide synthase activity and/or changes in the endocannabinoid system. Thus, we investigated the expression and extinction of contextual fear conditioning of inducible nitric oxide knockout mice and possible involvement of endocannabinoids in these responses. Methods: We evaluated the effects of a preferential neuronal nitric oxide synthase inhibitor, 7-nitroindazol, nitric oxide synthase activity, and mRNA changes of nitrergic and endocannabinoid systems components in the medial prefrontal cortex and hippocampus of wild-type and knockout mice. The effects of URB597, an inhibitor of the fatty acid amide hydrolase enzyme, which metabolizes the endocannabinoid anandamide, WIN55,212-2, a nonselective cannabinoid agonist, and AM281, a selective CB1 antagonist, on contextual fear conditioning were also evaluated. Results: Contextual fear conditioning expression was similar in wild-type and knockout mice, but the latter presented extinction deficits and increased basal nitric oxide synthase activity in the medial prefrontal cortex. 7-Nitroindazol decreased fear expression and facilitated extinction in wild-type and knockout mice. URB597 decreased fear expression in wild-type and facilitated extinction in knockout mice, whereas WIN55,212-2 and AM281 increased it in wild-type mice. Nonconditioned knockout mice showed changes in the mRNA expression of nitrergic and endocannabinoid system components in the medial prefrontal cortex and hippocampus that were modified by fear conditioning. Conclusion: These data reinforce the involvement of the nitric oxide and endocannabinoids (anandamide) in stress-related disorders and point to a deregulation of the endocannabinoid system in

  8. Endocannabinoids and Human Sperm Cells

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    Giovanna Zolese

    2010-10-01

    Full Text Available N-acylethanolamides (NAEs are naturally occurring signaling lipids consisting of amides and esters of long-chain polyunsaturated fatty acids. Usually they are present in a very small amounts in many mammalian tissues and cells, including human reproductive tracts and fluids. Recently, the presence of N-arachidonoylethanolamide (anandamide, AEA, the most characterised member of endocannabinoids, and its congeners palmitoylethanolamide (PEA and oleylethanolamide (OEA in seminal plasma, oviductal fluid, and follicular fluids was demonstrated. AEA has been shown to bind not only type-1 (CB1 and type-2 (CB2 cannabinoid receptors, but also type-1 vanilloid receptor (TRPV1, while PEA and OEA are inactive with respect to classical cannabinoid CB1 and CB2 but activate TRPV1 or peroxisome proliferator activate receptors (PPARs. This review concerns the most recent experimental data on PEA and OEA, endocannabinoid-like molecules which appear to exert their action exclusively on sperm cells with altered features, such as membrane characteristics and kinematic parameters. Their beneficial effects on these cells could suggest a possible pharmacological use of PEA and OEA on patients affected by some forms of idiopathic infertility.

  9. Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

    DEFF Research Database (Denmark)

    Frost, M; Nielsen, T L; Wraae, K

    2010-01-01

    Both animal and human studies have associated the endocannabinoid system with obesity and markers of metabolic dysfunction. Blockade of the cannabinoid receptor 1 (CB1) caused weight loss and reduction in waist size in both obese and type II diabetics. Recent studies on common variants of the CB1...... receptor gene (CNR1) and the link to obesity have been conflicting. The aim of the present study was to evaluate whether selected common variants of the CNR1 are associated with measures of obesity and fat distribution....

  10. Updates in Reproduction Coming from the Endocannabinoid System

    Science.gov (United States)

    Bradshaw, Heather B.

    2014-01-01

    The endocannabinoid system (ECS) is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators—deeply modulated by the activity of biosynthetic and hydrolyzing machineries—regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility. PMID:24550985

  11. Updates in Reproduction Coming from the Endocannabinoid System

    Directory of Open Access Journals (Sweden)

    Rosaria Meccariello

    2014-01-01

    Full Text Available The endocannabinoid system (ECS is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators—deeply modulated by the activity of biosynthetic and hydrolyzing machineries—regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility.

  12. A Preliminary Model for the Protective Role of the Endocannabinoid 2-Arachydonylglycerol in Neuroinflammation

    Science.gov (United States)

    2015-09-30

    Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy . J Pharmacol Exp Ther, 307:129-137. Zhang M, Chen C. 2008. Endocannabinoid 2... Disorders . Brain Res Rev, 52(2):201-43. Pope C, Mechoulam R, Parsons L. 2010. Endocannabinoid Signaling in Neurotoxicity and Neuroprotection

  13. Potential of Endocannabinoids to Control Bladder Pain

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    Dale E. Bjorling

    2018-05-01

    Full Text Available Bladder-related pain is one of the most common forms of visceral pain, and visceral pain is among the most common complaints for which patients seek physician consultation. Despite extensive studies of visceral innervation and treatment of visceral pain, opioids remain a mainstay for management of bladder pain. Side effects associated with opioid therapy can profoundly diminish quality of life, and improved options for treatment of bladder pain remain a high priority. Endocannabinoids, primarily anandamide (AEA and 2-arachidonoylglycerol (2-AG, are endogenously-produced fatty acid ethanolamides with that induce analgesia. Animal experiments have demonstrated that inhibition of enzymes that degrade AEA or 2-AG have the potential to prevent development of visceral and somatic pain. Although experimental results in animal models have been promising, clinical application of this approach has proven difficult. In addition to fatty acid amide hydrolase (FAAH; degrades AEA and monacylglycerol lipase (MAGL; degrades 2-AG, cyclooxygenase (COX acts to metabolize endocannabinoids. Another potential limitation of this strategy is that AEA activates pro-nociceptive transient receptor potential vanilloid 1 (TRPV1 channels. Dual inhibitors of FAAH and TRPV1 or FAAH and COX have been synthesized and are currently undergoing preclinical testing for efficacy in providing analgesia. Local inhibition of FAAH or MAGL within the bladder may be viable options to reduce pain associated with cystitis with fewer systemic side effects, but this has not been explored. Further investigation is required before manipulation of the endocannabinoid system can be proven as an efficacious alternative for management of bladder pain.

  14. Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum.

    Science.gov (United States)

    Oleson, Erik B; Beckert, Michael V; Morra, Joshua T; Lansink, Carien S; Cachope, Roger; Abdullah, Rehab A; Loriaux, Amy L; Schetters, Dustin; Pattij, Tommy; Roitman, Mitchell F; Lichtman, Aron H; Cheer, Joseph F

    2012-01-26

    Transient increases in nucleus accumbens (NAc) dopamine concentration are observed when animals are presented with motivationally salient stimuli and are theorized to energize reward seeking. They arise from high-frequency firing of dopamine neurons in the ventral tegmental area (VTA), which also results in the release of endocannabinoids from dopamine cell bodies. In this context, endocannabinoids are thought to regulate reward seeking by modulating dopamine signaling, although a direct link has never been demonstrated. To test this, we pharmacologically manipulated endocannabinoid neurotransmission in the VTA while measuring transient changes in dopamine concentration in the NAc during reward seeking. Disrupting endocannabinoid signaling dramatically reduced, whereas augmenting levels of the endocannabinoid 2-arachidonoylglycerol (2AG) increased, cue-evoked dopamine concentrations and reward seeking. These data suggest that 2AG in the VTA regulates reward seeking by sculpting ethologically relevant patterns of dopamine release during reward-directed behavior. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Alternative Argets Within the Endocannabinoid System for Future Treatment of Gastrointestinal Diseases

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    Rudolf Schicho

    2011-01-01

    Full Text Available Many beneficial effects of herbal and synthetic cannabinoids on gut motility and inflammation have been demonstrated, suggesting a vast potential for these compounds in the treatment of gastrointestinal disorders. These effects are based on the so-called ‘endocannabinoid system’ (ECS, a cooperating network of molecules that regulate the metabolism of the body’s own and of exogenously administered cannabinoids. The ECS in the gastrointestinal tract quickly responds to homeostatic disturbances by de novo synthesis of its components to maintain homeostasis, thereby offering many potential targets for pharmacological intervention. Of major therapeutic interest are nonpsychoactive cannabinoids or compounds that do not directly target cannabinoid receptors but still possess cannabinoid-like properties. Drugs that inhibit endocannabinoid degradation and raise the level of endocannabinoids are becoming increasingly promising alternative therapeutic tools to manipulate the ECS.

  16. A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena.

    Science.gov (United States)

    Solbrig, Marylou V; Adrian, Russell; Baratta, Janie; Piomelli, Daniele; Giuffrida, Andrea

    2005-08-01

    Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.

  17. Fatty Acid Modulation of the Endocannabinoid System and the Effect on Food Intake and Metabolism

    Directory of Open Access Journals (Sweden)

    Shaan S. Naughton

    2013-01-01

    Full Text Available Endocannabinoids and their G-protein coupled receptors (GPCR are a current research focus in the area of obesity due to the system’s role in food intake and glucose and lipid metabolism. Importantly, overweight and obese individuals often have higher circulating levels of the arachidonic acid-derived endocannabinoids anandamide (AEA and 2-arachidonoyl glycerol (2-AG and an altered pattern of receptor expression. Consequently, this leads to an increase in orexigenic stimuli, changes in fatty acid synthesis, insulin sensitivity, and glucose utilisation, with preferential energy storage in adipose tissue. As endocannabinoids are products of dietary fats, modification of dietary intake may modulate their levels, with eicosapentaenoic and docosahexaenoic acid based endocannabinoids being able to displace arachidonic acid from cell membranes, reducing AEA and 2-AG production. Similarly, oleoyl ethanolamide, a product of oleic acid, induces satiety, decreases circulating fatty acid concentrations, increases the capacity for β-oxidation, and is capable of inhibiting the action of AEA and 2-AG in adipose tissue. Thus, understanding how dietary fats alter endocannabinoid system activity is a pertinent area of research due to public health messages promoting a shift towards plant-derived fats, which are rich sources of AEA and 2-AG precursor fatty acids, possibly encouraging excessive energy intake and weight gain.

  18. Targeting the endocannabinoid system : future therapeutic strategies

    NARCIS (Netherlands)

    Aizpurua-Olaizola, Oier; Elezgarai, Izaskun; Rico-Barrio, Irantzu; Zarandona, Iratxe; Etxebarria, Nestor; Usobiaga, Aresatz

    2017-01-01

    The endocannabinoid system (ECS) is involved in many physiological regulation pathways in the human body, which makes this system the target of many drugs and therapies. In this review, we highlight the latest studies regarding the role of the ECS and the drugs that target it, with a particular

  19. Moderate-vigorous physical activity across body mass index in females: moderating effect of endocannabinoids and temperament.

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    Fernando Fernández-Aranda

    Full Text Available Endocannabinoids and temperament traits have been linked to both physical activity and body mass index (BMI however no study has explored how these factors interact in females. The aims of this cross-sectional study were to 1 examine differences among distinct BMI groups on daytime physical activity and time spent in moderate-vigorous physical activity (MVPA, temperament traits and plasma endocannabinoid concentrations; and 2 explore the association and interaction between MVPA, temperament, endocannabinoids and BMI.Physical activity was measured with the wrist-worn accelerometer Actiwatch AW7, in a sample of 189 female participants (43 morbid obese, 30 obese, and 116 healthy-weight controls. The Temperament and Character Inventory-Revised questionnaire was used to assess personality traits. BMI was calculated by bioelectrical impedance analysis via the TANITA digital scale. Blood analyses were conducted to measure levels of endocannabinoids and endocannabinoid-related compounds. Path-analysis was performed to examine the association between predictive variables and MVPA.Obese groups showed lower MVPA and dysfunctional temperament traits compared to healthy-weight controls. Plasma concentrations of 2-arachidonoylglyceryl (2-AG were greater in obese groups. Path-analysis identified a direct effect between greater MVPA and low BMI (b = -0.13, p = .039 and high MVPA levels were associated with elevated anandamide (AEA levels (b = 0.16, p = .049 and N-oleylethanolamide (OEA levels (b = 0.22, p = .004, as well as high Novelty seeking (b = 0.18, p<.001 and low Harm avoidance (b = -0.16, p<.001.Obese individuals showed a distinct temperament profile and circulating endocannabinoids compared to controls. Temperament and endocannabinoids may act as moderators of the low MVPA in obesity.

  20. Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Palomino, Ana; Pavón, Francisco J; Rivera, Patricia; Serrano, Antonia; Alen, Francisco; Rubio, Leticia; Vargas, Antonio; Castilla-Ortega, Estela; Decara, Juan; Bilbao, Ainhoa; de Fonseca, Fernando Rodríguez; Suárez, Juan

    2016-03-01

    In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could

  1. Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala.

    Science.gov (United States)

    Di, Shi; Itoga, Christy A; Fisher, Marc O; Solomonow, Jonathan; Roltsch, Emily A; Gilpin, Nicholas W; Tasker, Jeffrey G

    2016-08-10

    Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA). Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid-induced endocannabinoid regulation of synaptic inhibition in the rat BLA. Glucocorticoid application to amygdala slices elicited a rapid, nonreversible suppression of spontaneous, but not evoked, GABAergic synaptic currents in BLA principal neurons; the effect was also seen with a membrane-impermeant glucocorticoid, but not with intracellular glucocorticoid application, implicating a membrane-associated glucocorticoid receptor. The glucocorticoid suppression of GABA currents was not blocked by antagonists of nuclear corticosteroid receptors, or by inhibitors of gene transcription or protein synthesis, but was blocked by inhibiting postsynaptic G-protein activity, suggesting a postsynaptic nongenomic steroid signaling mechanism that stimulates the release of a retrograde messenger. The rapid glucocorticoid-induced suppression of inhibition was prevented by blocking CB1 receptors and 2-arachidonoylglycerol (2-AG) synthesis, and it was mimicked and occluded by CB1 receptor agonists, indicating it was mediated by the retrograde release of the endocannabinoid 2-AG. The rapid glucocorticoid effect in BLA neurons in vitro was occluded by prior in vivo acute stress-induced, or prior in vitro glucocorticoid-induced, release of endocannabinoid. Acute stress also caused an increase in anxiety-like behavior that was attenuated by blocking CB1 receptor activation and inhibiting 2-AG synthesis in the BLA. Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis. We provide a cellular mechanism in the basolateral amygdala (BLA) for the rapid stress

  2. Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations

    DEFF Research Database (Denmark)

    Benzinou, Michael; Chèvre, Jean-Claude; Ward, Kirsten J

    2008-01-01

    The therapeutic effects of cannabinoid receptor blockade on obesity-associated phenotypes underline the importance of the endocannabinoid pathway on the energy balance. Using a staged-approach, we examined the contribution of the endocannabinoid receptor 1 gene (CNR1) on obesity and body mass ind...... variations increase the risk for obesity and modulate BMI in our European population. As CB1 is a drug target for obesity, a pharmacogenetic analysis of the endocannabinoid blockade obesity treatment may be of interest to identify best responders....

  3. Fabp1 gene ablation inhibits high-fat diet-induced increase in brain endocannabinoids.

    Science.gov (United States)

    Martin, Gregory G; Landrock, Danilo; Chung, Sarah; Dangott, Lawrence J; Seeger, Drew R; Murphy, Eric J; Golovko, Mikhail Y; Kier, Ann B; Schroeder, Friedhelm

    2017-01-01

    The endocannabinoid system shifts energy balance toward storage and fat accumulation, especially in the context of diet-induced obesity. Relatively little is known about factors outside the central nervous system that may mediate the effect of high-fat diet (HFD) on brain endocannabinoid levels. One candidate is the liver fatty acid binding protein (FABP1), a cytosolic protein highly prevalent in liver, but not detected in brain, which facilitates hepatic clearance of fatty acids. The impact of Fabp1 gene ablation (LKO) on the effect of high-fat diet (HFD) on brain and plasma endocannabinoid levels was examined and data expressed for each parameter as the ratio of high-fat diet/control diet. In male wild-type mice, HFD markedly increased brain N-acylethanolamides, but not 2-monoacylglycerols. LKO blocked these effects of HFD in male mice. In female wild-type mice, HFD slightly decreased or did not alter these endocannabinoids as compared with male wild type. LKO did not block the HFD effects in female mice. The HFD-induced increase in brain arachidonic acid-derived arachidonoylethanolamide in males correlated with increased brain-free and total arachidonic acid. The ability of LKO to block the HFD-induced increase in brain arachidonoylethanolamide correlated with reduced ability of HFD to increase brain-free and total arachidonic acid in males. In females, brain-free and total arachidonic acid levels were much less affected by either HFD or LKO in the context of HFD. These data showed that LKO markedly diminished the impact of HFD on brain endocannabinoid levels, especially in male mice. © 2016 International Society for Neurochemistry.

  4. Endocannabinoid system in cardiovascular disorders - new pharmacotherapeutic opportunities

    Directory of Open Access Journals (Sweden)

    Pedro Cunha

    2011-01-01

    Full Text Available The long history of Cannabis sativa had its development stimulated and oriented for medicine after the discovery and chemical characterization of its main active ingredient, the 9-tetrahydrocannabinol (9-THC. Consequently, a binding site for 9-THC was identified in rat brains and the first cannabinoid receptor (CB1 was cloned, followed by the CB2 and by the discover of two endogenous agonists: anandamide and 2-arachidonoyl glycerol. Cannabinoid receptors, endocannabinoids and the enzymes that catalyze its synthesis and degradation constitute the endocannabinoid system (ECS, which plays an important role in the cardiovascular system. In vivo experiments with rats have demonstrated the action of anandamide and 2-AG on the development of atherosclerotic plaque, as well as an effect on heart rate, blood pressure, vasoactivity and energy metabolism (action in dyslipidemia and obesity. Recent studies with an antagonist of CB1 receptors showed that the modulation of ECS can play an important role in reducing cardiovascular risk in obese and dyslipidemic patients. Similarly, studies in rats have demonstrated the action of CB2 receptors in adhesion, migration, proliferation and function of immune cells involved in the atherosclerotic plaque formation process. The evidence so far gathered shows that the modulation of ECS (as agonism or antagonism of its receptors is an enormous potential field for research and intervention in multiple areas of human pathophysiology. The development of selective drugs for the CB1 and CB2 receptors may open a door to new therapeutic regimens.This review article aims to address the key findings and evidences on the modulation of ECS, in order to prospect future forms of therapeutic intervention at the cardiovascular level. A recent, emerging, controversial and of undoubted scientific interest subject, which states as a potential therapeutic target to reach in the 21 st century.

  5. From Fertilisation to Implantation in Mammalian Pregnancy—Modulation of Early Human Reproduction by the Endocannabinoid System

    Directory of Open Access Journals (Sweden)

    Justin C. Konje

    2010-09-01

    Full Text Available There is an increasing recognition that the endocannabinoid system is the crucial cytokine-hormone system regulating early human pregnancy. The synchronous development of the fertilized embryo and the endometrium to ensure timely implantation has been shown to be one of the pivotal steps to successful implantation. This development is thought to be regulated by a finely balanced relationship between various components of the endocannabinoid system in the endometrium, the embryo and the Fallopian tube. In addition, this system has also been shown to be involved in the regulation of the development and maturation of the gametes prior to fertilization. In this review, we will examine the evidence from animal and human studies to support the role of the endocannabinoid system in gametogenesis, fertilization, implantation, early pregnancy maintenance, and in immunomodulation of pregnancy. We will discuss the role of the cannabinoid receptors and the enzymes involved in the synthesis and degradation of the key endocannabinoid ligands (e.g., anandamide and 2-arachinoylglycerol in early reproduction.

  6. Limited Access to a High Fat Diet Alters Endocannabinoid Tone in Female Rats

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    Valentina Satta

    2018-02-01

    Full Text Available Emerging evidence suggest an impaired endocannabinoid activity in the pathophysiology of binge eating disorder (BED. Herein, we investigated whether endocannabinoid tone could be modified as a consequence of dietary-induced binge eating in female rats. For this purpose, brain levels of the endocannabinoids anandamide (AEA and 2-arachidonoyl glycerol (2-AG, as well as two endocannabinoid-like lipids, oleoylethanolamide (OEA and palmitoylethanolamide (PEA, were assessed in different brain areas involved in the hedonic feeding (i.e., prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and hypothalamus. The brain density of cannabinoid type-1 receptors (CB1 was also evaluated. Furthermore, we determined plasma levels of leptin, ghrelin, and corticosterone hormones, which are well-known to control the levels of endocannabioids and/or CB1 receptors in the brain. To induce binge eating behavior, rats were subject to an intermittent and limited access to a high fat diet (HFD (margarine. Three experimental groups were used, all with ad libitum access to chow: control (CTRL, with no access to margarine; low restriction (LR, with 2 h margarine access 7 days/week; high restriction (HR, with 2 h margarine access 3 days/week. Bingeing was established when margarine intake in the HR group exceeded that of the LR group. Our results show that, compared to CTRL, AEA significantly decreased in the caudate putamen, amygdala, and hippocampus of HR group. In contrast, 2-AG significantly increased in the hippocampus while OEA decreased in the hypothalamus. Similar to the HR group, AEA and OEA decreased respectively in the amygdala and hypothalamus and 2-AG increased in the hippocampus of LR group. Moreover, LR group also had AEA decreased in the prefrontal cortex and increased in the nucleus accumbens. In both groups we found the same reduction of CB1 receptor density in the prefrontal cortex compared to CTRL. Also, LR and HR groups showed alterations in both

  7. The endocannabinoid system within the dorsal lateral geniculate nucleus of the vervet monkey

    DEFF Research Database (Denmark)

    Javadi, P.; Bouskila, J.; Bouchard, J. -F.

    2015-01-01

    The endocannabinoid system mainly consists of cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), their endogenous ligands termed endocannabinoids (eCBs), and the enzymes responsible for the synthesis and degradation of eCBs. These cannabinoid receptors have been well characterized in rodent a...... layers may explain some of the behavioral effects of cannabinoids associated with the integrity of the dorsal visual pathway that plays a role in visual-spatial localization and motion perception....

  8. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility.

    Science.gov (United States)

    du Plessis, Stefan S; Agarwal, Ashok; Syriac, Arun

    2015-11-01

    Marijuana has the highest consumption rate among all of the illicit drugs used in the USA, and its popularity as both a recreational and medicinal drug is increasing especially among men of reproductive age. Male factor infertility is on the increase, and the exposure to the cannabinoid compounds released by marijuana could be a contributing cause. The endocannabinoid system (ECS) is deeply involved in the complex regulation of male reproduction through the endogenous release of endocannabinoids and binding to cannabinoid receptors. Disturbing the delicate balance of the ECS due to marijuana use can negatively impact reproductive potential. Various in vivo and in vitro studies have reported on the empirical role that marijuana plays in disrupting the hypothalamus-pituitary-gonadal axis, spermatogenesis, and sperm function such as motility, capacitation, and the acrosome reaction. In this review, we highlight the latest evidence regarding the effect of marijuana use on male fertility and also provide a detailed insight into the ECS and its significance in the male reproductive system.

  9. Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair.

    Science.gov (United States)

    Dyall, Simon C

    2017-11-01

    The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.

  10. The endocannabinoid system and appetite: relevance for food reward

    NARCIS (Netherlands)

    Jager, G.; Witkamp, R.F.

    2014-01-01

    Mounting evidence substantiates the central role of the endocannabinoid system (ECS) in the modulation of both homeostatic and hedonic elements of appetite and food intake. Conversely, feeding status and dietary patterns directly influence activity of the ECS. Following a general introduction on the

  11. The Endocannabinoid System as Pharmacological Target Derived from Its CNS Role in Energy Homeostasis and Reward. Applications in Eating Disorders and Addiction

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    Francisco-Javier Bermúdez-Silva

    2011-08-01

    Full Text Available The endocannabinoid system (ECS has been implicated in many physiological functions, including the regulation of appetite, food intake and energy balance, a crucial involvement in brain reward systems and a role in psychophysiological homeostasis (anxiety and stress responses. We first introduce this important regulatory system and chronicle what is known concerning the signal transduction pathways activated upon the binding of endogenous cannabinoid ligands to the Gi/0-coupled CB1 cannabinoid receptor, as well as its interactions with other hormones and neuromodulators which can modify endocannabinoid signaling in the brain. Anorexia nervosa (AN and bulimia nervosa (BN are severe and disabling psychiatric disorders, characterized by profound eating and weight alterations and body image disturbances. Since endocannabinoids modulate eating behavior, it is plausible that endocannabinoid genes may contribute to the biological vulnerability to these diseases. We present and discuss data suggesting an impaired endocannabinoid signaling in these eating disorders, including association of endocannabinoid components gene polymorphisms and altered CB1-receptor expression in AN and BN. Then we discuss recent findings that may provide new avenues for the identification of therapeutic strategies based on the endocannabinod system. In relation with its implications as a reward-related system, the endocannabinoid system is not only a target for cannabis but it also shows interactions with other drugs of abuse. On the other hand, there may be also a possibility to point to the ECS as a potential target for treatment of drug-abuse and addiction. Within this framework we will focus on enzymatic machinery involved in endocannabinoid inactivation (notably fatty acid amide hydrolase or FAAH as a particularly interesting potential target. Since a deregulated endocannabinoid system may be also related to depression, anxiety and pain symptomatology accompanying drug

  12. Dynamic changes to the endocannabinoid system in models of chronic pain

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    Rani Sagar, Devi; Burston, James J.; Woodhams, Stephen G.; Chapman, Victoria

    2012-01-01

    The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling. PMID:23108548

  13. Dual-acting compounds targeting endocannabinoid and endovanilloid systems — a novel treatment option for chronic pain management.

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    Natalia Malek

    2016-08-01

    Full Text Available Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time and is often resistant to medical treatment. Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments. The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects. Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target. A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain. Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme. Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins. The plasticity of the endocannabinoid system and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated. Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively. Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.

  14. Repeated homotypic stress elevates 2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at inhibitory synapses in basolateral amygdala.

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    Patel, Sachin; Kingsley, Philip J; Mackie, Ken; Marnett, Lawrence J; Winder, Danny G

    2009-12-01

    Psychosocial stress is a risk factor for development and exacerbation of neuropsychiatric illness. Repeated stress causes biochemical adaptations in endocannabinoid (eCB) signaling that contribute to stress-response habituation, however, the synaptic correlates of these adaptations have not been examined. Here, we show that the synthetic enzyme for the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol (DAG) lipase alpha, is heterogeneously expressed in the amygdala, and that levels of 2-AG and precursor DAGs are increased in the basolateral amygdala (BLA) after 10 days, but not 1 day, of restraint stress. In contrast, arachidonic acid was decreased after both 1 and 10 days of restraint stress. To examine the synaptic correlates of these alterations in 2-AG metabolism, we used whole-cell electrophysiology to determine the effects of restraint stress on depolarization-induced suppression of inhibition (DSI) in the BLA. A single restraint stress exposure did not alter DSI compared with control mice. However, after 10 days of restraint stress, DSI duration, but not magnitude, was significantly prolonged. Inhibition of 2-AG degradation with MAFP also prolonged DSI duration; the effects of repeated restraint stress and MAFP were mutually occlusive. These data indicate that exposure to repeated, but not acute, stress produces neuroadaptations that confer BLA neurons with an enhanced capacity to elevate 2-AG content and engage in 2-AG-mediated short-term retrograde synaptic signaling. We suggest stress-induced enhancement of eCB-mediated suppression of inhibitory transmission in the BLA could contribute to affective dysregulation associated with chronic stress.

  15. Time-Dependent Vascular Effects of Endocannabinoids Mediated by Peroxisome Proliferator-Activated Receptor Gamma (PPAR

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    Saoirse E. O'Sullivan

    2009-01-01

    Full Text Available The aim of the present study was to examine whether endocannabinoids cause PPAR-mediated vascular actions. Functional vascular studies were carried out in rat aortae. Anandamide and N-arachidonoyl-dopamine (NADA, but not palmitoylethanolamide, caused significant vasorelaxation over time (2 hours. Vasorelaxation to NADA, but not anandamide, was inhibited by CB1 receptor antagonism (AM251, 1 M, and vasorelaxation to both anandamide and NADA was inhibited by PPAR antagonism (GW9662, 1 M. Pharmacological inhibition of de novo protein synthesis, nitric oxide synthase, and super oxide dismutase abolished the responses to anandamide and NADA. Removal of the endothelium partly inhibited the vasorelaxant responses to anandamide and NADA. Inhibition of fatty acid amide hydrolase (URB597, 1 M inhibited the vasorelaxant response to NADA, but not anandamide. These data indicate that endocannabinoids cause time-dependent, PPAR-mediated vasorelaxation. Activation of PPAR in the vasculature may represent a novel mechanism by which endocannabinoids are involved in vascular regulation.

  16. Regulation of brain reward by the endocannabinoid system: a critical review of behavioral studies in animals.

    Science.gov (United States)

    Vlachou, S; Panagis, G

    2014-01-01

    The endocannabinoid system has been implicated in the regulation of a variety of physiological processes, including a crucial involvement in brain reward systems and the regulation of motivational processes. Behavioral studies have shown that cannabinoid reward may involve the same brain circuits and similar brain mechanisms with other drugs of abuse, such as nicotine, cocaine, alcohol and heroin, as well as natural rewards, such as food, water and sucrose, although the conditions under which cannabinoids exert their rewarding effects may be more limited. The purpose of the present review is to briefly describe and evaluate the behavioral and pharmacological research concerning the major components of the endocannabinoid system and reward processes. Special emphasis is placed on data received from four procedures used to test the effects of the endocannabinoid system on brain reward in animals; namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure and the drug-discrimination procedure. The effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonists, antagonists and endocannabinoid modulators in these procedures are examined. Further, the involvement of CB1 and CB2 receptors, as well the fatty acid amid hydrolase (FAAH) enzyme in reward processes is investigated through presentation of respective genetic ablation studies in mice. We suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. Further research will provide us with a better understanding of these processes and, thus, could lead to the development of potential therapeutic compounds for the treatment of reward-related disorders.

  17. Deranged endocannabinoid responses to hedonic eating in underweight and recently weight-restored patients with anorexia nervosa.

    Science.gov (United States)

    Monteleone, Alessio Maria; Di Marzo, Vincenzo; Aveta, Teresa; Piscitelli, Fabiana; Dalle Grave, Riccardo; Scognamiglio, Pasquale; El Ghoch, Marwan; Calugi, Simona; Monteleone, Palmiero; Maj, Mario

    2015-02-01

    A dysregulation of reward mechanisms was suggested in the pathophysiology of anorexia nervosa (AN), but the role of the endogenous mediators of reward has been poorly investigated. Endocannabinoids, including anandamide and 2-arachidonoylglycerol, and the endocannabinoid-related compounds oleoylethanolamide and palmitoylethanolamide modulate food-related and unrelated reward. Hedonic eating, which is the consumption of food just for pleasure and not homeostatic need, is a suitable paradigm to explore food-related reward. We investigated responses of endocannabinoids and endocannabinoid-related compounds to hedonic eating in AN. Peripheral concentrations of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, and palmitoylethanolamide were measured in 7 underweight and 7 weight-restored AN patients after eating favorite and nonfavorite foods in the condition of no homeostatic needs, and these measurements were compared with those of previously studied healthy control subjects. 1) In healthy controls, plasma 2-arachidonoylglycerol concentrations decreased after both types of meals but were significantly higher in hedonic eating; in underweight AN patients, 2-arachidonoylglycerol concentrations did not show specific time patterns after eating either favorite or nonfavorite foods, whereas in weight-restored patients, 2-arachidonoylglycerol concentrations showed similar increases with both types of meals. 2) Anandamide plasma concentrations exhibited no differences in their response patterns to hedonic eating in the groups. 3) Compared with 2-arachidonoylglycerol, palmitoylethanolamide concentrations exhibited an opposite response pattern to hedonic eating in healthy controls; this pattern was partially preserved in underweight AN patients but not in weight-restored ones. 4) Like palmitoylethanolamide, oleoylethanolamide plasma concentrations tended to be higher in nonhedonic eating than in hedonic eating in healthy controls; moreover, no difference between healthy

  18. Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

    Science.gov (United States)

    Karlsson, Jessica; Fowler, Christopher J

    2014-01-01

    In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  19. Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

    Directory of Open Access Journals (Sweden)

    Jessica Karlsson

    Full Text Available In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG and anandamide (AEA by cyclooxygenase-2 (COX-2 and fatty acid amide hydrolase (FAAH, respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen.COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1 and arachidonic acid and 2-AG (for COX-2. FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds.It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  20. Antioxidant status and endocannabinoid concentration in postpartum depressive women

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    Mina Ranjbaran

    2015-02-01

    Conclusion: Women’s Job, husband’s job, wanted or unwanted pregnancy from husbands and marital period are associated to postpartum depression. In postpartum depression, TAC, AEA and 2-AG are reduced. So it can be concluded that both antioxidant system and endocannabinoid concentration involved in the development of postpartum depression.

  1. Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.

    Science.gov (United States)

    Micale, Vincenzo; Stepan, Jens; Jurik, Angela; Pamplona, Fabricio A; Marsch, Rudolph; Drago, Filippo; Eder, Matthias; Wotjak, Carsten T

    2017-07-01

    The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans.

    Science.gov (United States)

    Cedernaes, Jonathan; Fanelli, Flaminia; Fazzini, Alessia; Pagotto, Uberto; Broman, Jan-Erik; Vogel, Heike; Dickson, Suzanne L; Schiöth, Helgi B; Benedict, Christian

    2016-12-01

    Following binding to cannabinoid receptors, endocannabinoids regulate a variety of central nervous system processes including appetite and mood. Recent evidence suggests that the systemic release of these lipid metabolites can be altered by acute exercise and that their levels also vary across the 24-h sleep-wake cycle. The present study utilized a within-subject design (involving 16 normal-weight men) to determine whether daytime circulating endocannabinoid concentrations differ following three nights of partial sleep deprivation (4.25-h sleep opportunity, 2:45-7a.m. each night) vs. normal sleep (8.5-h sleep opportunity, 10:30p.m.-7a.m. each night), before and after an acute bout of ergometer cycling in the morning. In addition, subjective hunger and stress were measured. Pre-exercise plasma concentrations of 2-arachidonoylglycerol (2AG) were 80% higher 1.5h after awakening (vs. normal sleep, pexercise (+44%, pexercise-induced rise. Finally, subjective stress was generally lower on the day after three nights of short sleep vs. normal sleep, especially after exercise (pexercise-induced elevations of endocannabinoids appear to be less affected by short sleep duration. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  3. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

    Science.gov (United States)

    Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

    2016-01-01

    Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders. PMID:26514583

  4. Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system

    Science.gov (United States)

    Zamberletti, Erica; Piscitelli, Fabiana; De Castro, Valentina; Murru, Elisabetta; Gabaglio, Marina; Colucci, Paola; Fanali, Chiara; Prini, Pamela; Bisogno, Tiziana; Maccarrone, Mauro; Campolongo, Patrizia; Banni, Sebastiano; Rubino, Tiziana; Parolaro, Daniela

    2017-01-01

    Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition. PMID:27903595

  5. Modulation of the Endocannabinoids N-Arachidonoylethanolamine (AEA and 2-Arachidonoylglycerol (2-AG on Executive Functions in Humans.

    Directory of Open Access Journals (Sweden)

    Ana B Fagundo

    Full Text Available Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA and 2-Arachidonoylglycerol (2-AG and executive functions (decision making, response inhibition and cognitive flexibility in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = -.37; p<.05. A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05 and decision making performance (r = .23; P<.05. There was no significant correlation between either 2-AG (r = -.17 or AEA (r = -.08 concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders. Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches.

  6. The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

    Directory of Open Access Journals (Sweden)

    Thomas Schwitzer

    2016-01-01

    Full Text Available Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.

  7. Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa.

    Science.gov (United States)

    Monteleone, Palmiero; Matias, Isabelle; Martiadis, Vassilis; De Petrocellis, Luciano; Maj, Mario; Di Marzo, Vincenzo

    2005-06-01

    The endocannabinoid system, consisting of two cannabinoid receptors (CB1 and CB2) and the endogenous ligands anandamide (arachidonoylethanolamide (AEA)) and 2-arachidonoylglycerol (2-AG), has been shown to control food intake in both animals and humans, modulating either rewarding or quantitative aspects of the eating behavior. Moreover, hypothalamic endocannabinoids seem to be part of neural circuitry involved in the modulating effects of leptin on energy homeostasis. Therefore, alterations of the endocannabinoid system could be involved in the pathophysiology of eating disorders, where a deranged leptin signalling has been also reported. In order to verify this hypothesis, we measured plasma levels of AEA, 2-AG, and leptin in 15 women with anorexia nervosa (AN), 12 women with bulimia nervosa (BN), 11 women with binge-eating disorder (BED), and 15 healthy women. Plasma levels of AEA resulted significantly enhanced in both anorexic and BED women, but not in bulimic patients. No significant change occurred in the plasma levels of 2-AG in all the patients' groups. Moreover, circulating AEA levels were significantly and inversely correlated with plasma leptin concentrations in both healthy controls and anorexic women. These findings show for the first time a derangement in the production of the endogenous cannabinoid AEA in drug-free symptomatic women with AN or with BED. Although the pathophysiological significance of this alteration awaits further studies to be clarified, it suggests a possible involvement of AEA in the mediation of the rewarding aspects of the aberrant eating behaviors occurring in AN and BED.

  8. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system.

    Science.gov (United States)

    McPartland, John M; Guy, Geoffrey W; Di Marzo, Vincenzo

    2014-01-01

    The "classic" endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the "eCB deficiency syndrome" as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system--ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation. We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances--alcohol, tobacco, coffee, cannabis) also modulate the eCB system. Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

  9. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

    Science.gov (United States)

    2014-01-01

    Background Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. Methods To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. Results GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. Conclusions This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism. PMID:24739187

  10. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages.

    Science.gov (United States)

    Siniscalco, Dario; Bradstreet, James Jeffrey; Cirillo, Alessandra; Antonucci, Nicola

    2014-04-17

    Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.

  11. Processing cardiovascular information in the vlPAG during electroacupuncture in rats: roles of endocannabinoids and GABA

    Science.gov (United States)

    Tjen-A-Looi, Stephanie C.; Li, Peng; Longhurst, John C.

    2009-01-01

    A long-loop pathway, involving the hypothalamic arcuate nucleus (ARC), ventrolateral periaqueductal gray (vlPAG), and the rostral ventrolateral medulla (rVLM), is essential in electroacupuncture (EA) attenuation of sympathoexcitatory cardiovascular reflex responses. The ARC provides excitatory input to the vlPAG, which, in turn, inhibits neuronal activity in the rVLM. Although previous studies have shown that endocannabinoid CB1 receptor activation modulates γ-aminobutyric acid (GABA)-ergic and glutamatergic neurotransmission in the dorsolateral PAG in stress-induced analgesia, an important role for endocannabinoids in the vlPAG has not yet been observed. We recently have shown (Fu LW, Longhurst JC. J Appl Physiol; doi:10.1152/japplphysiol.91648.2008) that EA reduces the local vlPAG concentration of GABA, but not glutamate, as measured with high-performance liquid chromatography from extracellular samples collected by microdialysis. We, therefore, hypothesized that, during EA, endocannabinoids, acting through CB1 receptors, presynaptically inhibit GABA release to disinhibit the vlPAG and ultimately modulate excitatory reflex blood pressure responses. Rats were anesthetized, ventilated, and instrumented to measure heart rate and blood pressure. Gastric distention-induced blood pressure responses of 18 ± 5 mmHg were reduced to 6 ± 1 mmHg by 30 min of low-current, low-frequency EA applied bilaterally at pericardial P 5–6 acupoints overlying the median nerves. Like EA, microinjection of the fatty acid amide hydrolase inhibitor URB597 (0.1 nmol, 50 nl) into the vlPAG to increase endocannabinoids locally reduced the gastric distention cardiovascular reflex response from 21 ± 5 to 3 ± 4 mmHg. This inhibition was reversed by pretreatment with the GABAA antagonist gabazine (27 mM, 50 nl), suggesting that endocannabinoids exert their action through a GABAergic receptor mechanism in the vlPAG. The EA-related inhibition from 18 ± 3 to 8 ± 2 mmHg was reversed to 14

  12. Binge Alcohol Exposure Transiently Changes the Endocannabinoid System: A Potential Target to Prevent Alcohol-Induced Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Daniel J. Liput

    2017-11-01

    Full Text Available Excessive alcohol consumption leads to neurodegeneration, which contributes to cognitive decline that is associated with alcohol use disorders (AUDs. The endocannabinoid system has been implicated in the development of AUDs, but little is known about how the neurotoxic effects of alcohol impact the endocannabinoid system. Therefore, the current study investigated the effects of neurotoxic, binge-like alcohol exposure on components of the endocannabinoid system and related N-acylethanolamines (NAEs, and then evaluated the efficacy of fatty acid amide hydrolase (FAAH inhibition on attenuating alcohol-induced neurodegeneration. Male rats were administered alcohol according to a binge model, which resulted in a transient decrease in [3H]-CP-55,940 binding in the entorhinal cortex and hippocampus following two days, but not four days, of treatment. Furthermore, binge alcohol treatment did not change the tissue content of the three NAEs quantified, including the endocannabinoid and anandamide. In a separate study, the FAAH inhibitor, URB597 was administered to rats during alcohol treatment and neuroprotection was assessed by FluoroJade B (FJB staining. The administration of URB597 during binge treatment did not significantly reduce FJB+ cells in the entorhinal cortex or hippocampus, however, a follow up “target engagement” study found that NAE augmentation by URB597 was impaired in alcohol intoxicated rats. Thus, potential alcohol induced alterations in URB597 pharmacodynamics may have contributed to the lack of neuroprotection by FAAH inhibition.

  13. Plasma endocannabinoid levels in lean, overweight and obese humans: relationships with intestinal permeability markers, inflammation and incretin secretion.

    Science.gov (United States)

    Little, Tanya J; Cvijanovic, Nada; DiPatrizio, Nicholas V; Argueta, Donovan A; Rayner, Christopher K; Feinle-Bisset, Christine; Young, Richard L

    2018-02-13

    Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation, however little is known of these effects in humans. This study aimed to: (i) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl-sn-glycerol (2-AG) and OEA in humans, and (ii) examine relationships with intestinal permeability, inflammation markers and incretin hormone secretion. 20 lean, 18 overweight and 19 obese participants underwent intraduodenal Intralipid® infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumour necrosis factor-α (TNF-α), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and toll-like receptor-4 (TLR4) (RT-PCR), were assessed. Fasting plasma AEA was increased in obese, compared with lean and overweight (Plean (Plean and overweight. The relationships between plasma AEA with duodenal ZO-1 and IAP, and GIP, suggest that altered endocannabinoid signalling may contribute to changes in intestinal permeability, inflammation and incretin release in human obesity.

  14. The endocannabinoid system: a new pharmacological target for obesity treatment?

    Science.gov (United States)

    Hu, Jia; Zhu, Chao; Huang, Mao

    2009-06-01

    Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.

  15. Cannabinoid exposure during zebra finch sensorimotor vocal learning persistently alters expression of endocannabinoid signaling elements and acute agonist responsiveness

    Directory of Open Access Journals (Sweden)

    Lichtman Aron H

    2011-01-01

    Full Text Available Abstract Background Previously we have found that cannabinoid treatment of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. Such persistently altered behavior must be attributable to changes in physiological substrates responsible for song. We are currently working to identify the nature of such physiological changes, and to understand how they contribute to altered vocal learning. One possibility is that developmental agonist exposure results in altered expression of elements of endocannabinoid signaling systems. To test this hypothesis we have studied effects of the potent cannabinoid receptor agonist WIN55212-2 (WIN on endocannabinoid levels and densities of CB1 immunostaining in zebra finch brain. Results We found that late postnatal WIN treatment caused a long-term global disregulation of both levels of the endocannabinoid, 2-arachidonyl glycerol (2-AG and densities of CB1 immunostaining across brain regions, while repeated cannabinoid treatment in adults produced few long-term changes in the endogenous cannabinoid system. Conclusions Our findings indicate that the zebra finch endocannabinoid system is particularly sensitive to exogenous agonist exposure during the critical period of song learning and provide insight into susceptible brain areas.

  16. Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes.

    Science.gov (United States)

    Russo, Ethan B

    2016-01-01

    Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.

  17. The endocannabinoid anandamide inhibits potassium conductance in rat cortical astrocytes

    Czech Academy of Sciences Publication Activity Database

    Vignali, M.; Benfenati, V.; Caprini, M.; Anděrová, Miroslava; Nobile, M.; Ferroni, S.

    2009-01-01

    Roč. 57, č. 7 (2009), s. 791-806 ISSN 0894-1491 R&D Projects: GA ČR GA305/06/1316; GA ČR GA305/06/1464; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50390512 Keywords : cortical astroglia * potassium conductance * endocannabinoids Subject RIV: FH - Neurology Impact factor: 4.932, year: 2009

  18. Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli.

    Science.gov (United States)

    Rea, Kieran; Olango, Weredeselam M; Okine, Bright N; Madasu, Manish K; McGuire, Iseult C; Coyle, Kathleen; Harhen, Brendan; Roche, Michelle; Finn, David P

    2014-01-01

    Pain is both a sensory and an emotional experience, and is subject to modulation by a number of factors including genetic background modulating stress/affect. The Wistar-Kyoto (WKY) rat exhibits a stress-hyper-responsive and depressive-like phenotype and increased sensitivity to noxious stimuli, compared with other rat strains. Here, we show that this genotype-dependent hyperalgesia is associated with impaired pain-related mobilisation of endocannabinoids and transcription of their synthesising enzymes in the rostral ventromedial medulla (RVM). Pharmacological blockade of the Cannabinoid1 (CB1) receptor potentiates the hyperalgesia in WKY rats, whereas inhibition of the endocannabinoid catabolising enzyme, fatty acid amide hydrolase, attenuates the hyperalgesia. The latter effect is mediated by CB1 receptors in the RVM. Together, these behavioural, neurochemical, and molecular data indicate that impaired endocannabinoid signalling in the RVM underpins hyper-responsivity to noxious stimuli in a genetic background prone to heightened stress/affect. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  19. Translational Evidence for a Role of Endocannabinoids in the Etiology and Treatment of Posttraumatic Stress Disorder

    Science.gov (United States)

    Neumeister, Alexander; Seidel, Jordan; Ragen, Benjamin J.; Pietrzak, Robert H.

    2014-01-01

    Introduction Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. Recently, an accumulating body of evidence has implicated the endocannabinoid system in the etiology of PTSD, and targets within this system are believed to be suitable for treatment development. Methods Herein, we describe evidence from translational studies arguing for the relevance of the endocannabinoid system in the etiology of PTSD. We also show mechanisms relevant for treatment development. Results There is convincing evidence from multiple studies for reduced endocannabinoid availability in PTSD. Brain imaging studies show molecular adaptations with elevated cannabinoid type 1 (CB1) receptor availability in PTSD which is linked to abnormal threat processing and anxious arousal symptoms. Conclusion Of particular relevance is evidence showing reduced levels of the endocannabinoid anandamide and compensatory increase of CB1 receptor availability in PTSD, and an association between increased CB1 receptor availability in the amygdala and abnormal threat processing, as well as increased severity of hyperarousal, but not dysphoric symptomatology, in trauma survivors. Given that hyperarousal symptoms are the key drivers of more disabling aspects of PTSD such as emotional numbing or suicidality, novel, mechanism-based pharmacotherapies that target this particular symptom cluster in patients with PTSD may have utility in mitigating the chronicity and morbidity of the disorder. PMID:25456347

  20. Profiling the Oxylipin and Endocannabinoid Metabolome by UPLC-ESI-MS/MS in Human Plasma to Monitor Postprandial Inflammation.

    Science.gov (United States)

    Gouveia-Figueira, Sandra; Späth, Jana; Zivkovic, Angela M; Nording, Malin L

    2015-01-01

    Bioactive lipids, including oxylipins, endocannabinoids, and related compounds may function as specific biochemical markers of certain aspects of inflammation. However, the postprandial responsiveness of these compounds is largely unknown; therefore, changes in the circulating oxylipin and endocannabinoid metabolome in response to a challenge meal were investigated at six occasions in a subject who freely modified her usual diet. The dietary change, and especially the challenge meal itself, represented a modification of precursor fatty acid status, with expectedly subtle effects on bioactive lipid levels. To detect even the slightest alteration, highly sensitive ultra-performance liquid chromatography (UPLC) coupled to electrospray ionization (ESI) tandem mass spectrometry (MS/MS) methods for bioactive lipid profiling was employed. A previously validated UPLC-ESI-MS/MS method for profiling the endocannabinoid metabolome was used, while validation of an UPLC-ESI-MS/MS method for oxylipin analysis was performed with acceptable outcomes for a majority of the parameters according to the US Food and Drug Administration guidelines for linearity (0.9938 metabolome, caused by changes in diet and ii) responsiveness to a challenge meal for a subset of the oxylipin and endocannabinoid metabolome. To summarize, we have shown proof-of-concept of our UPLC-ESI-MS/MS bioactive lipid protocols for the purpose of monitoring subtle shifts, and thereby useful to address lipid-mediated postprandial inflammation.

  1. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system.

    Directory of Open Access Journals (Sweden)

    John M McPartland

    Full Text Available The "classic" endocannabinoid (eCB system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA and 2-arachidonoylglycerol (2-AG, and their metabolic enzymes. An emerging literature documents the "eCB deficiency syndrome" as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system--ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances--alcohol, tobacco, coffee, cannabis also modulate the eCB system.Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

  2. Western Blotting of the Endocannabinoid System.

    Science.gov (United States)

    Wager-Miller, Jim; Mackie, Ken

    2016-01-01

    Measuring expression levels of G protein-coupled receptors (GPCRs) is an important step for understanding the distribution, function, and regulation of these receptors. A common approach for detecting proteins from complex biological systems is Western blotting. In this chapter, we describe a general approach to Western blotting protein components of the endocannabinoid system using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and nitrocellulose membranes, with a focus on detecting type 1 cannabinoid (CB1) receptors. When this technique is carefully used, specifically with validation of the primary antibodies, it can provide quantitative information on protein expression levels. Additional information can also be inferred from Western blotting such as potential posttranslational modifications that can be further evaluated by specific analytical techniques.

  3. Role of the endocannabinoid system in human brain functions relevant for psychiatric disorders

    NARCIS (Netherlands)

    Bossong, M.G.

    2012-01-01

    Impaired cognitive function is a fundamental characteristic of many psychiatric and neurological disorders such as schizophrenia or Alzheimer’s disease. The endocannabinoid (eCB) system, consisting of cannabinoid receptors and accompanying ligands, has been implicated in these disorders. In

  4. Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

    Science.gov (United States)

    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; McGaugh, James L.; Roozendaal, Benno

    2012-01-01

    There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3–3 mg/kg) to male Sprague–Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal β-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212–2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences. PMID:22331883

  5. Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge.

    Science.gov (United States)

    Nass, Sara R; Long, Jonathan Z; Schlosburg, Joel E; Cravatt, Benjamin F; Lichtman, Aron H; Kinsey, Steven G

    2015-06-01

    Cannabinoid receptor agonists, such as Δ(9)-THC, the primary active constituent of Cannabis sativa, have anti-pyrogenic effects in a variety of assays. Recently, attention has turned to the endogenous cannabinoid system and how endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide, regulate multiple homeostatic processes, including thermoregulation. Inhibiting endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH), elevates levels of 2-AG or anandamide in vivo, respectively. The purpose of this experiment was to test the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. In separate experiments, male C57BL/6J mice were administered a MAGL or FAAH inhibitor, and then challenged with the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/kg ip) or a cold (4 °C) ambient environment. Systemic LPS administration caused a significant decrease in core body temperature after 6 h, and this hypothermia persisted for at least 12 h. Similarly, cold environment induced mild hypothermia that resolved within 30 min. JZL184 exacerbated hypothermia induced by either LPS or cold challenge, both of which effects were blocked by rimonabant, but not SR144528, indicating a CB1 cannabinoid receptor mechanism of action. In contrast, the FAAH inhibitor, PF-3845, had no effect on either LPS-induced or cold-induced hypothermia. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit profound hypothermic responses on their own, neither MAGL nor FAAH inhibitors affect normal body temperature. However, these endocannabinoid catabolic enzymes play distinct roles in thermoregulation following hypothermic challenges.

  6. Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

    DEFF Research Database (Denmark)

    Nielsen, Morten Frost; Nielsen, T L; Wraae, K

    2010-01-01

    OBJECTIVE: Both animal and human studies have associated the endocannabinoid system with obesity and markers of metabolic dysfunction. Blockade of the cannabinoid receptor 1 (CB1) caused weight loss and reduction in waist size in both obese and type II diabetics. Recent studies on common variants...... of the CB1 receptor gene (CNR1) and the link to obesity have been conflicting. The aim of the present study was to evaluate whether selected common variants of the CNR1 are associated with measures of obesity and fat distribution. DESIGN AND METHODS: The single nucleotide polymorphisms (SNPs) rs806381, rs......10485179 and rs1049353 were genotyped, and body fat and fat distribution were assessed by the use of dual-energy X-ray absorptiometry and magnetic resonance imaging in a population-based study comprising of 783 Danish men, aged 20-29 years. RESULTS: The rs806381 polymorphism was significantly associated...

  7. Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

    Science.gov (United States)

    Acharya, Nandini; Penukonda, Sasi; Shcheglova, Tatiana; Hagymasi, Adam T; Basu, Sreyashi; Srivastava, Pramod K

    2017-05-09

    Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1 hi macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1 -/- or CB2 -/- mice have fewer CX3CR1 hi Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4 + cells, the Tr1 cells, in an IL-27-dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4 + T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.

  8. Astrocytes in endocannabinoid signalling.

    Science.gov (United States)

    Navarrete, Marta; Díez, Adolfo; Araque, Alfonso

    2014-10-19

    Astrocytes are emerging as integral functional components of synapses, responding to synaptically released neurotransmitters and regulating synaptic transmission and plasticity. Thus, they functionally interact with neurons establishing tripartite synapses: a functional concept that refers to the existence of communication between astrocytes and neurons and its crucial role in synaptic function. Here, we discuss recent evidence showing that astrocytes are involved in the endocannabinoid (ECB) system, responding to exogenous cannabinoids as well as ECBs through activation of type 1 cannabinoid receptors, which increase intracellular calcium and stimulate the release of glutamate that modulates synaptic transmission and plasticity. We also discuss the consequences of ECB signalling in tripartite synapses on the astrocyte-mediated regulation of synaptic function, which reveal novel properties of synaptic regulation by ECBs, such as the spatially controlled dual effect on synaptic strength and the lateral potentiation of synaptic efficacy. Finally, we discuss the potential implications of ECB signalling for astrocytes in brain pathology and animal behaviour. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  9. Adipose tissue endocannabinoid system gene expression: depot differences and effects of diet and exercise

    Directory of Open Access Journals (Sweden)

    Yang Rongze

    2011-10-01

    Full Text Available Abstract Background Alterations of endocannabinoid system in adipose tissue play an important role in lipid regulation and metabolic dysfunction associated with obesity. The purpose of this study was to determine whether gene expression levels of cannabinoid type 1 receptor (CB1 and fatty acid amide hydrolase (FAAH are different in subcutaneous abdominal and gluteal adipose tissue, and whether hypocaloric diet and aerobic exercise influence subcutaneous adipose tissue CB1 and FAAH gene expression in obese women. Methods Thirty overweight or obese, middle-aged women (BMI = 34.3 ± 0.8 kg/m2, age = 59 ± 1 years underwent one of three 20-week weight loss interventions: caloric restriction only (CR, N = 9, caloric restriction plus moderate-intensity aerobic exercise (CRM, 45-50% HRR, N = 13, or caloric restriction plus vigorous-intensity aerobic exercise (CRV, 70-75% HRR, N = 8. Subcutaneous abdominal and gluteal adipose tissue samples were collected before and after the interventions to measure CB1 and FAAH gene expression. Results At baseline, FAAH gene expression was higher in abdominal, compared to gluteal adipose tissue (2.08 ± 0.11 vs. 1.78 ± 0.10, expressed as target gene/β-actin mRNA ratio × 10-3, P Conclusions There are depot differences in subcutaneous adipose tissue endocannabinoid system gene expression in obese individuals. Aerobic exercise training may preferentially modulate abdominal adipose tissue endocannabinoid-related gene expression during dietary weight loss. Trial Registration ClinicalTrials.gov: NCT00664729.

  10. Peripheral Endocannabinoid Responses to Hedonic Eating in Binge-Eating Disorder

    Directory of Open Access Journals (Sweden)

    Alessio Maria Monteleone

    2017-12-01

    Full Text Available Reward mechanisms are likely implicated in the pathophysiology of binge-eating behaviour, which is a key symptom of binge-eating disorder (BED. Since endocannabinoids modulate food-related reward, we aimed to investigate the responses of anandamide (AEA and 2-arachidonoylglycerol (2-AG to hedonic eating in patients with BED. Peripheral levels of AEA and 2-AG were measured in 7 obese BED patients before and after eating favorite (hedonic eating and non-favorite (non-hedonic eating foods. We found that plasma levels of AEA progressively decreased after eating the non-favorite food and significantly increased after eating the favorite food, whereas plasma levels of 2-AG did not differ significantly between the two test conditions, although they showed a trend toward significantly different time patterns. The changes in peripheral AEA levels were positively correlated to the subjects’ sensations of the urge to eat and the pleasantness while eating the presented food, while changes in peripheral 2-AG levels were positively correlated to the subjects’ sensation of the pleasantness while eating the presented food and to the amount of food they would eat. These results suggest the occurrence of distinctive responses of endocannabinoids to food-related reward in BED. The relevance of such findings to the pathophysiology of BED remains to be elucidated.

  11. Distinct neuronal activation patterns are associated with PCP-induced social withdrawal and its reversal by the endocannabinoid-enhancing drug URB597.

    Science.gov (United States)

    Matricon, Julien; Seillier, Alexandre; Giuffrida, Andrea

    2016-09-01

    The fatty acid amide hydrolase inhibitor, URB597, an endocannabinoid enhancing drug, reverses social withdrawal in the sub-chronic PCP rat model of schizophrenia, but reduces social interaction (SI) in controls. To identify the anatomical substrates associated with PCP-induced social withdrawal and the contrasting effects of URB597 on SI in PCP- versus saline-treated rats, we analyzed SI-induced c-Fos expression in 28 brain areas relevant to schizophrenia and/or social behavior following vehicle or URB597 administration. In saline-treated rats, SI was accompanied by changes in c-Fos expression in the infralimbic and orbitofrontal cortices, dorsomedial caudate putamen, ventrolateral nucleus of the septum, dorsolateral periaqueductal gray (dlPAG) and central amygdala. Except for the dlPAG, these changes were not observed in PCP-treated rats or in saline-treated rats receiving URB597. In the dorsomedial part of the bed nucleus of the stria terminalis (dmBNST), SI-induced c-Fos expression was observed only in PCP-treated rats. Interestingly, URB597 in PCP-treated rats restored a similar c-Fos expression pattern as observed in saline-treated rats: activation of the orbitofrontal cortex, inhibition of the central amygdala and suppression of activation of the dmBNST. These data suggest that orbitofrontal cortex, central amygdala and dmBNST play a critical role in the reversal of PCP-induced social withdrawal by URB597. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  12. Impaired fear memory specificity associated with deficient endocannabinoid-dependent long-term plasticity.

    Science.gov (United States)

    Lovelace, Jonathan W; Vieira, Philip A; Corches, Alex; Mackie, Ken; Korzus, Edward

    2014-06-01

    In addition to its central role in learning and memory, N-methyl D-aspartate receptor (NMDAR)-dependent signaling regulates central glutamatergic synapse maturation and has been implicated in schizophrenia. We have transiently induced NMDAR hypofunction in infant mice during postnatal days 7-11, followed by testing fear memory specificity and presynaptic plasticity in the prefrontal cortex (PFC) in adult mice. We show that transient NMDAR hypofunction during early brain development, coinciding with the maturation of cortical plasticity results in a loss of an endocannabinoid (eCB)-mediated form of long-term depression (eCB-LTD) at adult central glutamatergic synapses, while another form of presynaptic long-term depression mediated by the metabotropic glutamate receptor 2/3 (mGluR2/3-LTD) remains intact. Mice with this selective impairment of presynaptic plasticity also showed deficits in fear memory specificity. The observed deficit in cortical presynaptic plasticity may represent a neural maladaptation contributing to network instability and abnormal cognitive functioning.

  13. Genetic Disruption of 2-Arachidonoylglycerol Synthesis Reveals a Key Role for Endocannabinoid Signaling in Anxiety Modulation

    Directory of Open Access Journals (Sweden)

    Brian C. Shonesy

    2014-12-01

    Full Text Available Summary: Endocannabinoid (eCB signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG in the physiological regulation of affective behaviors is not well understood. Here, we show that genetic deletion of the 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα in mice reduces brain, but not circulating, 2-AG levels. DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated with impaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders. : The role of the primary endogenous cannabinoid 2-AG in mood and anxiety regulation is not well understood. Shonesy et al. show that deletion of a primary 2-AG synthetic enzyme, DAGLα, results in anxiety and sex-specific depressive phenotypes, which can be rapidly reversed by pharmacological normalization of endocannabinoid levels.

  14. Caloric restriction lowers endocannabinoid tonus and improves cardiac function in type 2 diabetes

    NARCIS (Netherlands)

    Eyk, van H.J.; Schinkel, van L.D.; Kantae, V.; Dronkers, C.E.A.; Westenberg, J.J.M.; Roos, de A.; Lamb, H.J.; Jukema, J.W.; Harms, A.C.; Hankemeier, T.; Stelt, van der M.; Jazet, I.M.; Rensen, P.C.N.; Smit, J.W.A.

    2018-01-01

    Background/ObjectivesEndocannabinoids (ECs) are associated with obesity and ectopic fat accumulation, both of which play a role in the development of cardiovascular disease (CVD) in type 2 diabetes (T2D). The effect of prolonged caloric restriction on ECs in relation to fat distribution and cardiac

  15. A biophysical model of endocannabinoid-mediated short term depression in hippocampal inhibition.

    Directory of Open Access Journals (Sweden)

    Margarita Zachariou

    Full Text Available Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. The plasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basis of learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespread action on brain function through modulation of synaptic transmission and plasticity. Recent experimental studies have characterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brain regions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning and memory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level and investigate how this signalling mediates depolarisation induced suppression of inhibition (DSI, a prominent form of short-term synaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the key characteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematical description of the major signalling molecules and cascades involved. More specifically, this model serves as a framework to test hypotheses on the factors determining the variability of DSI and investigate under which conditions it can be evoked. The model reveals the frequency and duration bands in which the post-synaptic cell can be sufficiently stimulated to elicit DSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firing rate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigate experimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as a stepping stone for future deciphering of the role of

  16. The Endocannabinoid System: A Dynamic Signalling System at the Crossroads Between Metabolism and Disease

    NARCIS (Netherlands)

    Witkamp, R.F.

    2014-01-01

    The discovery of the endocannabinoid system (ECS) in the early 1990s of last century generated high expectations of new therapeutic opportunities. Its central role and pleiotropic character seemed to offer promising indications in the fields of pain, inflammation, CNS disorders, weight management

  17. The endocannabinoid system and appetite: relevance for food reward.

    Science.gov (United States)

    Jager, Gerry; Witkamp, Renger F

    2014-06-01

    Mounting evidence substantiates the central role of the endocannabinoid system (ECS) in the modulation of both homeostatic and hedonic elements of appetite and food intake. Conversely, feeding status and dietary patterns directly influence activity of the ECS. Following a general introduction on the functioning of the ECS, the present review specifically addresses its role in the modulation of hedonic eating. Humans possess strong motivational systems triggered by rewarding aspects of food. Food reward is comprised of two components: one appetitive (orienting towards food); the other consummatory (hedonic evaluation), also referred to as 'wanting' and 'liking', respectively. Endocannabinoid tone seems to influence both the motivation to feed and the hedonic value of foods, probably by modifying palatability. Human physiology underlying hedonic eating is still not fully understood. A better understanding of the role of the ECS in the rewarding value of specific foods or diets could offer new possibilities to optimise the balance between energy and nutrient intake for different target groups. These groups include the obese and overweight, and potentially individuals suffering from malnutrition. Examples for the latter group are patients with disease-related anorexia, as well as the growing population of frail elderly suffering from persistent loss of food enjoyment and appetite resulting in malnutrition and involuntary weight loss. It has become clear that the psychobiology of food hedonics is extremely complex and the clinical failure of CB1 inverse agonists including rimonabant (Accomplia®) has shown that 'quick wins' in this field are unlikely.

  18. A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena

    OpenAIRE

    Solbrig, MV; Adrian, R; Baratta, J; Piomelli, D; Giuffrida, A

    2005-01-01

    Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endoca...

  19. Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

    Directory of Open Access Journals (Sweden)

    Douglas R Smith

    Full Text Available Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1, were found to be significantly associated with pain sensitivity (especially migraine, sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

  20. Stress Response Recruits the Hippocampal Endocannabinoid System for the Modulation of Fear Memory

    Science.gov (United States)

    Alvares, Lucas de Oliveira; Engelke, Douglas Senna; Diehl, Felipe; Scheffer-Teixeira, Robson; Haubrich, Josue; Cassini, Lindsey de Freitas; Molina, Victor Alejandro; Quillfeldt, Jorge Alberto

    2010-01-01

    The modulation of memory processes is one of the several functions of the endocannabinoid system (ECS) in the brain, with CB1 receptors highly expressed in areas such as the dorsal hippocampus. Experimental evidence suggested an important role of the ECS in aversively motivated memories. Similarly, glucocorticoids released in response to stress…

  1. Role of the endocannabinoid system in food intake, energy homeostasis and regulation of the endocrine pancreas.

    Science.gov (United States)

    Li, Chen; Jones, Peter M; Persaud, Shanta J

    2011-03-01

    The endocannabinoid system (ECS) is a signalling cascade consisting of CB1 and CB2 receptors, and enzymes for the synthesis and degradation of endogenous ligands for these receptors. Central CB1 receptors have been most widely studied since they play key roles in energy homeostasis and rimonabant, a CB1 receptor antagonist, was used clinically to treat obesity. Less is known about CB2 receptors, but their abundant expression by lymphocytes and macrophages has led to suggestions of their importance in immune and inflammatory reactions. More recently, it has become apparent that both CB1 and CB2 receptors are more widely expressed than originally thought, and the capacity of endocannabinoids to regulate energy balance also occurs through their interactions with cannabinoid receptors on a variety of peripheral tissues. In general, pathological overactivation of the ECS contributes to weight gain, reduced sensitivity to insulin and glucose intolerance, and blockade of CB1 receptors reduces body weight through increased secretion of anorectic signals and improved insulin sensitivity. However, the notion that the ECS per se is detrimental to energy homeostasis is an oversimplification, since activation of cannabinoid receptors expressed by islet cells can stimulate insulin secretion, which is obviously beneficial under conditions of impaired glucose tolerance or type 2 diabetes. We propose that under normal physiological conditions cannabinoid signalling in the endocrine pancreas is a bona fide mechanism of regulating insulin secretion to maintain blood glucose levels, but that energy balance becomes dysregulated with excessive food intake, leading to adipogenesis and fat accumulation through enhanced cannabinoid synthesis. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

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    Patrizia eCampolongo

    2012-03-01

    Full Text Available Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p. on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimental settings, named High Arousal and Low Arousal conditions. The two different experimental conditions influenced emotional reactivity independently of drug administration. Indeed, vehicle-treated rats exposed to the Low Arousal condition spent more time in the centre of the arena than vehicle-treated rats exposed to the High Arousal context. Conversely, the different arousal conditions did not affect the cognitive performances of vehicle-treated animals such as the capability to discriminate a spatial displacement of the objects or an object substitution.AM404 administration did not alter the locomotor activity of the animals exposed to both environmental conditions. Interestingly, AM404 administration increased the emotional reactivity of rats exposed to the High Arousal condition but did not influence emotionality of rats exposed to the Low Arousal condition. Moreover, AM404 administration influenced the cognitive parameters depending on the level of emotional arousal: it impaired the capability of rats exposed to the High Arousal condition to recognize a novel object while it did not induce any impairing effect in rats exposed to the Low Arousal condition.These findings suggest that drugs which enhance the endocannabinoid signalling induce different effects on recognition memory performance depending on the level of emotional arousal induced by the environmental conditions.

  3. The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings.

    Science.gov (United States)

    Berardi, Andrea; Schelling, Gustav; Campolongo, Patrizia

    2016-09-01

    Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal. There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the "so-called" cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients' prognosis. In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other. The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes. First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed. In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss.

    Science.gov (United States)

    Dawson, Alison J; Kilpatrick, Eric S; Coady, Anne-Marie; Elshewehy, Abeer M M; Dakroury, Youssra; Ahmed, Lina; Atkin, Stephen L; Sathyapalan, Thozhukat

    2017-07-14

    Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD). Treatment with rimonabant for 12 weeks reduced both ALT and weight (p weight. There was a significant reduction of weight with orlistat (p weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD. ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

  5. Altering endocannabinoid neurotransmission at critical developmental ages: impact on rodent emotionality and cognitive performance

    Directory of Open Access Journals (Sweden)

    Viviana eTrezza

    2012-01-01

    Full Text Available The endocannabinoid system shows functional activity from early stages of brain development: it plays an important role in fundamental developmental processes such as cell proliferation, migration and differentiation, thus shaping brain organization during pre- and postnatal life. Cannabis sativa preparations are among the illicit drugs most commonly used by young people, including pregnant women. The developing brain can be therefore exposed to cannabis preparations during two critical periods: first, in offspring of cannabis-using mothers through perinatal and/or prenatal exposure; second, in adolescent cannabis users during neural maturation. In the last decade, it has become clear that the endocannabinoid system critically modulates memory processing and emotional responses. Therefore, it is well possible that developmental exposure to cannabinoid compounds induces enduring changes in behaviors and neural processes belonging to the cognitive and emotional domains. We address this issue by focusing on rodent studies, in order to provide a framework for understanding the impact of cannabinoid exposure on the developing brain.

  6. Immune system modulation in the central nervous system: A possible role for endocannabinoids

    International Nuclear Information System (INIS)

    Abd-Allah, Adel R.A.

    2007-01-01

    The immune system is designed to protect the body from infection and tumor formation. To perform this function, cells of the immune system can be dangerous for the survival and function of the neuronal network in the brain under the influence of infection or immune imbalance. An attack of immune cells inside the brain includes the potential for severe neuronal damage or cell death and therefore impairment of the CNS function. To avoid such undesirable action of the immune system, the CNS performs a cascade of cellular and molecular mechanisms enabling strict control of immune reactions i mmune privilege . Under inflammatory and patholological conditions, uncontrolled immune system results in the activation of neuronal damage that is frequently associated with neurological diseases. On the other hand, processes of neuroprotection and neurorepair after neuronal damage depend on a steady and tightly controlled immunesurvelliance. Many immunoprotectants play a role to imbalance the immune reactions in the CNS and other organs which presents an important therapeutic target. It has been reported recently that endocannabinoids are secreted in abundance in the CNS following neuronal insult, probably for its protection. There are at least two types of cannabinoid receptors, CB1 and CB2. Both are coupled to G proteins. CB1 receptors exist primarily on central and peripheral neurons. CB2 receptors are present mainly on immune cells. Endogenous agonists for cannabinoid receptors (endocannabinoids), have been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol (2AG), and 2-archidonyl glyceryl ether. Following their release, endocannabinoids are removed from the extracellular space and then degraded by intracellular enzymic hydrolysis. Therapeutic uses of cannabinoid receptor agonists/antagonists include the management of many disease conditions. They are also involved in immune system suppression and in cell to cell communication

  7. Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects.

    Science.gov (United States)

    Monteleone, P; Bifulco, M; Di Filippo, C; Gazzerro, P; Canestrelli, B; Monteleone, F; Proto, M C; Di Genio, M; Grimaldi, C; Maj, M

    2009-10-01

    Endocannabinoids modulate eating behavior; hence, endocannabinoid genes may contribute to the biological vulnerability to eating disorders. The rs1049353 (1359 G/A) single nucleotide polymorphism (SNP) of the gene coding the endocannabinoid CB1 receptor (CNR1) and the rs324420 (cDNA 385C to A) SNP of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, have been suggested to have functional effects on mature proteins. Therefore, we explored the possibility that those SNPs were associated to anorexia nervosa and/or bulimia nervosa. The distributions of the CNR1 1359 G/A SNP and of the FAAH cDNA 385C to A SNP were investigated in 134 patients with anorexia nervosa, 180 patients with bulimia nervosa and 148 normal weight healthy controls. Additive effects of the two SNPs in the genetic susceptibility to anorexia nervosa and bulimia nervosa were also tested. As compared to healthy controls, anorexic and bulimic patients showed significantly higher frequencies of the AG genotype and the A allele of the CNR1 1359 G/A SNP. Similarly, the AC genotype and the A allele of the FAAH cDNA 385C to A SNP were significantly more frequent in anorexic and bulimic individuals. A synergistic effect of the two SNPs was evident in anorexia nervosa but not in bulimia nervosa. Present findings show for the first time that the CNR1 1359 G/A SNP and the FAAH cDNA 385C to A SNP are significantly associated to anorexia nervosa and bulimia nervosa, and demonstrate a synergistic effect of the two SNPs in anorexia nervosa.

  8. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

    Energy Technology Data Exchange (ETDEWEB)

    Frampton, Gabriel; Coufal, Monique [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Li, Huang [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Ramirez, Jonathan [Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States); DeMorrow, Sharon, E-mail: demorrow@medicine.tamhsc.edu [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States)

    2010-05-15

    The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the {gamma}-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-{gamma}-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the {gamma}-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

  9. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

    International Nuclear Information System (INIS)

    Frampton, Gabriel; Coufal, Monique; Li, Huang; Ramirez, Jonathan; DeMorrow, Sharon

    2010-01-01

    The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the γ-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-γ-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the γ-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

  10. Individual differences in response to positive and negative stimuli: endocannabinoid-based insight on approach and avoidance behaviors

    Directory of Open Access Journals (Sweden)

    Daniela eLaricchiuta

    2014-12-01

    Full Text Available Approach and avoidance behaviors - the primary responses to the environmental stimuli of danger, novelty and reward - are associated with the brain structures that mediate cognitive functionality, reward sensitivity and emotional expression. Individual differences in approach and avoidance behaviors are modulated by the functioning of amygdaloid-hypothalamic-striatal and striatal-cerebellar networks implicated in action and reaction to salient stimuli. The nodes of these networks are strongly interconnected and by acting on them the endocannabinoid and dopaminergic systems increase the intensity of appetitive or defensive motivation. This review analyzes the approach and avoidance behaviors in humans and rodents, addresses neurobiological and neurochemical aspects of these behaviors, and proposes a possible synaptic plasticity mechanism, related to endocannabinoid-dependent long-term potentiation and depression that allows responding to salient positive and negative stimuli.

  11. Don't Worry, Be Happy: Endocannabinoids and Cannabis at the Intersection of Stress and Reward.

    Science.gov (United States)

    Volkow, Nora D; Hampson, Aidan J; Baler, Ruben D

    2017-01-06

    Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and reward. This effect, in vulnerable individuals, can lead to addiction and other adverse consequences. The recent shift toward legalization of medical or recreational cannabis has renewed interest in investigating the physiological role of the ECS as well as the potential health effects, both adverse and beneficial, of cannabis. Here we review our current understanding of the ECS and its complex physiological roles. We discuss the implications of this understanding vis-á-vis the ECS's modulation of stress and reward and its relevance to mental disorders in which these processes are disrupted (i.e., addiction, depression, posttraumatic stress disorder, schizophrenia), along with the therapeutic potential of strategies to manipulate the ECS for these conditions.

  12. Driving the need to feed: Insight into the collaborative interaction between ghrelin and endocannabinoid systems in modulating brain reward systems.

    Science.gov (United States)

    Edwards, Alexander; Abizaid, Alfonso

    2016-07-01

    Independent stimulation of either the ghrelin or endocannabinoid system promotes food intake and increases adiposity. Given the similar distribution of their receptors in feeding associated brain regions and organs involved in metabolism, it is not surprising that evidence of their interaction and its importance in modulating energy balance has emerged. This review documents the relationship between ghrelin and endocannabinoid systems within the periphery and hypothalamus (HYP) before presenting evidence suggesting that these two systems likewise work collaboratively within the ventral tegmental area (VTA) to modulate non-homeostatic feeding. Mechanisms, consistent with current evidence and local infrastructure within the VTA, will be proposed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Song-associated reward correlates with endocannabinoid-related gene expression in male European starlings (Sturnus vulgaris).

    Science.gov (United States)

    Hahn, Allison H; Merullo, Devin P; Spool, Jeremy A; Angyal, Caroline S; Stevenson, Sharon A; Riters, Lauren V

    2017-03-27

    Vocal communication is required for successful social interactions in numerous species. During the breeding season, songbirds produce songs that are reinforced by behavioral consequences (e.g., copulation). However, some songbirds also produce songs not obviously directed at other individuals. The consequences maintaining or reinforcing these songs are less obvious and the neural mechanisms associated with undirected communication are not well-understood. Previous studies indicate that undirected singing is intrinsically rewarding and mediated by opioid or dopaminergic systems; however, endocannabinoids are also involved in regulating reward and singing behavior. We used a conditioned place preference paradigm to examine song-associated reward in European starlings and quantitative real-time PCR to measure expression of endocannabinoid-related neural markers (CB 1 , FABP7, FABP5, FAAH, DAGLα), in brain regions involved in social behavior, reward and motivation (ventral tegmental area [VTA], periaqueductal gray [PAG], and medial preoptic nucleus [POM]), and a song control region (Area X). Our results indicate that starlings producing high rates of song developed a conditioned place preference, suggesting that undirected song is associated with a positive affective state. We found a significant positive relationship between song-associated reward and CB 1 receptors in VTA and a significant negative relationship between song-associated reward and CB 1 in PAG. There was a significant positive relationship between reward and the cannabinoid transporter FABP7 in POM and a significant negative relationship between reward and FABP7 in PAG. In Area X, FABP5 and DAGLα correlated positively with singing. These results suggest a role for endocannabinoid signaling in vocal production and reward associated with undirected communication. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients

    Directory of Open Access Journals (Sweden)

    Verde Roberta

    2010-04-01

    Full Text Available Abstract Background The endocannabinoids, anandamide and 2-AG, are produced by adipocytes, where they stimulate lipogenesis via cannabinoid CB1 receptors and are under the negative control of leptin and insulin. Endocannabinoid levels are elevated in the blood of obese individuals and nonobese type 2 diabetes patients. To date, no study has evaluated endocannabinoid levels in subcutaneous adipose tissue (SAT of subjects with both obesity and type 2 diabetes (OBT2D, characterised by similar adiposity and whole body insulin resistance and lower plasma leptin levels as compared to non-diabetic obese subjects (OB. Design and Methods The levels of anandamide and 2-AG, and of the anandamide-related PPARα ligands, oleoylethanolamide (OEA and palmitoylethanolamide (PEA, in the SAT obtained by abdominal needle biopsy in 10 OBT2D, 11 OB, and 8 non-diabetic normal-weight (NW subjects, were measured by liquid chromatography-mass spectrometry. All subjects underwent a hyperinsulinaemic euglycaemic clamp. Results As compared to NW, anandamide, OEA and PEA levels in the SAT were 2-4.4-fold elevated (p Conclusions The observed alterations emphasize, for the first time in humans, the potential different role and regulation of adipose tissue anandamide (and its congeners and 2-AG in obesity and type 2 diabetes.

  15. Molecular selectivity of graphene-enhanced Raman scattering.

    Science.gov (United States)

    Huang, Shengxi; Ling, Xi; Liang, Liangbo; Song, Yi; Fang, Wenjing; Zhang, Jin; Kong, Jing; Meunier, Vincent; Dresselhaus, Mildred S

    2015-05-13

    Graphene-enhanced Raman scattering (GERS) is a recently discovered Raman enhancement phenomenon that uses graphene as the substrate for Raman enhancement and can produce clean and reproducible Raman signals of molecules with increased signal intensity. Compared to conventional Raman enhancement techniques, such as surface-enhanced Raman scattering (SERS) and tip-enhanced Raman scattering (TERS), in which the Raman enhancement is essentially due to the electromagnetic mechanism, GERS mainly relies on a chemical mechanism and therefore shows unique molecular selectivity. In this paper, we report graphene-enhanced Raman scattering of a variety of different molecules with different molecular properties. We report a strong molecular selectivity for the GERS effect with enhancement factors varying by as much as 2 orders of magnitude for different molecules. Selection rules are discussed with reference to two main features of the molecule, namely its molecular energy levels and molecular structures. In particular, the enhancement factor involving molecular energy levels requires the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies to be within a suitable range with respect to graphene's Fermi level, and this enhancement effect can be explained by the time-dependent perturbation theory of Raman scattering. The enhancement factor involving the choice of molecular structures indicates that molecular symmetry and substituents similar to that of the graphene structure are found to be favorable for GERS enhancement. The effectiveness of these factors can be explained by group theory and the charge-transfer interaction between molecules and graphene. Both factors, involving the molecular energy levels and structural symmetry of the molecules, suggest that a remarkable GERS enhancement requires strong molecule-graphene coupling and thus effective charge transfer between the molecules and graphene. These conclusions are further

  16. Obesity, the endocannabinoid system, and bias arising from pharmaceutical sponsorship.

    Directory of Open Access Journals (Sweden)

    John M McPartland

    Full Text Available Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees. This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor.A MEDLINE search was performed for rimonabant review articles, limited to articles authored by USA physicians who served as consultants for the company that manufactures rimonabant. Extracted articles were examined for industry-friendly bias, identified by three methods: analysis with a validated instrument for monitoring bias in continuing medical education (CME; analysis for bias defined as statements that ran contrary to external evidence; and a tally of misrepresentations about the endocannabinoid system. Eight review articles were identified, but only three disclosed authors' financial conflicts of interest, despite easily accessible information to the contrary. The Takhar CME bias instrument demonstrated statistically significant bias in all the review articles. Biased statements that were nearly identical reappeared in the articles, including disease mongering, exaggerating rimonabant's efficacy and safety, lack of criticisms regarding rimonabant clinical trials, and speculations about surrogate markers stated as facts. Distinctive and identical misrepresentations regarding the endocannabinoid system also reappeared in articles by different authors.The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

  17. Obesity, the endocannabinoid system, and bias arising from pharmaceutical sponsorship.

    Science.gov (United States)

    McPartland, John M

    2009-01-01

    Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees. This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor. A MEDLINE search was performed for rimonabant review articles, limited to articles authored by USA physicians who served as consultants for the company that manufactures rimonabant. Extracted articles were examined for industry-friendly bias, identified by three methods: analysis with a validated instrument for monitoring bias in continuing medical education (CME); analysis for bias defined as statements that ran contrary to external evidence; and a tally of misrepresentations about the endocannabinoid system. Eight review articles were identified, but only three disclosed authors' financial conflicts of interest, despite easily accessible information to the contrary. The Takhar CME bias instrument demonstrated statistically significant bias in all the review articles. Biased statements that were nearly identical reappeared in the articles, including disease mongering, exaggerating rimonabant's efficacy and safety, lack of criticisms regarding rimonabant clinical trials, and speculations about surrogate markers stated as facts. Distinctive and identical misrepresentations regarding the endocannabinoid system also reappeared in articles by different authors. The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

  18. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids

    Science.gov (United States)

    Covey, Dan P.; Bunner, Kendra D.; Schuweiler, Douglas R.; Cheer, Joseph F.; Garris, Paul A.

    2018-01-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  19. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

    Science.gov (United States)

    Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

    2016-06-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  20. Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids.

    Science.gov (United States)

    Pataky, Zoltan; Carrard, Isabelle; Gay, Valerie; Thomas, Aurélien; Carpentier, Anne; Bobbioni-Harsch, Elisabetta; Golay, Alain

    2018-04-10

    To evaluate the effects of weight loss on endocannabinoids, cardiometabolic and psychological parameters, eating disorders (ED) as well as quality of life (QoL) and to elucidate the role of endocannabinoids in metabolic syndrome (MS). In total, 114 patients with obesity were prospectively included in a 12-month weight loss program. Plasma endocannabinoids were measured by mass spectrometry; ED, psychological and QoL-related parameters were evaluated by self-reported questionnaires; physical activity was measured by accelerometer. Nutritional assessment was done by a 3-day food diary. Among completers (n = 87), body weight decreased in 35 patients (-9.1 ± 8.6 kg), remained stable in 39 patients, and increased in 13 patients (+5.8 ± 3.4 kg). 75% of patients with MS at baseline were free of MS at follow-up, and their baseline plasma N-palmitoylethanolamide (PEA) values were significantly lower when compared to patients with persisting MS. At baseline, there was a positive relationship between PEA and waist circumference (p = 0.005, R2 = 0.08), fasting glucose (p < 0.0001, R2 = 0.12), total cholesterol (p = 0.001, R2 = 0.11), triglycerides (p = 0.001, R2 = 0.11), LDL-cholesterol (p = 0.03, R2 = 0.05) as well as depression score (p = 0.002, R2 = 0.29). Plasma PEA might play a role in metabolic improvement after weight loss. Even in subjects without weight loss, a multidisciplinary intervention improves psychological outcomes, ED, and QoL. © 2018 The Author(s) Published by S. Karger GmbH, Freiburg.

  1. Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids?

    Directory of Open Access Journals (Sweden)

    Zoltan Pataky

    2018-04-01

    Full Text Available Objective: To evaluate the effects of weight loss on endocannabinoids, cardiometabolic and psychological parameters, eating disorders (ED as well as quality of life (QoL and to elucidate the role of endocannabinoids in metabolic syndrome (MS. Methods: In total, 114 patients with obesity were prospectively included in a 12-month weight loss program. Plasma endocannabinoids were measured by mass spectrometry; ED, psychological and QoL-related parameters were evaluated by self-reported questionnaires; physical activity was measured by accelerometer. Nutritional assessment was done by a 3-day food diary. Results: Among completers (n = 87, body weight decreased in 35 patients (-9.1 ± 8.6 kg, remained stable in 39 patients, and increased in 13 patients (+5.8 ± 3.4 kg. 75% of patients with MS at baseline were free of MS at follow-up, and their baseline plasma N-palmitoylethanolamide (PEA values were significantly lower when compared to patients with persisting MS. At baseline, there was a positive relationship between PEA and waist circumference (p = 0.005, R2 = 0.08, fasting glucose (p 2 = 0.12, total cholesterol (p = 0.001, R2 = 0.11, triglycerides (p = 0.001, R2 = 0.11, LDL-cholesterol (p = 0.03, R2 = 0.05 as well as depression score (p = 0.002, R2 = 0.29. Conclusion: Plasma PEA might play a role in metabolic improvement after weight loss. Even in subjects without weight loss, a multidisciplinary intervention improves psychological outcomes, ED, and QoL.

  2. Automatic anatomically selective image enhancement in digital chest radiography

    International Nuclear Information System (INIS)

    Sezan, M.I.; Minerbo, G.N.; Schaetzing, R.

    1989-01-01

    The authors develop a technique for automatic anatomically selective enhancement of digital chest radiographs. Anatomically selective enhancement is motivated by the desire to simultaneously meet the different enhancement requirements of the lung field and the mediastinum. A recent peak detection algorithm and a set of rules are applied to the image histogram to determine automatically a gray-level threshold between the lung field and mediastinum. The gray-level threshold facilitates anatomically selective gray-scale modification and/or unsharp masking. Further, in an attempt to suppress possible white-band or black-band artifacts due to unsharp masking at sharp edges, local-contrast adaptivity is incorporated into anatomically selective unsharp masking by designing an anatomy-sensitive emphasis parameter which varies asymmetrically with positive and negative values of the local image contrast

  3. Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation?

    Science.gov (United States)

    Gertsch, Jürg

    2017-06-01

    The endocannabinoid system (ECS) is a major lipid signalling network that plays important pro-homeostatic (allostatic) roles not only in the nervous system but also in peripheral organs. There is increasing evidence that there is a dietary component in the modulation of the ECS. Cannabinoid receptors in hominids co-evolved with diet, and the ECS constitutes a feedback loop for food selection and energy metabolism. Here, it is postulated that the mismatch of ancient lipid genes of hunter-gatherers and pastoralists with the high-carbohydrate diet introduced by agriculture could be compensated for via dietary modulation of the ECS. In addition to the fatty acid precursors of endocannabinoids, the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed. Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid-type 2 (CB 2 ) receptors may provide adaptive metabolic advantages and counteract inflammation. In contrast, chronic CB 1 receptor activation in hedonic obese individuals may enhance pathophysiological processes related to hyperlipidaemia, diabetes, hepatorenal inflammation and cardiometabolic risk. Food able to modulate the CB 1 /CB 2 receptor activation ratio may thus play a role in the nutrition transition of Western high-calorie diets. In this review, the interplay between diet and the ECS is highlighted from an evolutionary perspective. The emerging potential of cannabimimetic food as a nutraceutical strategy is critically discussed. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2016 The British Pharmacological Society.

  4. Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders

    Science.gov (United States)

    Coleman, Jonathan R. I.; Roberts, Susanna; Keers, Robert; Breen, Gerome; Bögels, Susan; Creswell, Cathy; Hudson, Jennifer L.; McKinnon, Anna; Nauta, Maaike; Rapee, Ronald M.; Schneider, Silvia; Silverman, Wendy K.; Thastum, Mikael; Waite, Polly; Wergeland, Gro Janne H.; Eley, Thalia C.

    2016-01-01

    Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re‐emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre‐ and post‐treatment and during the follow‐up period in the full sample and a subset with fear‐based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow‐up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear‐based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID:27346075

  5. Automatic, anatomically selective, artifact-free enhancement of digital chest radiographs

    International Nuclear Information System (INIS)

    Sezan, M.I.; Tekalp, A.M.; Schaetzing, R.

    1988-01-01

    The authors propose a technique for automatic, anatomically selective, artifact-free enhancement of digital chest radiographs. Anatomically selective enhancement is motivated by the different enhancement requirements of the lung field and the mediastinum. A recent peak detection algorithm is applied to the image histogram to automatically determine a gray-level threshold between the lung and mediastinum fields. The gray-level threshold facilitates anatomically selective gray-scale modification and unsharp masking. Further, in an attempt to suppress possible white-band artifacts due to unsharp masking at sharp edges, local-contrast adaptivity is incorporated into anatomically selective unsharp masking by designing an anatomy-sensitive emphasis parameter that varied asymmetrically with positive and negative values of the local image contrast

  6. Essential fatty acids and lipid mediators. Endocannabinoids

    Directory of Open Access Journals (Sweden)

    G. Caramia

    2012-03-01

    Full Text Available In 1929 Burr and Burr discovered the essential fatty acids omega-6 and omega-3. Since then, researchers have shown a growing interest in polyunsaturated fatty acids (PUFA as precursors of “lipid mediator” molecules, often with opposing effects, prostaglandins, prostacyclins, thromboxanes, leukotrienes, lipossines, resolvines, protectines, maresins that regulate immunity, platelet aggregation, inflammation, etc. They showed that the balance between omega-3 and omega-6 acids has a profound influence on all the body’s inflammatory responses and a raised level of PUFA omega-3 in tissue correlate with a reduced incidence of degenerative cardiovascular disease, some mental illnesses such as depression, and neuro-degenerative diseases such as Alzheimer’s. The CYP-catalyzed epoxidation and hydroxylation of arachidonic acid (AA were established recently as the so-called third branch of AGE cascade. Cytochrome P450 (CYP epoxygenases convert AA to four epoxyeicosatrienoic acid (EET regioisomers, that produce vascular relaxation anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. Eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA are accessible to CYP enzymes in the same way as AA. Metabolites derived from EPA include epoxyeicosatetraenoic acids (EETR and hydroxyeicosapentaenoic acids (19- and 20-HEPE, whereas DHA include epoxydocosapentaenoic acids (EDPs hydroxydocosahexaenoic acids (21- and 22-HDoHE. For many of the CYP isoforms, the n-3 PUFAs are the preferred substrates and the available data suggest that some of the vasculo- and cardioprotective effects attributed to dietary n-3 PUFAs may be mediated by CYP-dependent metabolites of EPA and DHA. From AA derives also endocannabinoids like anandamide (N-arachidonoylethanolamine and 2-arachidonoylglycerol, capable of mimicking the pharmacological actions of the active principle of Cannabis sativa preparations such as

  7. Tunable graphene antennas for selective enhancement of THz-emission

    KAUST Repository

    Filter, Robert; Farhat, Mohamed; Steglich, Mathias; Alaee, Rasoul; Rockstuhl, Carsten; Lederer, Falk L.

    2013-01-01

    In this paper, we will introduce THz graphene antennas that strongly enhance the emission rate of quantum systems at specific frequencies. The tunability of these antennas can be used to selectively enhance individual spectral features. We will show as an example that any weak transition in the spectrum of coronene can become the dominant contribution. This selective and tunable enhancement establishes a new class of graphene-based THz devices, which will find applications in sensors, novel light sources, spectroscopy, and quantum communication devices. © 2013 Optical Society of America.

  8. Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years

    Directory of Open Access Journals (Sweden)

    Mauro Maccarrone

    2017-05-01

    Full Text Available Cannabis extracts have been used for centuries, but its main active principle ∆9-tetrahydrocannabinol (THC was identified about 50 years ago. Yet, it is only 25 years ago that the first endogenous ligand of the same receptors engaged by the cannabis agents was discovered. This “endocannabinoid (eCB” was identified as N-arachidonoylethanolamine (or anandamide (AEA, and was shown to have several receptors, metabolic enzymes and transporters that altogether drive its biological activity. Here I report on the latest advances about AEA metabolism, with the aim of focusing open questions still awaiting an answer for a deeper understanding of AEA activity, and for translating AEA-based drugs into novel therapeutics for human diseases.

  9. Circulating Endocannabinoids and Insulin Resistance in Patients with Obstructive Sleep Apnea

    Directory of Open Access Journals (Sweden)

    Xiaoya Wang

    2016-01-01

    Full Text Available Objectives. The purpose of this study is to investigate the relationship between plasma endocannabinoids and insulin resistance (IR in patients with obstructive sleep apnea (OSA. Methods. A population of 64 with OSA and 24 control subjects was recruited. Body mass index (BMI, waist circumference, lipids, blood glucose and insulin, homeostasis model of assessment for insulin resistance index (HOMA-IR, anandamide (AEA, 1/2-arachidonoylglycerol (1/2-AG, and apnea-hypopnea index (AHI were analyzed. Results. Fasting blood insulin (22.9 ± 7.8 mIU/L versus 18.5 ± 7.2 mIU/L, P<0.05, HOMA-IR (2.9 ± 1.0 versus 2.4 ± 0.9, P<0.01, AEA (3.2 ± 0.7 nmol/L versus 2.5 ± 0.6 nmol/L, P<0.01, and 1/2-AG (40.8 ± 5.7 nmol/L versus 34.3 ± 7.7 nmol/L, P<0.01 were higher in OSA group than those in control group. In OSA group, AEA, 1/2-AG, and HOMA-IR increase with the OSA severity. The correlation analysis showed significant positive correlation between HOMA-IR and AHI (r=0.44, P<0.01, AEA and AHI (r=0.52, P<0.01, AEA and HOMA-IR (r=0.62, P<0.01, and 1/2-AG and HOMA-IR (r=0.33, P<0.01. Further analysis showed that only AEA was significantly correlated with AHI and HOMA-IR after adjusting for confounding factors. Conclusions. The present study indicated that plasma endocannabinoids levels, especially AEA, were associated with IR and AHI in patients with OSA.

  10. Seeing through the smoke: human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

    Science.gov (United States)

    Silveira, Mason M.; Arnold, Jonathon C.; Laviolette, Steven R.; Hillard, Cecilia J.; Celorrio, Marta; Aymerich, María S.; Adams, Wendy K.

    2016-01-01

    Public opinion surrounding the recreational use and therapeutic potential of cannabis is shifting. This review describes new work examining the behavioural and neural effects of cannabis and the endocannabinoid system, highlighting key regions within corticolimbic brain circuits. First, we consider the role of human genetic factors and cannabis strain chemotypic differences in contributing to interindividual variation in the response to cannabinoids, such as THC, and review studies demonstrating that THC-induced impairments in decision-making processes are mediated by actions at prefrontal CB1 receptors. We further describe evidence that signalling through prefrontal or ventral hippocampal CB1 receptors modulates mesolimbic dopamine activity, aberrations of which may contribute to emotional processing deficits in schizophrenia. Lastly, we review studies suggesting that endocannabinoid tone in the amygdala is a critical regulator of anxiety, and report new data showing that FAAH activity is integral to this response. Together, these findings underscore the importance of cannabinoid signalling in the regulation of cognitive and affective behaviours, and encourage further research given their social, political, and therapeutic implications. PMID:27639448

  11. Contractor Selection for Enhancing the Quality of University ...

    African Journals Online (AJOL)

    Contractor Selection for Enhancing the Quality of University Education in Nigeria using the Hamming Distance. DEA Omorogbe, SO Aibieyi. Abstract. The need for contractor selection in our university education system cannot be over emphasized. And applying scientific techniques for appropriateness and accuracy in the ...

  12. The endocannabinoid gene faah2a modulates stress-associated behavior in zebrafish.

    Directory of Open Access Journals (Sweden)

    Randall G Krug

    Full Text Available The ability to orchestrate appropriate physiological and behavioral responses to stress is important for survival, and is often dysfunctional in neuropsychiatric disorders that account for leading causes of global disability burden. Numerous studies have shown that the endocannabinoid neurotransmitter system is able to regulate stress responses and could serve as a therapeutic target for the management of these disorders. We used quantitative reverse transcriptase-polymerase chain reactions to show that genes encoding enzymes that synthesize (abhd4, gde1, napepld, enzymes that degrade (faah, faah2a, faah2b, and receptors that bind (cnr1, cnr2, gpr55-like endocannabinoids are expressed in zebrafish (Danio rerio. These genes are conserved in many other vertebrates, including humans, but fatty acid amide hydrolase 2 has been lost in mice and rats. We engineered transcription activator-like effector nucleases to create zebrafish with mutations in cnr1 and faah2a to test the role of these genes in modulating stress-associated behavior. We showed that disruption of cnr1 potentiated locomotor responses to hyperosmotic stress. The increased response to stress was consistent with rodent literature and served to validate the use of zebrafish in this field. Moreover, we showed for the first time that disruption of faah2a attenuated the locomotor responses to hyperosmotic stress. This later finding suggests that FAAH2 may be an important mediator of stress responses in non-rodent vertebrates. Accordingly, FAAH and FAAH2 modulators could provide distinct therapeutic options for stress-aggravated disorders.

  13. The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders.

    Science.gov (United States)

    Kolla, Nathan J; Mishra, Achal

    2018-01-01

    Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

  14. The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Nathan J. Kolla

    2018-03-01

    Full Text Available Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

  15. A preliminary study of endocannabinoid system regulation in psychosis: Distinct alterations of CNR1 promoter DNA methylation in patients with schizophrenia.

    Science.gov (United States)

    D'Addario, Claudio; Micale, Vincenzo; Di Bartolomeo, Martina; Stark, Tibor; Pucci, Mariangela; Sulcova, Alexandra; Palazzo, Mariacarlotta; Babinska, Zuzana; Cremaschi, Laura; Drago, Filippo; Carlo Altamura, A; Maccarrone, Mauro; Dell'Osso, Bernardo

    2017-10-01

    Compelling evidence supports the involvement of the endocannabinoid system (ECS) in psychosis vulnerability. We here evaluated the transcriptional regulation of ECS components in human peripheral blood mononuclear cells (PBMCs) obtained from subjects suffering from bipolar disorder, major depressive disorder and schizophrenia, focusing in particular on the effects of DNA methylation. We observed selective alterations of DNA methylation at the promoter of CNR1, the gene coding for the type-1 cannabinoid receptor, in schizophrenic patients (N=25) with no changes in any other disorder. We confirmed the regulation of CNR1 in a well-validated animal model of schizophrenia, induced by prenatal methylazoxymethanol (MAM) acetate exposure (N=7 per group) where we found, in the prefrontal cortex, a significant increase in CNR1 expression and a consistent reduction in DNA methylation at specific CpG sites of gene promoter. Overall, our findings suggest a selective dysregulation of ECS in psychosis, and highlight the evaluation of CNR1 DNA methylation levels in PBMCs as a potential biomarker for schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Endocannabinoids: Multi-scaled, Global Homeostatic Regulators of Cells and Society

    Science.gov (United States)

    Melamede, Robert

    Living systems are far from equilibrium open systems that exhibit many scales of emergent behavior. They may be abstractly viewed as a complex weave of dissipative structures that maintain organization by passing electrons from reduced hydrocarbons to oxygen. Free radicals are unavoidable byproducts of biological electron flow. Due to their highly reactive chemical properties, free radicals modify all classes of biological molecules (carbohydrates, lipids, nucleic acids, and proteins). As a result, free radicals are destructive. The generally disruptive nature of free radicals makes them the "friction of life." As such, they are believed to be the etiological agents behind age related illnesses such as cardiovascular, immunological, and neurological diseases, cancer, and ageing itself. Free radicals also play a critical constructive role in living systems. From a thermodynamic perspective, life can only exist if a living system takes in sufficient negative entropy from its environment to overcome the obligatory increase in entropy that would result if the system could not appropriately exchange mass, energy and information with its environment. Free radicals are generated in response to perturbations in the relationship between a living system and its environment. However, evolution has selected for biological response systems to free radicals so that the cellular biochemistry can adapt to environmental perturbations by modifying cellular gene expression and biochemistry. Endocannabinoids are marijuana-like compounds that have their origins hundreds of millions of years in the evolutionary past. They serve as fundamental modulators of energy homeostasis in all vertebrates. Their widespread biological activities may often be attributed to their ability to minimize the negative consequences of free radicals.

  17. Endocannabinoid and Mood Responses to Exercise in Adults with Varying Activity Levels.

    Science.gov (United States)

    Brellenthin, Angelique G; Crombie, Kevin M; Hillard, Cecilia J; Koltyn, Kelli F

    2017-08-01

    Acute aerobic exercise improves mood and activates the endocannabinoid (eCB) system in physically active individuals; however, both mood and eCB responses to exercise may vary based on habitual levels of physical activity. This study aimed to examine eCB and mood responses to prescribed and preferred exercises among individuals with low, moderate, and high levels of physical activity. Thirty-six healthy adults (21 ± 4 yr) were recruited from low (≤60 min moderate-vigorous physical activity [MVPA] per week), moderate (150-299 min MVPA per week), and high (≥300 MVPA per week) physical activity groups. Participants performed both prescribed (approximately 70%-75% max) and preferred (i.e., self-selected) aerobic exercise on separate days. Mood states and eCB concentrations were assessed before and after exercise conditions. Both preferred and prescribed exercise resulted in significant increases (P exercise elicited positive mood improvements compared with preexercise values, but changes in state anxiety, total mood disturbance, and confusion were greater in the preferred condition (P mood disturbance in the preferred condition (P mood or eCB outcomes. These results indicate that eCB and mood responses to exercise do not differ significantly between samples with varying physical activity levels. This study also demonstrates that in addition to prescribed exercise, preferred exercise activates the eCB system, and this activation may contribute to positive mood outcomes with exercise.

  18. Changes in the Peripheral Endocannabinoid System as a Risk Factor for the Development of Eating Disorders.

    Science.gov (United States)

    Capasso, Anna; Milano, Walter; Cauli, Omar

    2018-02-12

    Eating Disorder (ED) is characterized by persistently and severely disturbed eating behaviours. They arise from a combination of long-standing behavioural, emotional, psychological, interpersonal, and social factors and result in insufficient nutrient ingestion and/or adsorption. The three main EDs are: anorexia nervosa, bulimia nervosa, and binge eating disorder. We review the role of peripheral endocannabinoids in eating behaviour. The neuronal pathways involved in feeding behaviours are closely related to catecholaminergic, serotoninergic and peptidergic systems. Accordingly, feeding is promoted by serotonin, dopamine, and prostaglandin and inhibited by neuropeptide Y, norepinephrine, GABA, and opioid peptides. The endocannabinoid system plays a role in EDs, and multiple lines of evidence indicate that the cannabinoid signalling system is a key modulatory factor of the activity in the brain areas involved in EDs as well as in reward processes. Besides their central role in controlling food behaviours, peripheral cannabinoids are also involved in regulating adipose tissue and insulin signalling as well as cell metabolism in peripheral tissues such as liver, pancreas, fatty tissue, and skeletal muscle. Altogether, these data indicate that peripheral cannabinoids can provide new therapeutic targets not only for EDs but also for metabolic disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. FEMALE MICE ARE RESISTANT TO Fabp1 GENE ABLATION-INDUCED ALTERATIONS IN BRAIN ENDOCANNABINOID LEVELS

    Science.gov (United States)

    Martin, Gregory G.; Chung, Sarah; Landrock, Danilo; Landrock, Kerstin K.; Dangott, Lawrence J.; Peng, Xiaoxue; Kaczocha, Martin; Murphy, Eric J.; Kier, Ann B.; Schroeder, Friedhelm

    2017-01-01

    Although liver fatty acid binding protein (FABP1, L-FABP) is not detectable in brain, Fabp1 gene ablation (LKO) markedly increases endocannabinoids (EC) in brains of male mice. Since the brain EC system of females differs significantly from that of males, it was important to determine if LKO differently impacted the brain EC system. LKO did not alter brain levels of arachidonic acid (ARA)-containing ECs, i.e arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), but decreased non-ARA-containing N-acylethanolamides (OEA, PEA) and 2-oleoylglycerol (2-OG) that potentiate the actions of AEA and 2-AG. These changes in brain potentiating EC levels were not associated with: i) a net decrease in levels of brain membrane proteins associated with fatty acid uptake and EC synthesis; ii) a net increase in brain protein levels of cytosolic EC chaperones and enzymes in EC degradation; or iii) increased brain protein levels of EC receptors (CB1, TRVP1). Instead, the reduced or opposite responsiveness of female brain EC levels to loss of FABP1 (LKO) correlated with intrinsically lower FABP1 level in livers of WT females than males. These data show that female mouse brain endocannabinoid levels were unchanged (AEA, 2-AG) or decreased (OEA, PEA, 2-OG) by complete loss of FABP1 (LKO). PMID:27450559

  20. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    OpenAIRE

    Campolongo, Patrizia; Ratano, Patrizia; Manduca, Antonia; Scattoni, Maria L.; Palmery, Maura; Trezza, Viviana; Cuomo, Vincenzo

    2012-01-01

    Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p.) on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimenta...

  1. Marijuana, the Endocannabinoid System and the Female Reproductive System.

    Science.gov (United States)

    Brents, Lisa K

    2016-06-01

    Marijuana use among women is highly prevalent, but the societal conversation on marijuana rarely focuses on how marijuana affects female reproduction and endocrinology. This article reviews the current scientific literature regarding marijuana use and hypothalamic-pituitary-ovarian (HPO) axis regulation, ovarian hormone production, the menstrual cycle, and fertility. Evidence suggests that marijuana can reduce female fertility by disrupting hypothalamic release of gonadotropin releasing hormone (GnRH), leading to reduced estrogen and progesterone production and anovulatory menstrual cycles. Tolerance to these effects has been shown in rhesus monkeys, but the effects of chronic marijuana use on human female reproduction are largely unknown. Marijuana-induced analgesia, drug reinforcement properties, tolerance, and dependence are influenced by ovarian hormones, with estrogen generally increasing and progesterone decreasing sensitivity to marijuana. Carefully controlled regulation of the Endocannabinoid System (ECS) is required for successful reproduction, and the exogenous cannabinoids in marijuana may disrupt the delicate balance of the ECS in the female reproductive system.

  2. Stress and Memory: A Selective Review on Recent Developments in the Understanding of Stress Hormone Effects on Memory and Their Clinical Relevance.

    Science.gov (United States)

    Wolf, O T; Atsak, P; de Quervain, D J; Roozendaal, B; Wingenfeld, K

    2016-08-01

    Stress causes a neuroendocrine response cascade, leading to the release of catecholamines and glucocorticoids (GCs). GCs influence learning and memory by acting on mineralocorticoid (MR) and glucocorticoid (GR) receptors. Typically, GCs enhance the consolidation of memory processing at the same time as impairing the retrieval of memory of emotionally arousing experiences. The present selective review addresses four recent developments in this area. First, the role of the endocannabinoid system in mediating the rapid, nongenomic effects of GCs on memory is illustrated in rodents. Subsequently, studies on the impact of the selective stimulation of MRs on different memory processes in humans are summarised. Next, a series of human experiments on the impact of stress or GC treatment on fear extinction and fear reconsolidation is presented. Finally, the clinical relevance of the effects of exogenous GC administration is highlighted by the description of patients with anxiety disorders who demonstrate an enhancement of extinction-based therapies by GC treatment. The review highlights the substantial progress made in our mechanistic understanding of the memory-modulating properties of GCs, as well as their clinical potential. © 2015 British Society for Neuroendocrinology.

  3. Restricted vs. unrestricted wheel running in mice: Effects on brain, behavior and endocannabinoids.

    Science.gov (United States)

    Biedermann, Sarah V; Auer, Matthias K; Bindila, Laura; Ende, Gabriele; Lutz, Beat; Weber-Fahr, Wolfgang; Gass, Peter; Fuss, Johannes

    2016-11-01

    Beneficial effects of voluntary wheel running on hippocampal neurogenesis, morphology and hippocampal-dependent behavior have widely been studied in rodents, but also serious side effects and similarities to stereotypy have been reported. Some mouse strains run excessively when equipped with running wheels, complicating the comparability to human exercise regimes. Here, we investigated how exercise restriction to 6h/day affects hippocampal morphology and metabolism, stereotypic and basal behaviors, as well as the endocannabinoid system in wheel running C57BL/6 mice; the strain most commonly used for behavioral analyses and psychiatric disease models. Restricted and unrestricted wheel running had similar effects on immature hippocampal neuron numbers, thermoregulatory nest building and basal home-cage behaviors. Surprisingly, hippocampal gray matter volume, assessed with magnetic resonance (MR) imaging at 9.4 Tesla, was only increased in unrestricted but not in restricted runners. Moreover, unrestricted runners showed less stereotypic behavior than restricted runners did. However, after blockage of running wheels for 24h stereotypic behavior also increased in unrestricted runners, arguing against a long-term effect of wheel running on stereotypic behavior. Stereotypic behaviors correlated with frontal glutamate and glucose levels assessed by 1 H-MR spectroscopy. While acute running increased plasma levels of the endocannabinoid anandamide in former studies in mice and humans, we found an inverse correlation of anandamide with the daily running distance after long-term running. In conclusion, although there are some diverging effects of restricted and unrestricted running on brain and behavior, restricted running does not per se seem to be a better animal model for aerobic exercise in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue

    Directory of Open Access Journals (Sweden)

    Lucie eGeurts

    2011-07-01

    Full Text Available Growing evidence supports the role of gut microbiota in the development of obesity, type 2 diabetes and low-grade inflammation. The endocrine activity of adipose tissue has been found to contribute to the regulation of glucose homeostasis and low-grade inflammation. Among the key hormones produced by this tissue, apelin has been shown to regulate glucose homeostasis. Recently, it has been proposed that gut microbiota participate in adipose tissue metabolism via the endocannabinoid system and gut microbiota-derived compounds, namely lipopolysaccharide (LPS. We have investigated gut microbiota composition in obese and diabetic leptin-resistant mice (db/db by combining pyrosequencing and phylogenetic microarray analysis of 16S ribosomal RNA gene sequences. We observed a significant higher abundance of Firmicutes, Proteobacteria and Fibrobacteres phyla in db/db mice compared to lean mice. The abundance of 10 genera was significantly affected by the genotype. We identified the roles of the endocannabinoid system and LPS in the regulation of apelinergic system tone (apelin and APJ mRNA expression in genetic obese and diabetic mice. By using in vivo and in vitro models, we have demonstrated that both the endocannabinoid system and low-grade inflammation differentially regulate apelin and APJ mRNA expression in adipose tissue. Finally, deep-gut microbiota profiling revealed that the gut microbial community of type 2 diabetic mice is significantly different from that of their lean counterparts. This indicates specific relationships between the gut microbiota and the regulation of the apelinergic system. However, the exact roles of specific bacteria in shaping the phenotype of db/db mice remain to be determined.

  5. Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Holubiec, Mariana I; Romero, Juan I; Logica, Tamara; Rivera, Patricia; Pavón, Francisco J; Suarez, Juan; Capani, Francisco; Rodríguez de Fonseca, Fernando

    2015-01-01

    Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.

  6. Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats

    Directory of Open Access Journals (Sweden)

    Eduardo eBlanco Calvo

    2015-11-01

    Full Text Available Perinatal asphyxia (PA is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory and mood. Endocannabinoids, and other acylethanolamides (AEs without endocannabinoid activity, have recently received growing attention as they have potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals that were delivered spontaneously or by caesarean section were employed as controls. At one month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and GFAP, enzymes responsible for synthesis (DAGLα and NAPE-PLD and degradation (FAAH of ECS/AEs and their receptors (CB1 and PPARα in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.

  7. Polarized cellular patterns of endocannabinoid production and detection shape cannabinoid signaling in neurons

    Directory of Open Access Journals (Sweden)

    Delphine eLadarre

    2015-01-01

    Full Text Available Neurons display important differences in plasma membrane composition between somatodendritic and axonal compartments, potentially leading to currently unexplored consequences in G-protein-coupled-receptor signaling. Here, by using highly-resolved biosensor imaging to measure local changes in basal levels of key signaling components, we explored features of type-1 cannabinoid receptor (CB1R signaling in individual axons and dendrites of cultured rat hippocampal neurons. Activation of endogenous CB1Rs led to rapid, Gi/o-protein- and cAMP-mediated decrease of cyclic-AMP-dependent protein kinase (PKA activity in the somatodendritic compartment. In axons, PKA inhibition was significantly stronger, in line with axonally-polarized distribution of CB1Rs. Conversely, inverse agonist AM281 produced marked rapid increase of basal PKA activation in somata and dendrites, but not in axons, removing constitutive activation of CB1Rs generated by local production of the endocannabinoid 2-arachidonoylglycerol (2-AG. Interestingly, somatodendritic 2-AG levels differently modified signaling responses to CB1R activation by Δ9-THC, the psychoactive compound of marijuana, and by the synthetic cannabinoids WIN55,212-2 and CP55,940. These highly contrasted differences in sub-neuronal signaling responses warrant caution in extrapolating pharmacological profiles, which are typically obtained in non-polarized cells, to predict in vivo responses of axonal (i.e. presynaptic GPCRs. Therefore, our results suggest that enhanced comprehension of GPCR signaling constraints imposed by neuronal cell biology may improve the understanding of neuropharmacological action.

  8. Selective separation of Eu3+ using polymer-enhanced ultrafiltration

    International Nuclear Information System (INIS)

    Norton, M.V.

    1994-03-01

    A process to selectively remove 241 Am from liquid radioactive waste was investigated as an actinide separation method applicable to Hanford and other waste sites. The experimental procedures involved removal of Eu, a nonradioactive surrogate for Am, from aqueous solutions at pH 5 using organic polymers in conjunction with ultrafiltration. Commercially available polyacrylic acid (60,000 MW) and Pacific Northwest Laboratory's (PNL) synthesized E3 copolymer (∼10,000 MW) were tested. Test solutions containing 10 μg/mL of Eu were dosed vath each polymer at various concentrations in order to bind Eu (i.e., by complexation and/or cation exchange) for subsequent rejection by an ultrafiltration coupon. Test solutions were filtered with and without polymer to determine if enhanced Eu separation could be achieved from polymer treatment. Both polymers significantly increased Eu removal. Optimum concentrations were 20 μg/mL of polyacrylic acid and 100 μg/mL of E3 for 100% Eu rejection by the Amicon PM10 membrane at 55 psi. In addition to enhancement of removal, the polymers selectively bound Eu over Na, suggesting that selective separation of Eu was possible. This suggests that polymer-enhanced ultrafiltration is a potential process for separation of 241 Am from Hanford tank waste, further investigation of binding agents and membranes effective under very alkaline and high ionic strength is warranted. This process also has potential applications for selective separation of toxic metals from industrial process streams

  9. Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study.

    Directory of Open Access Journals (Sweden)

    Jakub Fichna

    Full Text Available AIMS: Irritable bowel syndrome (IBS is a functional gastrointestinal (GI disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. METHODS: AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D and constipation-predominant (IBS-C patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. RESULTS: Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. CONCLUSION: IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.

  10. Oxyradical Stress, Endocannabinoids, and Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Anberitha T. Matthews

    2015-12-01

    Full Text Available Atherosclerosis is responsible for most cardiovascular disease (CVD and is caused by several factors including hypertension, hypercholesterolemia, and chronic inflammation. Oxidants and electrophiles have roles in the pathophysiology of atherosclerosis and the concentrations of these reactive molecules are an important factor in disease initiation and progression. Overactive NADPH oxidase (Nox produces excess superoxide resulting in oxidized macromolecules, which is an important factor in atherogenesis. Although superoxide and reactive oxygen species (ROS have obvious toxic properties, they also have fundamental roles in signaling pathways that enable cells to adapt to stress. In addition to inflammation and ROS, the endocannabinoid system (eCB is also important in atherogenesis. Linkages have been postulated between the eCB system, Nox, oxidative stress, and atherosclerosis. For instance, CB2 receptor-evoked signaling has been shown to upregulate anti-inflammatory and anti-oxidative pathways, whereas CB1 signaling appears to induce opposite effects. The second messenger lipid molecule diacylglycerol is implicated in the regulation of Nox activity and diacylglycerol lipase β (DAGLβ is a key biosynthetic enzyme in the biosynthesis eCB ligand 2-arachidonylglycerol (2-AG. Furthermore, Nrf2 is a vital transcription factor that protects against the cytotoxic effects of both oxidant and electrophile stress. This review will highlight the role of reactive oxygen species (ROS in intracellular signaling and the impact of deregulated ROS-mediated signaling in atherogenesis. In addition, there is also emerging knowledge that the eCB system has an important role in atherogenesis. We will attempt to integrate oxidative stress and the eCB system into a conceptual framework that provides insights into this pathology.

  11. Exposure to a highly caloric palatable diet during pregestational and gestational periods affects hypothalamic and hippocampal endocannabinoid levels at birth and induces adiposity and anxiety-like behaviors in male rat offspring

    Directory of Open Access Journals (Sweden)

    Maria Teresa eRamírez-López

    2016-01-01

    Full Text Available Exposure to unbalanced diets during pre-gestational and gestational periods may result in long-term alterations in metabolism and behavior. The contribution of the endocannabinoid system to these long-term adaptive responses is unknown. In the present study, we investigated the impact of female rat exposure to a hypercaloric-hypoproteic palatable diet during pre-gestational, gestational and lactational periods on the development of male offspring. In addition, the hypothalamic and hippocampal endocannabinoid contents at birth and the behavioral performance in adulthood were investigated. Exposure to a palatable diet resulted in low weight offspring who exhibited low hypothalamic contents of arachidonic acid and the two major endocannabinoids (anandamide and 2-arachidonoylglycerol at birth. Palmitoylethanolamide, but not oleoylethanolamide, also decreased. Additionally, pups from palatable diet-fed dams displayed lower levels of anandamide and palmitoylethanolamide in the hippocampus. The low-weight male offspring, born from palatable diet exposed mothers, gained less weight during lactation and, although they recovered weight during the post-weaning period, they developed abdominal adiposity in adulthood. These animals exhibited anxiety-like behavior in the elevated plus-maze and open field test and a low preference for a chocolate diet in a food preference test, indicating that maternal exposure to a hypercaloric diet induces long-term behavioral alterations in male offspring. These results suggest that maternal diet alterations in the function of the endogenous cannabinoid system can mediate the observed phenotype of the offspring, since both hypothalamic and hippocampal endocannabinoids regulate feeding, metabolic adaptions to caloric diets, learning, memory and emotions.

  12. Development and validation of a quantitative method for the determination of 12 endocannabinoids and related compounds in human plasma using liquid chromatography-tandem mass spectrometry

    NARCIS (Netherlands)

    Balvers, M.G.J.; Verhoeckx, K.C.M.; Witkamp, R.F.

    2009-01-01

    A sensitive and specific LC¿MS/MS method for the quantification of the endocannabinoids and related structures anandamide, 2-arachidonoyl glycerol, 2-arachidonyl glycerol ether, O-arachidonoyl ethanolamide, dihomo-¿-linolenoyl ethanolamide, docosatetraenoyl ethanolamide, N-arachidonoyl dopamine,

  13. Impact of cannabis, cannabinoids and endocannabinoids in the lungs

    Directory of Open Access Journals (Sweden)

    Caroline Turcotte

    2016-09-01

    Full Text Available Since the identification of cannabinoid receptors in the 1990s, a research field has been dedicated to exploring the role of the cannabinoid system in immunity and the inflammatory response in human tissues and animal models. Although the cannabinoid system is present and crucial in many human tissues, studying the impact of cannabinoids on the lungs is particularly relevant because of their contact with exogenous cannabinoids is the context of marijuana consumption. In the past two decades, the scientific community has gathered a large body of evidence supporting that the activation of the cannabinoid system alleviates pain and reduces inflammation. In the context of lung inflammation, exogenous and endogenous cannabinoids have shown therapeutic potential because of their inhibitory effects on immune cell recruitment and functions. On the other hand, cannabinoids were shown to be deleterious to lung function and to impact respiratory pathogen clearance. In this review, we present the existing data on the regulation of lung immunity and inflammation by phytocannabinoids, synthetic cannabinoids and endocannabinoids.

  14. Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system

    Science.gov (United States)

    Okine, Bright N; Norris, Leonie M; Woodhams, Stephen; Burston, James; Patel, Annie; Alexander, Stephen PH; Barrett, David A; Kendall, David A; Bennett, Andrew J; Chapman, Victoria

    2012-01-01

    BACKGROUND AND PURPOSE Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of cannabinoid receptor-mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour. EXPERIMENTAL APPROACH Effects of pre-treatment with a single dose, versus 4 day repeated dosing with the selective FAAH inhibitor, URB597 (i.p. 0.3 mg·kg−1), on carrageenan-induced inflammatory pain behaviour and spinal pro-inflammatory gene induction were determined in rats. Effects of pain induction and of the drug treatments on levels of arachidonoyl ethanolamide (AEA), palmitoyl ethanolamide (PEA) and oleolyl ethanolamide (OEA) in the spinal cord were determined. KEY RESULTS Single, but not repeated, URB597 treatment significantly attenuated the development of inflammatory hyperalgesia (P < 0.001, vs. vehicle-treated animals). Neither mode of URB597 treatment altered levels of AEA, PEA and OEA in the hind paw, or carrageenan-induced paw oedema. Single URB597 treatment produced larger increases in AEA, PEA and OEA in the spinal cord, compared with those after repeated administration. Single and repeated URB597 treatment decreased levels of immunoreactive N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) in the spinal cord and attenuated carrageenan-induced spinal pro-inflammatory gene induction. CONCLUSION AND IMPLICATIONS Changes in the endocannabinoid system may contribute to the loss of analgesic effects following repeated administration of low dose URB597 in this model of inflammatory pain. PMID:22595021

  15. Effects of the antipsychotic paliperidone on stress-induced changes in the endocannabinoid system in rat prefrontal cortex.

    Science.gov (United States)

    MacDowell, Karina S; Sayd, Aline; García-Bueno, Borja; Caso, Javier R; Madrigal, José L M; Leza, Juan Carlos

    2017-09-01

    Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility.

  16. The multiple functions of the endocannabinoid system: a focus on the regulation of food intake

    Directory of Open Access Journals (Sweden)

    Tibiriça Eduardo

    2010-01-01

    Full Text Available Abstract Background Cannabis sativa (also known as marijuana has been cultivated by man for more than 5,000 years. However, there was a rise in its use in the 20th century for recreational, religious or spiritual, and medicinal purposes. The main psychoactive constituent of cannabis, whose structure was identified in the 1960's, is Δ9-tetrahydrocannabinol. On the other hand, the discovery of cannabinoid receptors and their endogenous agonists took place only very recently. In fact, the first cannabinoid receptor (CB1 was cloned in 1990, followed 3 years later by the characterization of a second cannabinoid receptor (CB2. Since the 19th century, the use of cannabis has been reported to stimulate appetite and increase the consumption of sweet and tasty food, sometimes resulting in significant weight gain. The recent description of the endocannabinoid system, not only in the central nervous system but also in peripheral tissues, points to its involvement in the regulation of appetite, food intake and energy metabolism. Consequently, the pharmacological modulation of the over-activity of this system could be useful in the treatment of the metabolic syndrome. Conclusions The endocannabinoid system has important physiological functions not only in the central nervous system but also in peripheral tissues. The activation of central CB1 receptors, particularly in hypothalamic nuclei and in the limbic system, is involved in the regulation of feeding behavior, and especially in the control of the intake of palatable food. In the periphery, cannabinoid receptors are present in adipocytes, skeletal muscle, gastrointestinal tract and liver, modulating energy metabolism.

  17. Endocannabinoids and Endovanilloids: A Possible Balance in the Regulation of the Testicular GnRH Signalling

    Directory of Open Access Journals (Sweden)

    Rosanna Chianese

    2013-01-01

    Full Text Available Reproductive functions are regulated both at central (brain and gonadal levels. In this respect, the endocannabinoid system (eCS has a very influential role. Interestingly, the characterization of eCS has taken many advantages from the usage of animal models different from mammals. Therefore, this review is oriented to summarize the main pieces of evidence regarding eCS coming from the anuran amphibian Rana esculenta, with particular interest to the morphofunctional relationship between eCS and gonadotropin releasing hormone (GnRH. Furthermore, a novel role for endovanilloids in the regulation of a testicular GnRH system will be also discussed.

  18. Selective Acylation Enhances Membrane Charge Sensitivity of the Antimicrobial Peptide Mastoparan-X

    DEFF Research Database (Denmark)

    Etzerodt, Thomas Povl; Henriksen, Jonas Rosager; Rasmussen, Palle

    2011-01-01

    and positioning of the peptide in the membrane caused by either PA or OA acylation play a critical role in the fine-tuning of the effective charge of the peptide and thereby the fine-tuning of the peptide's selectivity between neutral and negatively charged lipid membranes. This finding is unique compared...... to previous reports where peptide acylation enhanced membrane affinity but also resulted in impaired selectivity. Our result may provide a method of enhancing selectivity of antimicrobial peptides toward bacterial membranes due to their high negative charge—a finding that should be investigated for other...

  19. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

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    Ibrahim Knani

    2016-12-01

    Full Text Available Objective: Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS. Among numerous metabolic regulators, the endocannabinoid (eCB system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. Methods: We studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. Results: Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Conclusions: Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS. Author Video: Author Video Watch what authors say about their articles Keywords: Endocannabinoids, PWS, Magel2, Peripheral CB1 blockade, Metabolic syndrome

  20. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    Science.gov (United States)

    Rigamonti, Antonello E.; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G.; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Background Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity. PMID:26546790

  1. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults.

    Science.gov (United States)

    Rigamonti, Antonello E; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

  2. Anticipatory and consummatory effects of (hedonic chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    Directory of Open Access Journals (Sweden)

    Antonello E. Rigamonti

    2015-11-01

    Full Text Available Background: Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods: To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1, peptide YY (PYY, anandamide (AEA, 2-AG, palmitoylethanolamide (PEA, and oleoylethanolamide (OEA in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results: The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions: When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

  3. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    Science.gov (United States)

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

  4. Endocannabinoids and cardiovascular prevention: real progress?

    Directory of Open Access Journals (Sweden)

    Livio Dei Cas

    2009-08-01

    Full Text Available ABSTRACT: The prevalence of obesity continues to increase and represents one of the principal causes of cardiovascular morbidity and mortality. After the discovery of a specific receptor of the psychoactive principle of marijuana, the cannabinoid receptors and their endogenous ligands, several studies have demonstrated the role of this system in the control of food intake and energy balance and its overactivity in obesity. Recent studies with the CB1 receptor antagonist rimonabant have demonstrated favorable effects such as a reduction in body weight and waist circumference and an improvement in metabolic factors (cholesterol, triglycerides, glycemia etc. Therefore, the antagonism of the endocannabinoid (EC system, if recent data can be confirmed, could be a new treatment target for high risk overweight or obese patients. Obesity is a growing problem that has epidemic proportions worldwide and is associated with an increased risk of premature death (1-3. Individuals with a central deposition of fats have elevated cardiovascular morbidity and mortality (including stroke, heart failure and myocardial infarction and, because of a growing prevalence not only in adults but also in adolescents, it was reclassified in AHA guidelines as a “major modifiable risk factor” for coronary heart disease (4, 5. Although first choice therapy in obesity is based on correcting lifestyle (diet and physical activity in patients with abdominal obesity and high cardiovascular risk and diabetes, often it is necessary to use drugs which reduce the risks. The EC system represents a new target for weight control and the improvement of lipid and glycemic metabolism (6, 7. (Heart International 2007; 3: 27-34

  5. State-dependent, bidirectional modulation of neural network activity by endocannabinoids.

    Science.gov (United States)

    Piet, Richard; Garenne, André; Farrugia, Fanny; Le Masson, Gwendal; Marsicano, Giovanni; Chavis, Pascale; Manzoni, Olivier J

    2011-11-16

    The endocannabinoid (eCB) system and the cannabinoid CB1 receptor (CB1R) play key roles in the modulation of brain functions. Although actions of eCBs and CB1Rs are well described at the synaptic level, little is known of their modulation of neural activity at the network level. Using microelectrode arrays, we have examined the role of CB1R activation in the modulation of the electrical activity of rat and mice cortical neural networks in vitro. We find that exogenous activation of CB1Rs expressed on glutamatergic neurons decreases the spontaneous activity of cortical neural networks. Moreover, we observe that the net effect of the CB1R antagonist AM251 inversely correlates with the initial level of activity in the network: blocking CB1Rs increases network activity when basal network activity is low, whereas it depresses spontaneous activity when its initial level is high. Our results reveal a complex role of CB1Rs in shaping spontaneous network activity, and suggest that the outcome of endogenous neuromodulation on network function might be state dependent.

  6. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

    OpenAIRE

    Siniscalco, Dario; Bradstreet, James Jeffrey; Cirillo, Alessandra; Antonucci, Nicola

    2014-01-01

    Background Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor...

  7. Effects of Adolescent Intermittent Alcohol Exposure on the Expression of Endocannabinoid Signaling-Related Proteins in the Spleen of Young Adult Rats

    Science.gov (United States)

    Vázquez, Mariam; Sánchez, Laura; Rivera, Patricia; Gavito, Ana; Mela, Virginia; Alén, Francisco; Decara, Juan; Suárez, Juan; Giné, Elena; López-Moreno, José Antonio; Chowen, Julie; Rodríguez-de-Fonseca, Fernando; Serrano, Antonia; Viveros, María Paz

    2016-01-01

    Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS), which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID) procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v) in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif) ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in young adult rats

  8. Effects of Adolescent Intermittent Alcohol Exposure on the Expression of Endocannabinoid Signaling-Related Proteins in the Spleen of Young Adult Rats.

    Directory of Open Access Journals (Sweden)

    Francisco Javier Pavón

    Full Text Available Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS, which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in

  9. Levels of oxylipins, endocannabinoids and related lipids in plasma before and after low-level exposure to acrolein in healthy individuals and individuals with chemical intolerance.

    Science.gov (United States)

    Claeson, Anna-Sara; Gouveia-Figueira, Sandra; Häggström, Jenny; Fowler, Christopher J; Nording, Malin L

    2017-06-01

    Oxylipins and endocannabinoids play important biological roles, including effects upon inflammation. It is not known whether the circulating levels of these lipids are affected by inhalation of the environmental pollutant acrolein. In the present study, we have investigated the consequences of low-level exposure to acrolein on oxylipin, endocannabinoid and related lipid levels in the plasma of healthy individuals and individuals with chemical intolerance (CI), an affliction with a suggested inflammatory origin. Participants were exposed twice (60min) to heptane and a mixture of heptane and acrolein. Blood samples were collected before exposure, after and 24h post-exposure. There were no overt effects of acrolein exposure on the oxylipin lipidome or endocannibinoids detectable in the bloodstream at the time points investigated. No relationship between basal levels or levels after exposure to acrolein and CI could be identified. This implicates a minor role of inflammatory mediators on the systemic level in CI. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Enhancing Web Service Selection by User Preferences of Non-Functional Features

    OpenAIRE

    Badr , Youakim; Abraham , Ajith; Biennier , Frédérique; Grosan , Crina

    2008-01-01

    International audience; Selection of an appropriate Web service for a particular task has become a difficult challenge due to the increasing number of Web services offering similar functionalities. The functional properties describe what the service can do and the nonfunctional properties depict how the service can do it. Non-functional properties involving qualitative or quantitative features have become essential criteria to enhance the selection process of services making the selection pro...

  11. Trust-Enhanced Cloud Service Selection Model Based on QoS Analysis.

    Science.gov (United States)

    Pan, Yuchen; Ding, Shuai; Fan, Wenjuan; Li, Jing; Yang, Shanlin

    2015-01-01

    Cloud computing technology plays a very important role in many areas, such as in the construction and development of the smart city. Meanwhile, numerous cloud services appear on the cloud-based platform. Therefore how to how to select trustworthy cloud services remains a significant problem in such platforms, and extensively investigated owing to the ever-growing needs of users. However, trust relationship in social network has not been taken into account in existing methods of cloud service selection and recommendation. In this paper, we propose a cloud service selection model based on the trust-enhanced similarity. Firstly, the direct, indirect, and hybrid trust degrees are measured based on the interaction frequencies among users. Secondly, we estimate the overall similarity by combining the experience usability measured based on Jaccard's Coefficient and the numerical distance computed by Pearson Correlation Coefficient. Then through using the trust degree to modify the basic similarity, we obtain a trust-enhanced similarity. Finally, we utilize the trust-enhanced similarity to find similar trusted neighbors and predict the missing QoS values as the basis of cloud service selection and recommendation. The experimental results show that our approach is able to obtain optimal results via adjusting parameters and exhibits high effectiveness. The cloud services ranking by our model also have better QoS properties than other methods in the comparison experiments.

  12. Selective recognition of Pr3+ based on fluorescence enhancement sensor

    International Nuclear Information System (INIS)

    Ganjali, M.R.; Hosseini, M.; Ghafarloo, A.; Khoobi, M.; Faridbod, F.; Shafiee, A.; Norouzi, P.

    2013-01-01

    (E)-2-(1-(4-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene) hydrazinecarbothioamide (L) has been used to detect trace amounts of praseodymium ion in acetonitrile–water solution (MeCN/H 2 O) by fluorescence spectroscopy. The fluorescent probe undergoes fluorescent emission intensity enhancement upon binding to Pr 3+ ions in MeCN/H 2 O (9/1:v/v) solution. The fluorescence enhancement of L is attributed to a 1:1 complex formation between L and Pr 3+ , which has been utilized as the basis for selective detection of Pr 3+ . The sensor can be applied to the quantification of praseodymium ion with a linear range of 1.6 × 10 −7 to 1.0 × 10 −5 M. The limit of detection was 8.3 × 10 −8 M. The sensor exhibits high selectivity toward praseodymium ions in comparison with common metal ions. The proposed fluorescent sensor was successfully used for determination of Pr 3+ in water samples. - Highlights: • A new fluorescent sensor is introduced as a selective probe for Pr 3+ detection. • Fluorescent intensity of the chemical probe enhances upon binding to Pr 3+ ion. • The sensor can be used for Pr 3+ determination in the range of 1.6 × 10 −7 –1.0 × 10 −5 M

  13. Selectivity/Specificity Improvement Strategies in Surface-Enhanced Raman Spectroscopy Analysis

    Directory of Open Access Journals (Sweden)

    Feng Wang

    2017-11-01

    Full Text Available Surface-enhanced Raman spectroscopy (SERS is a powerful technique for the discrimination, identification, and potential quantification of certain compounds/organisms. However, its real application is challenging due to the multiple interference from the complicated detection matrix. Therefore, selective/specific detection is crucial for the real application of SERS technique. We summarize in this review five selective/specific detection techniques (chemical reaction, antibody, aptamer, molecularly imprinted polymers and microfluidics, which can be applied for the rapid and reliable selective/specific detection when coupled with SERS technique.

  14. Adrenergic beta 2-selective blocker in isoprenaline-enhanced essential tremor.

    Science.gov (United States)

    Teräväinen, H; Huttunen, J

    1987-01-01

    A beta 2-selective adrenergic-receptor-blocking drug, ICI 118.551, 150 mg/day, prevented almost as effectively as the nonselective antagonist propranolol, 240 mg/day, the isoprenaline enhancement of essential tremor amplitude.

  15. Nutritional status-dependent endocannabinoid signalling regulates the integration of rat visceral information.

    Science.gov (United States)

    Khlaifia, Abdessattar; Matias, Isabelle; Cota, Daniela; Tell, Fabien

    2017-06-01

    Vagal sensory inputs transmit information from the viscera to brainstem neurones located in the nucleus tractus solitarii to set physiological parameters. These excitatory synapses exhibit a CB1 endocannabinoid-induced long-term depression (LTD) triggered by vagal fibre stimulation. We investigated the impact of nutritional status on long-term changes in this long-term synaptic plasticity. Food deprivation prevents LTD induction by disrupting CB1 receptor signalling. Short-term refeeding restores the capacity of vagal synapses to express LTD. Ghrelin and cholecystokinin, respectively released during fasting and refeeding, play a key role in the control of LTD via the activation of energy sensing pathways such as AMPK and the mTOR and ERK pathways. Communication form the viscera to the brain is essential to set physiological homoeostatic parameters but also to drive more complex behaviours such as mood, memory and emotional states. Here we investigated the impact of the nutritional status on long-term changes in excitatory synaptic transmission in the nucleus tractus solitarii, a neural hub integrating visceral signals. These excitatory synapses exhibit a CB1 endocannabinoid (eCB)-induced long-term depression (LTD) triggered by vagal fibre stimulation. Since eCB signalling is known to be an important component of homoeostatic regulation of the body and is regulated during various stressful conditions, we tested the hypothesis that food deprivation alters eCB signalling in central visceral afferent fibres. Food deprivation prevents eCB-LTD induction due to the absence of eCB signalling. This loss was reversed by blockade of ghrelin receptors. Activation of the cellular fuel sensor AMP-activated protein kinase or inhibition of the mechanistic target of rapamycin pathway abolished eCB-LTD in free-fed rats. Signals associated with energy surfeit, such as short-term refeeding, restore eCB-LTD induction, which in turn requires activation of cholecystokinin receptors and

  16. Bifunctionalized Intrinsically Microporous Polyimides with Simultaneously Enhanced Gas Permeability and Selectivity

    KAUST Repository

    Ma, Xiaohua; Mukaddam, Mohsin Ahmed; Pinnau, Ingo

    2016-01-01

    Two novel intrinsically microporous copolyimides synthesized by condensation reaction of 4,4′-(hexafluoroisopropylidene) diphthalic anhydride (6FDA), 3,3,3′,3′-tetramethyl-1,1′-spirobisindane-5,5′-diamino-6,6′-diol, and 3,5-diaminobenzoic acid with diamine ratios of 80/20 (Co-80/20) and 50/50 (Co-50/50) are reported. Unexpectedly, the Co-80/20 not only demonstrates higher microporosity (300 m2 g−1) than the PIM-6FDA-OH homopolymer (190 m2 g−1) but also exhibits simultaneously enhanced CO2 permeability (from 119 to 171 Barrer) and CO2/CH4 selectivity (from 35 to 41) after thermal annealing at 250 °C. This higher permeability originates from enhanced diffusivity (D CO2) and the higher selectivity results from its increased diffusion selectivity (D CO2/D CH4). After crosslinking at 300 °C, the Co-80/20 exhibits an even higher CO2 permeability (261 Barrer) and almost unchanged CO2/CH4 selectivity.

  17. Bifunctionalized Intrinsically Microporous Polyimides with Simultaneously Enhanced Gas Permeability and Selectivity

    KAUST Repository

    Ma, Xiaohua

    2016-03-29

    Two novel intrinsically microporous copolyimides synthesized by condensation reaction of 4,4′-(hexafluoroisopropylidene) diphthalic anhydride (6FDA), 3,3,3′,3′-tetramethyl-1,1′-spirobisindane-5,5′-diamino-6,6′-diol, and 3,5-diaminobenzoic acid with diamine ratios of 80/20 (Co-80/20) and 50/50 (Co-50/50) are reported. Unexpectedly, the Co-80/20 not only demonstrates higher microporosity (300 m2 g−1) than the PIM-6FDA-OH homopolymer (190 m2 g−1) but also exhibits simultaneously enhanced CO2 permeability (from 119 to 171 Barrer) and CO2/CH4 selectivity (from 35 to 41) after thermal annealing at 250 °C. This higher permeability originates from enhanced diffusivity (D CO2) and the higher selectivity results from its increased diffusion selectivity (D CO2/D CH4). After crosslinking at 300 °C, the Co-80/20 exhibits an even higher CO2 permeability (261 Barrer) and almost unchanged CO2/CH4 selectivity.

  18. Selecting enhancing solutions for electrokinetic remediation of dredged sediments polluted with fuel.

    Science.gov (United States)

    Rozas, F; Castellote, M

    2015-03-15

    In this paper a procedure for selecting the enhancing solutions in electrokinetic remediation experiments is proposed. For this purpose, dredged marine sediment was contaminated with fuel, and a total of 22 different experimental conditions were tested, analysing the influence of different enhancing solutions by using three commercial non-ionic surfactants, one bio-surfactant, one chelating agent, and one weak acid. Characterisation, microelectrophoretic and electrokinetic remediation trials were carried out. The results are explained on the basis of the interactions between the fuel, the enhancing electrolytes and the matrix. For one specific system, the electrophoretic zeta potential, (ζ), of the contaminated matrix in the solution was found to be related to the electroosmotic averaged ζ in the experiment and not to the efficiency in the extraction. This later was correlated to a parameter accounting for both contributions, the contaminant and the enhancing solution, calculated on the basis of differences in the electrophoretic ζ in different conditions which has allowed to propose a methodology for selection of enhancing solutions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Automatic method for selective enhancement of different tissue densities at digital chest radiography

    International Nuclear Information System (INIS)

    McNitt-Gray, M.F.; Taira, R.K.; Eldredge, S.L.; Razavi, M.

    1991-01-01

    This paper reports that digital chest radiographs often are too bright and/or lack contrast when viewed on a video display. The authors have developed a method that can automatically provide a series of look-up tables that selectively enhance the radiographically soft or dense tissues on a digital chest radiograph. This reduces viewer interaction and improves displayed image quality. On the basis of a histogram analysis, gray-level ranges are approximated for the patient background, radiographically soft tissues, and radiographically dense tissues. A series of look-up tables is automatically created by varying the contrast in each range to achieve a level of enhancement for a selected tissue range. This is repeated for differing amounts of enhancement and for each tissue range. This allows the viewer to interactively select a tissue density range and degree of enhancement at the time of display via precalculated look-up tables. Preclinical trials in pediatric radiology using computed radiography images show that this method reduces viewer interaction and improves or maintains the displayed image quality

  20. Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB₁ receptors: implications for schizophrenia.

    Science.gov (United States)

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-08-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

  1. Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling

    Directory of Open Access Journals (Sweden)

    Balapal S. Basavarajappa

    2015-10-01

    Full Text Available One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS, which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD. Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD.

  2. Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids.

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    Gonzalo E Yévenes

    Full Text Available Glycine receptors (GlyRs are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA are positive modulators of α(1, α(2 and α(3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly potentiate α(1 GlyRs but inhibit α(2 and α(3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM region 2 and intracellular lysine 385 determine the positive modulation of α(1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α(2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α(1 GlyRs, without affecting inhibition of α(2 and α(3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain.

  3. Selective enhancement of orientation tuning before saccades.

    Science.gov (United States)

    Ohl, Sven; Kuper, Clara; Rolfs, Martin

    2017-11-01

    Saccadic eye movements cause a rapid sweep of the visual image across the retina and bring the saccade's target into high-acuity foveal vision. Even before saccade onset, visual processing is selectively prioritized at the saccade target. To determine how this presaccadic attention shift exerts its influence on visual selection, we compare the dynamics of perceptual tuning curves before movement onset at the saccade target and in the opposite hemifield. Participants monitored a 30-Hz sequence of randomly oriented gratings for a target orientation. Combining a reverse correlation technique previously used to study orientation tuning in neurons and general additive mixed modeling, we found that perceptual reports were tuned to the target orientation. The gain of orientation tuning increased markedly within the last 100 ms before saccade onset. In addition, we observed finer orientation tuning right before saccade onset. This increase in gain and tuning occurred at the saccade target location and was not observed at the incongruent location in the opposite hemifield. The present findings suggest, therefore, that presaccadic attention exerts its influence on vision in a spatially and feature-selective manner, enhancing performance and sharpening feature tuning at the future gaze location before the eyes start moving.

  4. Potential role of the endocannabinoid receptor antagonist rimonabant in the management of cardiometabolic risk: a narrative review of available data

    Directory of Open Access Journals (Sweden)

    Kirk A Bronander

    2007-05-01

    Full Text Available Kirk A Bronander1, Michael J Bloch21Division of General Internal Medicine, 2Divisions of Cardiology and General Internal Medicine, Department of Medicine, University of Nevada School of Medicine, Reno, NV, USAAbstract: The endocannabinoid system (ECS is an endogenous physiological system composed of two cannabinoid receptors and several endogenous ligands. The ECS is intimately involved in appetite regulation and energy homeostasis, which makes it an intriguing target for pharmacological treatment of obesity, diabetes, and the metabolic syndrome. Rimonabant is the first cannabinoid receptor (CB-1 antagonist being studied and utilized to treat obesity (it is approved in Europe but is currently under review in the United States. Large randomized trials with rimonabant have demonstrated efficacy in treatment of overweight and obese individuals with weight loss significantly greater than a reduced calorie diet alone. In addition, multiple other cardiometabolic parameters were improved in the treatment groups including increased levels of high density lipoprotein cholesterol, reduced triglycerides, reduced waist circumference, improved insulin sensitivity, decreased insulin levels, and in diabetic patients improvement in glycosylated hemoglobin percentage. There was an increase in the adverse effects of depression, anxiety, irritability, and nausea in rimonabant-treated groups. This novel medication may become an important therapeutic option in the fight to reduce cardiovascular disease worldwide through its unique action on cardiometabolic risk.Keywords: rimonabant, endocannabinoid, metabolic syndrome, obesity

  5. Antidepressants and changes in concentration of endocannabinoids and N-acylethanolamines in rat brain structures.

    Science.gov (United States)

    Smaga, Irena; Bystrowska, Beata; Gawliński, Dawid; Pomierny, Bartosz; Stankowicz, Piotr; Filip, Małgorzata

    2014-08-01

    The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery.

  6. Elevated Levels of Endocannabinoids in Chronic Hepatitis C May Modulate Cellular Immune Response and Hepatic Stellate Cell Activation

    Directory of Open Access Journals (Sweden)

    Eleonora Patsenker

    2015-03-01

    Full Text Available The endocannabinoid (EC system is implicated in many chronic liver diseases, including hepatitis C viral (HCV infection. Cannabis consumption is associated with fibrosis progression in patients with chronic hepatitis C (CHC, however, the role of ECs in the development of CHC has never been explored. To study this question, anandamide (AEA and 2-arachidonoyl glycerol (2-AG were quantified in samples of HCV patients and healthy controls by gas and liquid chromatography mass spectrometry. Fatty acid amide hydrolase (FAAH and monoaclyglycerol lipase (MAGL activity was assessed by [3H]AEA and [3H]2-AG hydrolysis, respectively. Gene expression and cytokine release were assayed by TaqMan PCR and ELISpot, respectively. AEA and 2-AG levels were increased in plasma of HCV patients, but not in liver tissues. Hepatic FAAH and MAGL activity was not changed. In peripheral blood mononuclear cells (PBMC, ECs inhibited IFN-γ, TNF-α, and IL-2 secretion. Inhibition of IL-2 by endogenous AEA was stronger in PBMC from HCV patients. In hepatocytes, 2-AG induced the expression of IL-6, -17A, -32 and COX-2, and enhanced activation of hepatic stellate cells (HSC co-cultivated with PBMC from subjects with CHC. In conclusion, ECs are increased in plasma of patients with CHC and might reveal immunosuppressive and profibrogenic effects.

  7. Exploração farmacológica do sistema endocanabinoide: novas perspectivas para o tratamento de transtornos de ansiedade e depressão? Pharmacological exploitation of the endocannabinoid system: new perspectives for the treatment of depression and anxiety disorders?

    Directory of Open Access Journals (Sweden)

    Viviane M. Saito

    2010-05-01

    Full Text Available OBJETIVO: Este artigo revisa o sistema endocanabinoide e as respectivas estratégias de intervenções farmacológicas. MÉTODO: Realizou-se uma revisão da literatura sobre o sistema endocanabinoide e a sua farmacologia, considerando-se artigos originais ou de revisão escritos em inglês. DISCUSSÃO: Canabinoides são um grupo de compostos presentes na Cannabis Sativa (maconha, a exemplo do Δ9-tetraidrocanabinol e seus análogos sintéticos. Estudos sobre o seu perfil farmacológico levaram à descoberta do sistema endocanabinoide do cérebro de mamíferos. Este sistema é composto por pelo menos dois receptores acoplados a uma proteína G, CB1 e CB2, pelos seus ligantes endógenos (endocanabinoides; a exemplo da anandamida e do 2-araquidonoil glicerol e pelas enzimas responsáveis por sintetizá-los e metabolizá-los. Os endocanabinoides representam uma classe de mensageiros neurais que são sintetizados sob demanda e liberados de neurônios pós-sinápticos para restringir a liberação de neurotransmissores clássicos de terminais pré-sinápticos. Esta sinalização retrógrada modula uma diversidade de funções cerebrais, incluindo ansiedade, medo e humor, em que a ativação de receptores CB1 pode exercer efeitos dos tipos ansiolítico e antidepressivo em estudos préclínicos. CONCLUSÃO: Experimentos com modelos animais sugerem que drogas que facilitam a ação dos endocanabinoides podem representar uma nova estratégia para o tratamento de transtornos de ansiedade e depressão.OBJECTIVE: The present review provides a brief introduction into the endocannabinoid system and discusses main strategies of pharmacological interventions. METHOD: We have reviewed the literature relating to the endocannabinoid system and its pharmacology; both original and review articles written in English were considered. DISCUSSION: Cannabinoids are a group of compounds present in Cannabis Sativa (hemp, such as Δ9-tetrahydrocannabinol, and their synthetic

  8. Effects of mood inductions by meal ambiance and moderate alcohol consumption on endocannabinoids and N-acylethanolamines in humans: a randomized crossover trial.

    Directory of Open Access Journals (Sweden)

    Ilse C Schrieks

    Full Text Available The endocannabinoid system is suggested to play a regulatory role in mood. However, the response of circulating endocannabinoids (ECs to mood changes has never been tested in humans. In the present study, we examined the effects of mood changes induced by ambiance and moderate alcohol consumption on plasma ECs 2-arachidonoylglycerol (2-AG, anandamide (AEA, and some N-acylethanolamine (NAE congeners in humans.Healthy women (n = 28 participated in a randomized cross-over study. They consumed sparkling white wine (340 mL; 30 g alcohol or alcohol-free sparkling white wine (340 mL; <2 g alcohol as part of a standard evening meal in a room with either a pleasant or an unpleasant ambiance.Plasma concentrations of palmitoylethanolamide (PEA and stearoylethanolamide (SEA increased after 30 min in the unpleasant ambiance, while they decreased in the pleasant ambiance. Changes in ECs and their NAE congeners correlated with mood states, such as happiness and fatigue, but in the pleasant ambiance without alcohol only. ECs and their NAE congeners were correlated with serum free fatty acids and cortisol.This is the first human study to demonstrate that plasma NAEs are responsive to an unpleasant meal ambiance. Furthermore, associations between mood states and ECs and their NAE congeners were observed.Clinicaltrials.gov NCT01426022.

  9. Controlling surface adsorption to enhance the selectivity of porphyrin based gas sensors

    Energy Technology Data Exchange (ETDEWEB)

    Evyapan, M., E-mail: mevyapan@gmail.com [Department of Physics, University of Balikesir, Balikesir, 10145 (Turkey); Chemical and Biological Engineering, University of Sheffield, Mappin Building, S1 3JD (United Kingdom); Dunbar, A.D.F. [Chemical and Biological Engineering, University of Sheffield, Mappin Building, S1 3JD (United Kingdom)

    2016-01-30

    Graphical abstract: The enhancement in the selectivity of the vapor sensing properties of free base porphyrin by controlling the size of the pores in the surface structure was carried out. It can be used as a size selective surface layer which limits the diffusion of analyte molecules into the sensor and in extreme cases stopping the diffusion completely. - Highlights: • Surface of a thin film takes and important part for its sensing characteristics. • A systematic surface modification was carried out in order to control the vapor accessibility. • Size dependant surfaces were fabricated. • Vapor diffusion through into thin film was controlled by modifying the surface structure. • Remarkable quantitative results showed the control on selectivity of the sensor by controlling the surface. - Abstract: This study reports an enhancement in the selectivity of the vapor sensing properties of free base porphyrin 5,10,15,20-tetrakis[3,4-bis(2-ethylhexyloxy)phenyl]-21H,23H-porphine (EHO) Langmuir–Schaefer (LS) films. These sensors respond by changing color upon adsorption of the analyte gas to the sensor surface. The enhanced selectivity is achieved by adding selective barrier layers of 4-tert-Butylcalix[4]arene, 4-tert-Butylcalix[6]arene and 4-tert-Butylcalix[8]arene embedded in PMMA (Poly(methyl methacrylate)) on top of the porphyrin sensor films to control the gaseous adsorption onto the sensor surface. The Langmuir properties of EHO, PMMA and calix[n]arene monolayers were investigated by surface pressure–area (Π–A) isotherms in order to determine the most efficient transfer pressure. Six layer EHO films were transferred onto glass and silicon substrates to investigate their optical and structural characteristics. The three different calix[n]arenes were embedded within PMMA layers to act as the selective barrier layers which were deposited on top of the six layer EHO films. The different calix[n]arene molecules vary in size and each was mixed with PMMA in

  10. Differential Regulation of Eicosanoid and Endocannabinoid Production by Inflammatory Mediators in Human Choriodecidua.

    Directory of Open Access Journals (Sweden)

    M D Mitchell

    Full Text Available An increase in intrauterine prostaglandin production is critical for the onset and progression of labor in women and indeed all mammalian species studied. Endocannabinoids can act as substrates for enzymes of the prostaglandin biosynthetic pathways and can be utilized to generate other related compounds such as prostamides. The end products are indistinguishable by radioimmunoassay. We have separated such compounds by mass spectrometry. We now show that inflammatory stimuli such as LPS and proinflammatory cytokines act differentially on these pathways in human choriodecidua and preferentially create drive through to prostaglandin end products. These findings create doubt about the interpretation of data on prostaglandin biosynthesis in intrauterine tissues from pregnant women especially in the presence of an infection. The possibility is raised that separation of these products might reduce variability in results and lead to potential uses for their measurement in the diagnosis of preterm labor.

  11. Copolymers enhance selective bacterial community colonization for potential root zone applications.

    Science.gov (United States)

    Pham, Vy T H; Murugaraj, Pandiyan; Mathes, Falko; Tan, Boon K; Truong, Vi Khanh; Murphy, Daniel V; Mainwaring, David E

    2017-11-21

    Managing the impact of anthropogenic and climate induced stress on plant growth remains a challenge. Here we show that polymeric hydrogels, which maintain their hydrous state, can be designed to exploit functional interactions with soil microorganisms. This microbial enhancement may mitigate biotic and abiotic stresses limiting productivity. The presence of mannan chains within synthetic polyacrylic acid (PAA) enhanced the dynamics and selectivity of bacterial ingress in model microbial systems and soil microcosms. Pseudomonas fluorescens exhibiting high mannan binding adhesins showed higher ingress and localised microcolonies throughout the polymeric network. In contrast, ingress of Bacillus subtilis, lacking adhesins, was unaltered by mannan showing motility comparable to bulk liquids. Incubation within microcosms of an agricultural soil yielded hydrogel populations significantly increased from the corresponding soil. Bacterial diversity was markedly higher in mannan containing hydrogels compared to both control polymer and soil, indicating enhanced selectivity towards microbial families that contain plant beneficial species. Here we propose functional polymers applied to the potential root zone which can positively influence rhizobacteria colonization and potentially plant growth as a new approach to stress tolerance.

  12. Enhanced Plasmonic Wavelength Selective Infrared Emission Combined with Microheater

    Directory of Open Access Journals (Sweden)

    Hiroki Ishihara

    2017-09-01

    Full Text Available The indirect wavelength selective thermal emitter that we have proposed is constructed using a new microheater, demonstrating the enhancement of the emission peak generated by the surface plasmon polariton. The thermal isolation is improved using a 2 μm-thick Si membrane having 3.6 and 5.4 mm outer diameter. The emission at around the wavelength of the absorption band of CO2 gas is enhanced. The absorption signal increases, confirming the suitability for gas sensing. Against input power, the intensity at the peak wavelength shows a steeper increasing ratio than the background intensity. The microheater with higher thermal isolation gives larger peak intensity and its increasing ratio against the input power.

  13. Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

    Science.gov (United States)

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-01-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB1-dependent manner, whereas pharmacological blockade of CB1 receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB1 receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB1-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB1 receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission. PMID:23563893

  14. Enhanced selectivity in mixed matrix membranes for CO2 capture through efficient dispersion of amine-functionalized MOF nanoparticles

    Science.gov (United States)

    Ghalei, Behnam; Sakurai, Kento; Kinoshita, Yosuke; Wakimoto, Kazuki; Isfahani, Ali Pournaghshband; Song, Qilei; Doitomi, Kazuki; Furukawa, Shuhei; Hirao, Hajime; Kusuda, Hiromu; Kitagawa, Susumu; Sivaniah, Easan

    2017-07-01

    Mixed matrix membranes (MMMs) for gas separation applications have enhanced selectivity when compared with the pure polymer matrix, but are commonly reported with low intrinsic permeability, which has major cost implications for implementation of membrane technologies in large-scale carbon capture projects. High-permeability polymers rarely generate sufficient selectivity for energy-efficient CO2 capture. Here we report substantial selectivity enhancements within high-permeability polymers as a result of the efficient dispersion of amine-functionalized, nanosized metal-organic framework (MOF) additives. The enhancement effects under optimal mixing conditions occur with minimal loss in overall permeability. Nanosizing of the MOF enhances its dispersion within the polymer matrix to minimize non-selective microvoid formation around the particles. Amination of such MOFs increases their interaction with thepolymer matrix, resulting in a measured rigidification and enhanced selectivity of the overall composite. The optimal MOF MMM performance was verified in three different polymer systems, and also over pressure and temperature ranges suitable for carbon capture.

  15. Chronic stress and peripheral pain: Evidence for distinct, region-specific changes in visceral and somatosensory pain regulatory pathways.

    Science.gov (United States)

    Zheng, Gen; Hong, Shuangsong; Hayes, John M; Wiley, John W

    2015-11-01

    Chronic stress alters the hypothalamic-pituitary-adrenal (HPA) axis and enhances visceral and somatosensory pain perception. It is unresolved whether chronic stress has distinct effects on visceral and somatosensory pain regulatory pathways. Previous studies reported that stress-induced visceral hyperalgesia is associated with reciprocal alterations of endovanilloid and endocannabinoid pain pathways in DRG neurons innervating the pelvic viscera. In this study, we compared somatosensory and visceral hyperalgesia with respect to differential responses of peripheral pain regulatory pathways in a rat model of chronic, intermittent stress. We found that chronic stress induced reciprocal changes in the endocannabinoid 2-AG (increased) and endocannabinoid degradation enzymes COX-2 and FAAH (decreased), associated with down-regulation of CB1 and up-regulation of TRPV1 receptors in L6-S2 DRG but not L4-L5 DRG neurons. In contrast, sodium channels Nav1.7 and Nav1.8 were up-regulated in L4-L5 but not L6-S2 DRGs in stressed rats, which was reproduced in control DRGs treated with corticosterone in vitro. The reciprocal changes of CB1, TRPV1 and sodium channels were cell-specific and observed in the sub-population of nociceptive neurons. Behavioral assessment showed that visceral hyperalgesia persisted, whereas somatosensory hyperalgesia and enhanced expression of Nav1.7 and Nav1.8 sodium channels in L4-L5 DRGs normalized 3 days after completion of the stress phase. These data indicate that chronic stress induces visceral and somatosensory hyperalgesia that involves differential changes in endovanilloid and endocannabinoid pathways, and sodium channels in DRGs innervating the pelvic viscera and lower extremities. These results suggest that chronic stress-induced visceral and lower extremity somatosensory hyperalgesia can be treated selectively at different levels of the spinal cord. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system.

    Science.gov (United States)

    Seillier, Alexandre; Giuffrida, Andrea

    2016-02-01

    Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a "social" cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an "empty" cage, and spent more time exploring a "novel" cage (i.e. new stimulus rat) versus a "familiar" cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003-0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  17. The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with neuromyelitis optica.

    Directory of Open Access Journals (Sweden)

    Hannah L Pellkofer

    Full Text Available Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO. While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST following the protocol of the German Research Network on Neuropathic Pain (DFNS. Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11 suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG. These data emphasize the high prevalence of neuropathic pain and hyperalgesia

  18. Adverse social experiences in adolescent rats result in enduring effects on social competence, pain sensitivity and endocannabinoid signaling

    Directory of Open Access Journals (Sweden)

    Peggy Schneider

    2016-10-01

    Full Text Available Social affiliation is essential for many species and gains significant importance during adolescence. Disturbances in social affiliation, in particular social rejection experiences during adolescence, affect an individual’s well-being and are involved in the emergence of psychiatric disorders. The underlying mechanisms are still unknown, partly because of a lack of valid animal models. By using a novel animal model for social peer-rejection, which compromises adolescent rats in their ability to appropriately engage in playful activities, here we report on persistent impairments in social behavior and dysregulations in the endocannabinoid system. From postnatal day (pd 21 to pd 50 adolescent female Wistar rats were either reared with same-strain partners (control or within a group of Fischer 344 rats (inadequate social rearing, ISR, previously shown to serve as inadequate play partners for the Wistar strain. Adult ISR animals showed pronounced deficits in social interaction, social memory, processing of socially transmitted information, and decreased pain sensitivity. Molecular analysis revealed increased CB1 receptor protein levels and CP55,940 stimulated 35SGTPγS binding activity specifically in the amygdala and thalamus in previously peer-rejected rats. Along with these changes, increased levels of the endocannabinoid anandamide and a corresponding decrease of its degrading enzyme fatty acid amide hydrolase were seen in the amygdala. Our data indicate lasting consequences in social behavior and pain sensitivity following peer-rejection in adolescent female rats. These behavioral impairments are accompanied by persistent alterations in CB1 receptor signaling. Finally, we provide a novel translational approach to characterize neurobiological processes underlying social peer-rejection in adolescence.

  19. TRPV1 and Endocannabinoids: Emerging Molecular Signals that Modulate Mammalian Vision

    Directory of Open Access Journals (Sweden)

    Daniel A. Ryskamp

    2014-09-01

    Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 subunits form a polymodal cation channel responsive to capsaicin, heat, acidity and endogenous metabolites of polyunsaturated fatty acids. While originally reported to serve as a pain and heat detector in the peripheral nervous system, TRPV1 has been implicated in the modulation of blood flow and osmoregulation but also neurotransmission, postsynaptic neuronal excitability and synaptic plasticity within the central nervous system. In addition to its central role in nociception, evidence is accumulating that TRPV1 contributes to stimulus transduction and/or processing in other sensory modalities, including thermosensation, mechanotransduction and vision. For example, TRPV1, in conjunction with intrinsic cannabinoid signaling, might contribute to retinal ganglion cell (RGC axonal transport and excitability, cytokine release from microglial cells and regulation of retinal vasculature. While excessive TRPV1 activity was proposed to induce RGC excitotoxicity, physiological TRPV1 activity might serve a neuroprotective function within the complex context of retinal endocannabinoid signaling. In this review we evaluate the current evidence for localization and function of TRPV1 channels within the mammalian retina and explore the potential interaction of this intriguing nociceptor with endogenous agonists and modulators.

  20. Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine

    DEFF Research Database (Denmark)

    Artmann, Andreas; Petersen, Gitte; Hellgren, Lars

    2008-01-01

    and docosahexaenoylethanolamide) with similar changes in precursor lipids. The AA-diet and FO-diet had no effect on N-acylethanolamines, endocannabinoids or precursor lipids in brain. All N-acylethanolamines activated PPAR-alpha. In conclusion, short-term feeding of diets resembling human diets (Mediterranean diet high...... (AA)) on tissue levels of 2-arachidonoylglycerol, anandamide, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide, linoleoylethanolamide, eicosapentaenoylethanolamide, docosahexaenoylethanolamide and tissue fatty acid composition. The LA-diet increased linoleoylethanolamide and linoleic...... acid in brain, jejunum and liver. The OA-diet increased brain levels of anandamide and oleoylethanolamide (not 2-arachidonoylglycerol) without changing tissue fatty acid composition. The same diet increased oleoylethanolamide in liver. All five dietary fats decreased oleoylethanolamide in jejunum...

  1. Selective disulfide reduction for labeling and enhancement of Fab antibody fragments.

    Science.gov (United States)

    Kirley, Terence L; Greis, Kenneth D; Norman, Andrew B

    2016-11-25

    Many methods have been developed for chemical labeling and enhancement of the properties of antibodies and their common fragments, including the Fab and F(ab') 2 fragments. Somewhat selective reduction of some antibody disulfide bonds has been previously achieved, yielding antibodies and antibody fragments that can be labeled at defined sites, enhancing their utility and properties. Selective reduction of the two hinge disulfide bonds present in F(ab') 2 fragments using mild reduction has been useful. However, such reduction is often not quantitative and results in the reduction of multiple disulfide bonds, and therefore subsequent multiple labeling or conjugation sites are neither homogenous nor stoichiometric. Here, a simple and efficient selective reduction of the single disulfide bond linking the partial heavy chain and the intact light chain which compose the Fab fragment is accomplished utilizing tris(2-carboxyethyl)phosphine (TCEP) immobilized on agarose beads. The resultant reduced cysteine residues were labeled with several cysteine-selective fluorescent reagents, as well as by cysteine-directed PEGylation. These two cysteine residues can also be re-ligated by means of a bifunctional cysteine cross-linking agent, dibromobimane, thereby both restoring a covalent linkage between the heavy and light chains at this site, far removed from the antigen binding site, and also introducing a fluorescent probe. There are many other research and clinical uses for these selectively partially reduced Fab fragments, including biotinylation, toxin and drug conjugation, and incorporation of radioisotopes, and this technique enables simple generation of very useful Fab fragment derivatives with many potential applications. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Enhancing Auditory Selective Attention Using a Visually Guided Hearing Aid

    Science.gov (United States)

    2017-01-01

    Purpose Listeners with hearing loss, as well as many listeners with clinically normal hearing, often experience great difficulty segregating talkers in a multiple-talker sound field and selectively attending to the desired “target” talker while ignoring the speech from unwanted “masker” talkers and other sources of sound. This listening situation forms the classic “cocktail party problem” described by Cherry (1953) that has received a great deal of study over the past few decades. In this article, a new approach to improving sound source segregation and enhancing auditory selective attention is described. The conceptual design, current implementation, and results obtained to date are reviewed and discussed in this article. Method This approach, embodied in a prototype “visually guided hearing aid” (VGHA) currently used for research, employs acoustic beamforming steered by eye gaze as a means for improving the ability of listeners to segregate and attend to one sound source in the presence of competing sound sources. Results The results from several studies demonstrate that listeners with normal hearing are able to use an attention-based “spatial filter” operating primarily on binaural cues to selectively attend to one source among competing spatially distributed sources. Furthermore, listeners with sensorineural hearing loss generally are less able to use this spatial filter as effectively as are listeners with normal hearing especially in conditions high in “informational masking.” The VGHA enhances auditory spatial attention for speech-on-speech masking and improves signal-to-noise ratio for conditions high in “energetic masking.” Visual steering of the beamformer supports the coordinated actions of vision and audition in selective attention and facilitates following sound source transitions in complex listening situations. Conclusions Both listeners with normal hearing and with sensorineural hearing loss may benefit from the acoustic

  3. Selective disulfide reduction for labeling and enhancement of Fab antibody fragments

    International Nuclear Information System (INIS)

    Kirley, Terence L.; Greis, Kenneth D.; Norman, Andrew B.

    2016-01-01

    Many methods have been developed for chemical labeling and enhancement of the properties of antibodies and their common fragments, including the Fab and F(ab’) 2 fragments. Somewhat selective reduction of some antibody disulfide bonds has been previously achieved, yielding antibodies and antibody fragments that can be labeled at defined sites, enhancing their utility and properties. Selective reduction of the two hinge disulfide bonds present in F(ab’) 2 fragments using mild reduction has been useful. However, such reduction is often not quantitative and results in the reduction of multiple disulfide bonds, and therefore subsequent multiple labeling or conjugation sites are neither homogenous nor stoichiometric. Here, a simple and efficient selective reduction of the single disulfide bond linking the partial heavy chain and the intact light chain which compose the Fab fragment is accomplished utilizing tris(2-carboxyethyl)phosphine (TCEP) immobilized on agarose beads. The resultant reduced cysteine residues were labeled with several cysteine-selective fluorescent reagents, as well as by cysteine-directed PEGylation. These two cysteine residues can also be re-ligated by means of a bifunctional cysteine cross-linking agent, dibromobimane, thereby both restoring a covalent linkage between the heavy and light chains at this site, far removed from the antigen binding site, and also introducing a fluorescent probe. There are many other research and clinical uses for these selectively partially reduced Fab fragments, including biotinylation, toxin and drug conjugation, and incorporation of radioisotopes, and this technique enables simple generation of very useful Fab fragment derivatives with many potential applications. - Highlights: • TCEP agarose is effective for selective reduction of a single Fab disulfide bond. • This disulfide is solvent accessible and distant from the antigen binding site. • A variety of buffers of varying pHs can be used, simplifying

  4. Directional enhancement of selected high-order-harmonics from intense laser irradiated blazed grating targets.

    Science.gov (United States)

    Zhang, Guobo; Chen, Min; Liu, Feng; Yuan, Xiaohui; Weng, Suming; Zheng, Jun; Ma, Yanyun; Shao, Fuqiu; Sheng, Zhengming; Zhang, Jie

    2017-10-02

    Relativistically intense laser solid target interaction has been proved to be a promising way to generate high-order harmonics, which can be used to diagnose ultrafast phenomena. However, their emission direction and spectra still lack tunability. Based upon two-dimensional particle-in-cell simulations, we show that directional enhancement of selected high-order-harmonics can be realized using blazed grating targets. Such targets can select harmonics with frequencies being integer times of the grating frequency. Meanwhile, the radiation intensity and emission area of the harmonics are increased. The emission direction is controlled by tailoring the local blazed structure. Theoretical and electron dynamics analysis for harmonics generation, selection and directional enhancement from the interaction between multi-cycle laser and grating target are carried out. These studies will benefit the generation and application of laser plasma-based high order harmonics.

  5. Social exclusion impairs distractor suppression but not target enhancement in selective attention.

    Science.gov (United States)

    Xu, Mengsi; Li, Zhiai; Diao, Liuting; Fan, Lingxia; Zhang, Lijie; Yuan, Shuge; Yang, Dong

    2017-11-01

    Social exclusion has been thought to weaken one's ability to exert inhibitory control. Existing studies have primarily focused on the relationship between exclusion and behavioral inhibition, and have reported that exclusion impairs behavioral inhibition. However, whether exclusion also affects selective attention, another important aspect of inhibitory control, remains unknown. Therefore, the current study aimed to explore whether social exclusion impairs selective attention, and to specifically examine its effect on two hypothesized mechanisms of selective attention: target enhancement and distractor suppression. The Cyberball game was used to manipulate social exclusion. Participants then performed a visual search task while event-related potentials were recorded. In the visual search task, target and salient distractor were either both presented laterally or one was presented on the vertical midline and the other laterally. Results showed that social exclusion differentially affected target and distractor processing. While exclusion impaired distractor suppression, reflected as smaller distractor-positivity (Pd) amplitudes for the exclusion group compared to the inclusion group, it did not affect target enhancement, reflected as similar target-negativity (Nt) amplitudes for both the exclusion and inclusion groups. Together, these results extend our understanding of the relationship between exclusion and inhibitory control, and suggest that social exclusion affects selective attention in a more complex manner than previously thought. Copyright © 2017. Published by Elsevier B.V.

  6. The activity of the endocannabinoid metabolising enzyme fatty acid amide hydrolase in subcutaneous adipocytes correlates with BMI in metabolically healthy humans

    Directory of Open Access Journals (Sweden)

    Alexander Stephen PH

    2011-08-01

    Full Text Available Abstract Background The endocannabinoid system (ECS is a ubiquitously expressed signalling system, with involvement in lipid metabolism and obesity. There are reported changes in obesity of blood concentrations of the endocannabinoids anandamide (AEA and 2-arachidonoylglcyerol (2-AG, and of adipose tissue expression levels of the two key catabolic enzymes of the ECS, fatty acid amide hydrolase (FAAH and monoacylglycerol lipase (MGL. Surprisingly, however, the activities of these enzymes have not been assayed in conditions of increasing adiposity. The aim of the current study was to investigate whether FAAH and MGL activities in human subcutaneous adipocytes are affected by body mass index (BMI, or other markers of adiposity and metabolism. Methods Subcutaneous abdominal mature adipocytes, fasting blood samples and anthropometric measurements were obtained from 28 metabolically healthy subjects representing a range of BMIs. FAAH and MGL activities were assayed in mature adipocytes using radiolabelled substrates. Serum glucose, insulin and adipokines were determined using ELISAs. Results MGL activity showed no relationship with BMI or other adiposity indices, metabolic markers (fasting serum insulin or glucose or serum adipokine levels (adiponectin, leptin or resistin. In contrast, FAAH activity in subcutaneous adipocytes correlated positively with BMI and waist circumference, but not with skinfold thickness, metabolic markers or serum adipokine levels. Conclusions In this study, novel evidence is provided that FAAH activity in subcutaneous mature adipocytes increases with BMI, whereas MGL activity does not. These findings support the hypothesis that some components of the ECS are upregulated with increasing adiposity in humans, and that AEA and 2-AG may be regulated differently.

  7. Effect of biliary cirrhosis on nonadrenergic noncholinergic-mediated relaxation of rat corpus cavernosum: Role of nitric oxide pathway and endocannabinoid system

    Directory of Open Access Journals (Sweden)

    Dehpour A.R.

    2008-06-01

    Full Text Available Background: Relaxation of the corpus cavernosum plays a major role in penile erection. Nitric oxide (NO is known to be the most important factor mediating relaxation of corpus cavernosum, which is mainly derived from nonadrenergic noncholinergic (NANC nerves. The aim of the present study was to investigate the effect of biliary cirrhosis on nonadrenergic noncholinergic (NANC-mediated relaxation of rat corpus cavernosum as well as the possible relevant roles of endocannabinoid and nitric oxide systems.Methods: Corporal strips from sham-operated and biliary cirrhotic rats were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 µM and atropine (1 µM to induce adrenergic and cholinergic blockade. The strips were precontracted with phenylephrine hydrochloride (7.5 µM and electrical field stimulation was applied at different frequencies (2, 5, 10, 15 Hz to obtain NANC-mediated relaxation. In separate precontracted strips of the sham and cirrhotic groups, the concentration-dependent relaxant responses to sodium nitroprusside (10 nM-1mM, as an NO donor, were assessed.  Results: The NANC-mediated relaxation was significantly enhanced in cirrhotic animals (P<0.01. Anandamide potentiated the relaxations in both groups (P<0.05. The cannabinoid CB1 receptor antagonist AM251 (10 µM and the vanilloid receptor antagonist capsazepine (10 µM each significantly prevented the enhanced relaxations in cirrhotic rats (P<0.01. The CB2 receptor antagonist AM630 had no effect on relaxations in the cirrhotic group. In a concentration-dependent manner, L-NAME (30-1000 nM inhibited relaxations in both the sham and cirrhotic groups, although cirrhotic groups were more resistant to the inhibitory effects of L-NAME. The degree of relaxation induced by sodium nitroprusside (10 nM-1 mM was similar in the two groups.Conclusions: Biliary cirrhosis enhances the neurogenic relaxation in rat corpus cavernosum probably via the NO pathway and

  8. Fruit-Enhanced Resistance to Microbial Infection Induced by Selective Laser Excitation

    Directory of Open Access Journals (Sweden)

    Alicia G. Gonzálvez

    2013-01-01

    Full Text Available Table grapes were irradiated with laser pulses at two different wavelengths: one selected at 302.1 nm, that is, resonant with the transresveratrol biphoton absorption band, and another selected at 300 nm, that is a nonresonant wavelength where trans-resveratrol two-photon absorption is negligible. Attenuated total reflectance Fourier transformed infrared spectroscopic analyses of the irradiated grapes' skin showed an enhancement of polyphenols' content when the resonant wavelength was employed. Furthermore, microbiological analysis performed with nontreated (control, nonresonant, and resonantly irradiated grapes demonstrated how the last samples developed a significantly lower number of colony forming units. Since the only difference between the two (resonant and nonresonant irradiation conditions was just a couple of nanometres in the employed UV-B laser wavelengths, the germicidal effect should be considered very similar. As a result, the observed difference in the table grape resistance to microbial infection was attributed to a wavelength-dependent-induced photochemistry. Finally, the potentiality of this method to enhance the postharvest health status of table grapes is remarked.

  9. Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats.

    Science.gov (United States)

    Manduca, Antonia; Morena, Maria; Campolongo, Patrizia; Servadio, Michela; Palmery, Maura; Trabace, Luigia; Hill, Matthew N; Vanderschuren, Louk J M J; Cuomo, Vincenzo; Trezza, Viviana

    2015-08-01

    To date, our understanding of the relative contribution and potential overlapping roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of brain function and behavior is still limited. To address this issue, we investigated the effects of systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and adult rats. JZL195, administered at the dose of 0.01mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals. At both ages, these behavioral effects were antagonized by the CB1 cannabinoid receptor antagonist SR141716A and were associated with increased brain levels of 2-AG, but not AEA. Conversely, at the dose of 1mg/kg, JZL195 decreased general social exploration in adolescent rats without affecting social play behavior, and induced anxiogenic-like effects in the elevated plus-maze test both in adolescent and adult animals. These effects, mediated by activation of CB1 cannabinoid receptors, were paralleled by simultaneous increase in AEA and 2-AG levels in adolescent rats, and by an increase of only 2-AG levels in adult animals. These findings provide the first evidence for a role of 2-AG in social behavior, highlight the different contributions of AEA and 2-AG in the modulation of emotionality at different developmental ages and suggest that pharmacological inhibition of AEA and 2-AG hydrolysis is a useful approach to investigate the role of these endocannabinoids in neurobehavioral processes. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  10. Cholinergic enhancement reduces functional connectivity and BOLD variability in visual extrastriate cortex during selective attention.

    Science.gov (United States)

    Ricciardi, Emiliano; Handjaras, Giacomo; Bernardi, Giulio; Pietrini, Pietro; Furey, Maura L

    2013-01-01

    Enhancing cholinergic function improves performance on various cognitive tasks and alters neural responses in task specific brain regions. We have hypothesized that the changes in neural activity observed during increased cholinergic function reflect an increase in neural efficiency that leads to improved task performance. The current study tested this hypothesis by assessing neural efficiency based on cholinergically-mediated effects on regional brain connectivity and BOLD signal variability. Nine subjects participated in a double-blind, placebo-controlled crossover fMRI study. Following an infusion of physostigmine (1 mg/h) or placebo, echo-planar imaging (EPI) was conducted as participants performed a selective attention task. During the task, two images comprised of superimposed pictures of faces and houses were presented. Subjects were instructed periodically to shift their attention from one stimulus component to the other and to perform a matching task using hand held response buttons. A control condition included phase-scrambled images of superimposed faces and houses that were presented in the same temporal and spatial manner as the attention task; participants were instructed to perform a matching task. Cholinergic enhancement improved performance during the selective attention task, with no change during the control task. Functional connectivity analyses showed that the strength of connectivity between ventral visual processing areas and task-related occipital, parietal and prefrontal regions reduced significantly during cholinergic enhancement, exclusively during the selective attention task. Physostigmine administration also reduced BOLD signal temporal variability relative to placebo throughout temporal and occipital visual processing areas, again during the selective attention task only. Together with the observed behavioral improvement, the decreases in connectivity strength throughout task-relevant regions and BOLD variability within stimulus

  11. Cannabinoids and glucocorticoids modulate emotional memory after stress.

    Science.gov (United States)

    Akirav, Irit

    2013-12-01

    Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress. It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory. Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Selective recognition of monohydrogen phosphate by fluorescence enhancement of a new cerium complex

    International Nuclear Information System (INIS)

    Ganjali, Mohammad Reza; Hosseini, Morteza; Memari, Zahra; Faridbod, Farnoush; Norouzi, Parviz; Goldooz, Hassan; Badiei, Alireza

    2011-01-01

    Highlights: ► Finding a new fluorescent enhancing chemosensor for phosphate ions. ► Synthesis of a new complex (bis(8-hydroxy quinoline-5-solphonate) cerium(III) chloride (Ce(QS) 2 Cl)) as a practical fluorescent probe. ► Analysis of phosphate content in three kinds of fertilizers, mixed fertilizer (N–P–K), triple super phosphate (TSP), and single super phosphate (SSP) (from Zarrin Kood Co., Tehran, Iran). - Abstract: Bis(8-hydroxy quinoline-5-solphonate) cerium(III) chloride (Ce(QS) 2 Cl) (L) was synthesized and then used as a novel fluorescent sensor for anion recognition. Preliminarily study showed that fluorescence of L enhanced selectively in the presence of HPO 4 2− ion. This enhancement is attributed to a 1:1 complex formation between L and HPO 4 2− anion. The association constant of 1:1 complex of L-HPO 4 2− was calculated as 3.0 × 10 6 . Thus, L was utilized as a basis for a selective detection of HPO 4 2− anion in solution. The linear response range of the proposed fluorescent chemo-sensor covers a concentration range of HPO 4 2− from 3.3 × 10 −7 to 5.0 × 10 −6 mol L −1 with a detection limit of 2.5 × 10 −8 mol L −1 . L showed selective and sensitive fluorescence enhancement response toward HPO 4 2− ion in comparison with I 3 − , NO 3 − , CN − , CO 3 2− , Br − , Cl − , F − , H 2 PO 4 − and SO 4 2− ions. It was probably attributed to the higher stability of the inorganic complex between HPO 4 2− ion and L. The method was successfully applied for analysis of phosphate ions in some fertilizers samples.

  13. Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.

    Science.gov (United States)

    Dyck, Brian; Branstetter, Bryan; Gharbaoui, Tawfik; Hudson, Andrew R; Breitenbucher, J Guy; Gomez, Laurent; Botrous, Iriny; Marrone, Tami; Barido, Richard; Allerston, Charles K; Cedervall, E Peder; Xu, Rui; Sridhar, Vandana; Barker, Ryan; Aertgeerts, Kathleen; Schmelzer, Kara; Neul, David; Lee, Dong; Massari, Mark Eben; Andersen, Carsten B; Sebring, Kristen; Zhou, Xianbo; Petroski, Robert; Limberis, James; Augustin, Martin; Chun, Lawrence E; Edwards, Thomas E; Peters, Marco; Tabatabaei, Ali

    2017-04-27

    A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.

  14. Modulation of the Endocannabinoid System: Vulnerability Factor and New Treatment Target for Stimulant Addiction.

    Directory of Open Access Journals (Sweden)

    Stéphanie eOlière

    2013-09-01

    Full Text Available Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamine. Interestingly, recent accumulating evidence points toward the involvement of the endocannabinoid system (ECBS in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep-insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. The aims of this article are to: 1 review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and 2 evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoid in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants.

  15. Acylethanolamides and endocannabinoid signaling system in dorsal striatum of rats exposed to perinatal asphyxia.

    Science.gov (United States)

    Holubiec, Mariana I; Romero, Juan I; Blanco, Eduardo; Tornatore, Tamara Logica; Suarez, Juan; Rodríguez de Fonseca, Fernando; Galeano, Pablo; Capani, Francisco

    2017-07-13

    Endocannabinoids (eCBs) and acylethanolamides (AEs) have lately received more attention due to their neuroprotective functions in neurological disorders. Here we analyze the alterations induced by perinatal asphyxia (PA) in the main metabolic enzymes and receptors of the eCBs/AEs in the dorsal striatum of rats. To induce PA, we used a model developed by Bjelke et al. (1991). Immunohistochemical techniques were carried out to determine the expression of neuronal and glial markers (NeuN and GFAP), eCBs/AEs synthesis and degradation enzymes (DAGLα, NAPE-PLD and FAAH) and their receptors (CB1 and PPARα). We found a decrease in NAPE-PLD and PPARα expression. Since NAPE-PLD and PPARα take part in the production and reception of biochemical actions of AEs, such as oleoylethanolamide, these results may suggest that PA plays a key role in the regulation of this system. These data agree with previous results obtained in the hippocampus and encourage us to develop further studies using AEs as potential neuroprotective compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Shenglong Zou

    2018-03-01

    Full Text Available The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R and 2. The CB1R is the prominent subtype in the central nervous system (CNS and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.

  17. Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors

    Science.gov (United States)

    Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

    2016-01-01

    Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ9-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of meth-amphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled ‘CNS Stimulants’. PMID:24709540

  18. Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH neurons in an estrous cycle and endocannabinoid signaling dependent manner.

    Directory of Open Access Journals (Sweden)

    Imre Farkas

    Full Text Available The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca(2+-imaging revealed a ghrelin-triggered increase of the Ca(2+-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10 µM suggesting direct action of ghrelin. Estradiol (1nM eliminated the ghrelin-evoked rise of Ca(2+-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40 nM-4 μM administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1 antagonist AM251 (1µM and the intracellularly applied DAG-lipase inhibitor THL (10 µM, indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner.

  19. Plasmon-Induced Selective Enhancement of Green Emission in Lanthanide-Doped Nanoparticles.

    Science.gov (United States)

    Zhang, Weina; Li, Juan; Lei, Hongxiang; Li, Baojun

    2017-12-13

    By introducing an 18 nm thick Au nanofilm, selective enhancement of green emission from lanthanide-doped (β-NaYF 4 :Yb 3+ /Er 3+ ) upconversion nanoparticles (UCNPs) is demonstrated. The Au nanofilm is deposited on a microfiber surface by the sputtering method and then covered with the UCNPs. The plasma on the surface of the Au nanofilm can be excited by launching a 980 nm wavelength laser beam into the microfiber, resulting in an enhancement of the local electric field and a strong thermal effect. A 36-fold luminescence intensity enhancement of the UCNPs at 523 nm is observed, with no obvious reduction in the photostability of the UCNPs. Further, the intensity ratios of the emissions at 523-545 nm and at 523-655 nm are enhanced with increasing pump power, which is attributed to the increasing plasmon-induced thermal effect. Therefore, the fabricated device is further demonstrated to exhibit an excellent ability in temperature sensing. By controlling the pump power and the UCNP concentration, a wide temperature range (325-811 K) and a high temperature resolution (0.035-0.046 K) are achieved in the fabricated device.

  20. Phytoestrogens Enhance the Vascular Actions of the Endocannabinoid Anandamide in Mesenteric Beds of Female Rats

    Directory of Open Access Journals (Sweden)

    Roxana N. Peroni

    2012-01-01

    Full Text Available In rat isolated mesenteric beds that were contracted with NA as an in vitro model of the vascular adrenergic hyperactivity that usually precedes the onset of primary hypertension, the oral administration (3 daily doses of either 10 mg/kg genistein or 20 mg/kg daidzein potentiated the anandamide-induced reduction of contractility to NA in female but not in male rats. Oral treatment with phytoestrogens also restored the vascular effects of anandamide as well as the mesenteric content of calcitonin gene-related peptide (CGRP that were reduced after ovariectomy. The enhancement of anandamide effects caused by phytoestrogens was prevented by the concomitant administration of the estrogen receptor antagonist fulvestrant (2.5 mg/kg, s.c., 3 daily doses. It is concluded that, in the vasculature of female rats, phytoestrogens produced an estrogen-receptor-dependent enhancement of the anandamide-vascular actions that involves the modulation of CGRP levels and appears to be relevant whenever an adrenergic hyperactivity occurs.

  1. The endocannabinoid anandamide regulates the peristaltic reflex by reducing neuro-neuronal and neuro-muscular neurotransmission in ascending myenteric reflex pathways in rats.

    Science.gov (United States)

    Sibaev, Andrei; Yuece, Birol; Allescher, Hans Dieter; Saur, Dieter; Storr, Martin; Kurjak, Manfred

    2014-04-01

    Endocannabinoids (EC) and the cannabinoid-1 (CB1) receptor are involved in the regulation of motility in the gastrointestinal (GI) tract. However, the underlying physiological mechanisms are not completely resolved. The purpose of this work was to study the physiological influence of the endocannabinoid anandamide, the putative endogenous CB1 active cannabinoid, and of the CB1 receptor on ascending peristaltic activity and to identify the involved neuro-neuronal, neuro-muscular and electrophysiological mechanisms. The effects of anandamide and the CB1 receptor antagonist SR141716A were investigated on contractions of the circular smooth muscle of rat ileum and in longitudinal rat ileum segments where the ascending myenteric part of the peristaltic reflex was studied in a newly designed organ bath. Additionally intracellular recordings were performed in ileum and colon. Anandamide significantly reduced cholinergic twitch contractions of ileum smooth muscle whereas SR141716A caused an increase. Anandamide reduced the ascending peristaltic contraction by affecting neuro-neuronal and neuro-muscular neurotransmission. SR141716A showed opposite effects and all anandamide effects were antagonized by SR141716A (1 μM). Anandamide reduced excitatory junction potentials (EJP) and inhibitory junction potentials (IJP), whereas intestinal slow waves were not affected. CB1 receptors regulate force and timing of the intestinal peristaltic reflex and these actions involve interneurons and motor-neurons. The endogenous cannabinoid anandamide mediates these effects by activation of CB1 receptors. The endogenous cannabinoid system is permanently active, suggesting the CB1 receptor being a possible target for the treatment of motility related disorders. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  2. Cross-Selectivity Enhancement of Poly(vinylidene fluoride-hexafluoropropylene-Based Sensor Arrays for Detecting Acetone and Ethanol

    Directory of Open Access Journals (Sweden)

    Ali Daneshkhah

    2017-03-01

    Full Text Available Two methods for cross-selectivity enhancement of porous poly(vinylidene fluoride-hexafluoropropylene (PVDF-HFP/carbon black (CB composite-based resistive sensors are provided. The sensors are tested with acetone and ethanol in the presence of humid air. Cross-selectivity is enhanced using two different methods to modify the basic response of the PVDF-HFP/CB sensing platform. In method I, the adsorption properties of PVDF-HFP/CB are altered by adding a polyethylene oxide (PEO layer or by treating with infrared (IR. In method II, the effects of the interaction of acetone and ethanol are enhanced by adding diethylene carbonate (DEC or PEO dispersed in DEC (PEO/DEC to the film. The results suggest the approaches used in method I alter the composite ability to adsorb acetone and ethanol, while in method II, they alter the transduction characteristics of the composite. Using these approaches, sensor relative response to acetone was increased by 89% compared with the PVDF-HFP/CB untreated film, whereas sensor relative response to ethanol could be decreased by 57% or increased by 197%. Not only do these results demonstrate facile methods for increasing sensitivity of PVDF-HFP/CB film, used in parallel they demonstrate a roadmap for enhancing system cross-selectivity that can be applied to separate units on an array. Fabrication methods, experimental procedures and results are presented and discussed.

  3. Neurobiological Interactions Between Stress and the Endocannabinoid System.

    Science.gov (United States)

    Morena, Maria; Patel, Sachin; Bains, Jaideep S; Hill, Matthew N

    2016-01-01

    Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.

  4. Selective Attention to Auditory Memory Neurally Enhances Perceptual Precision.

    Science.gov (United States)

    Lim, Sung-Joo; Wöstmann, Malte; Obleser, Jonas

    2015-12-09

    Selective attention to a task-relevant stimulus facilitates encoding of that stimulus into a working memory representation. It is less clear whether selective attention also improves the precision of a stimulus already represented in memory. Here, we investigate the behavioral and neural dynamics of selective attention to representations in auditory working memory (i.e., auditory objects) using psychophysical modeling and model-based analysis of electroencephalographic signals. Human listeners performed a syllable pitch discrimination task where two syllables served as to-be-encoded auditory objects. Valid (vs neutral) retroactive cues were presented during retention to allow listeners to selectively attend to the to-be-probed auditory object in memory. Behaviorally, listeners represented auditory objects in memory more precisely (expressed by steeper slopes of a psychometric curve) and made faster perceptual decisions when valid compared to neutral retrocues were presented. Neurally, valid compared to neutral retrocues elicited a larger frontocentral sustained negativity in the evoked potential as well as enhanced parietal alpha/low-beta oscillatory power (9-18 Hz) during memory retention. Critically, individual magnitudes of alpha oscillatory power (7-11 Hz) modulation predicted the degree to which valid retrocues benefitted individuals' behavior. Our results indicate that selective attention to a specific object in auditory memory does benefit human performance not by simply reducing memory load, but by actively engaging complementary neural resources to sharpen the precision of the task-relevant object in memory. Can selective attention improve the representational precision with which objects are held in memory? And if so, what are the neural mechanisms that support such improvement? These issues have been rarely examined within the auditory modality, in which acoustic signals change and vanish on a milliseconds time scale. Introducing a new auditory memory

  5. Energy and water tradeoffs in enhancing food security: A selective international assessment

    International Nuclear Information System (INIS)

    Mushtaq, Shahbaz; Maraseni, Tek Narayan; Maroulis, Jerry; Hafeez, Mohsin

    2009-01-01

    Rice is the major staple food in most Asian countries. However, with rapidly growing populations, sustained high productivity and yields through improving water productivity is critically important. Increasingly complex energy-agriculture relationships require an in-depth understanding of water and energy tradeoffs. This study contributes to energy and food policies by analysing the complex energy, water and economics dynamics across a selection of major rice growing countries. The results show that tradeoffs exist between yield and energy inputs with high yield attributed to higher levels of energy input. The selected developed countries show higher energy productivity, relative to all other energy inputs, compared to the selected developing counties, owing to enhanced mechanisation, on-farm technology and improved farm management. Among all countries, China has the highest water productivity due to water-saving irrigation practices. These practices offer opportunities for developed and developing countries to increase water productivity at the same time taking advantage of economic and energy benefits of reduced pumping. Sustained production from agriculture is vital to food security. Improved irrigation practices can offset environmental footprints in the short run but their large-scale implementation remains an issue. In the long run, investments are needed to buffer the negative impacts of food production on the environment. Investments to boost water productivity and improved energy use efficiency in crop production are two pathways to reduce energy dependency, enhanced natural resource sustainability and ensuring future food security.

  6. Selecting odorant compounds to enhance sweet flavor perception by gas chromatography/olfactometry-associated taste (GC/O-AT).

    Science.gov (United States)

    Barba, Carmen; Beno, Noelle; Guichard, Elisabeth; Thomas-Danguin, Thierry

    2018-08-15

    Gas chromatography/olfactometry-associated taste (GC/O-AT) analysis combined with mass spectrometry allowed identification of odorant compounds associated with taste attributes (sweet, salty, bitter and sour) in a multi-fruit juice. Nine compounds were selected for their odor-associated sweetness enhancement in a multi-fruit juice odor context using Olfactoscan and for their odor-induced sweet taste enhancement in sucrose solution and sugar-reduced fruit juice through sensory tests. Sweetness of the fruit juice odor was significantly enhanced by methyl 2-methylbutanoate, ethyl butanoate, ethyl 2-methylbutanoate and linalool; sweet perception was significantly enhanced in 7% sucrose solution by ethyl 2-methylbutanoate, furaneol and γ-decalactone, and in 32% sugar-reduced fruit juice by ethyl 2-methylbutanoate. GC/O-AT analysis is a novel, efficient approach to select odorants associated with a given taste. The further screening of taste-associated odorants by Olfactoscan helps to identify the most efficient odorants to enhance a target taste perception and may be used to find new ways to modulate taste perception in foods and beverages. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Behavioural genetics: why eugenic selection is preferable to enhancement.

    Science.gov (United States)

    Savulescu, Julian; Hemsley, Melanie; Newson, Ainsley; Foddy, Bennett

    2006-01-01

    Criminal behaviour is but one behavioural tendency for which a genetic influence has been suggested. Whilst this research certainly raises difficult ethical questions and is subject to scientific criticism, one recent research project suggests that for some families, criminal tendency might be predicted by genetics. In this paper, supposing this research is valid, we consider whether intervening in the criminal tendency of future children is ethically justifiable. We argue that, if avoidance of harm is a paramount consideration, such an intervention is acceptable when genetic selection is employed instead of genetic enhancement. Moreover, other moral problems in avoiding having children with a tendency to criminal behaviour, such as the prospect of social discrimination, can also be overcome.

  8. Polygyny and extra-pair paternity enhance the opportunity for sexual selection in blue tits

    NARCIS (Netherlands)

    Vedder, Oscar; Komdeur, Jan; van der Velde, Marco; Schut, Elske; Magrath, Michael J. L.

    Polygyny and extra-pair paternity are generally thought to enhance sexual selection. However, the extent to which these phenomena increase variance in male reproductive success will depend on the covariance between success at these two strategies. We analysed these patterns over four breeding

  9. Selectivity enhancement of indium-doped SnO2 gas sensors

    International Nuclear Information System (INIS)

    Salehi, A.

    2002-01-01

    Indium doping was used to enhance the selectivity of SnO 2 gas sensor. Both indium-doped and undoped SnO 2 gas sensors fabricated with different deposition techniques were investigated. The changes in the sensitivity of the sensors caused by selective gases (hydrogen and wood smoke) ranging from 500 to 3000 ppm were measured at different temperatures from 50 to 300 deg. C. The sensitivity peaks of the samples exhibit different values for selective gases with a response time of approximately 0.5 s. Thermally evaporated indium-doped SnO 2 gas sensor shows a considerable increase in the sensitivity peak of 27% in response to wood smoke, whereas it shows a sensitivity peak of 7% to hydrogen. This is in contrast to the sputter deposited indium-doped SnO 2 gas sensor, which exhibits a much lower sensitivity peak of approximately 2% to hydrogen and wood smoke compared to undoped SnO 2 gas sensors fabricated by chemical vapor deposition and spray pyrolysis. Scanning electron microscopy shows that different deposition techniques result in different porosity of the films. It is observed that the thermally evaporated indium-doped SnO 2 gas sensor shows high porosity, while the sputtered sample exhibits almost no porosity

  10. Enhancement of selective attention by tDCS: interaction with interference in a Sternberg task

    NARCIS (Netherlands)

    Gladwin, T.E.; den Uyl, T.E.; Fregni, F.F.; Wiers, R.W.

    2012-01-01

    Transcranial Direct Current Stimulation (tDCS) enhances performance on working memory tasks. However, such effects may be dependent on modulation of specific aspects of working memory. We therefore tested the hypothesis that tDCS improves selective attention in the context of a Sternberg task.

  11. Endocannabinoids in Alzheimer's disease and their impact on normative cognitive performance: a case-control and cohort study

    Directory of Open Access Journals (Sweden)

    Christen Erica

    2009-01-01

    Full Text Available Abstract Background Neuropathological, animal, and cell culture studies point to a role for the body's own endogenous cannabinoids (eCBs system in Alzheimer's disease (AD pathology and treatment. To date, no published studies have investigated the potential utility of circulating eCBs as diagnostic biomarkers for AD or the impact of central eCBs on cognition. Results In comparison with healthy controls, there were no significant differences in measured eCB concentrations in plasma samples from patients with AD. Detectable eCBs in cerebrospinal fluid (CSF had no relationship to cognitive performance in healthy controls at risk for AD. In pooled plasma samples, an inverse correlation was observed between plasma levels of the eCB 2-AG (2-arachidonoylglycerol and TNF-α (r = -0.41, p Conclusion These results suggest that circulating endocannabinoids do not have utility as diagnostic biomarkers for AD and do not have a robust correlation with cognitive performance. Circulating levels of 2-AG may downregulate TNF-α production.

  12. Enhanced Size Selection in Two-Photon Excitation for CsPbBr3 Perovskite Nanocrystals.

    Science.gov (United States)

    Chen, Junsheng; Chábera, Pavel; Pascher, Torbjörn; Messing, Maria E; Schaller, Richard; Canton, Sophie; Zheng, Kaibo; Pullerits, Tõnu

    2017-10-19

    Cesium lead bromide (CsPbBr 3 ) perovskite nanocrystals (NCs), with large two-photon absorption (TPA) cross-section and bright photoluminescence (PL), have been demonstrated as stable two-photon-pumped lasing medium. With two-photon excitation, red-shifted PL spectrum and increased PL lifetime is observed compared with one-photon excitation. We have investigated the origin of such difference using time-resolved laser spectroscopies. We ascribe the difference to the enhanced size selection of NCs by two-photon excitation. Because of inherent nonlinearity, the size dependence of absorption cross-section under TPA is stronger. Consequently, larger size NCs are preferably excited, leading to longer excited-state lifetime and red-shifted PL emission. In a broad view, the enhanced size selection in two-photon excitation of CsPbBr 3 NCs is likely a general feature of the perovskite NCs and can be tuned via NC size distribution to influence their performance within NC-based nonlinear optical materials and devices.

  13. Process and analytical studies of enhanced low severity co-processing using selective coal pretreatment

    Energy Technology Data Exchange (ETDEWEB)

    Baldwin, R.M.; Miller, R.L.

    1991-12-01

    The findings in the first phase were as follows: 1. Both reductive (non-selective) alkylation and selective oxygen alkylation brought about an increase in liquefaction reactivity for both coals. 2. Selective oxygen alkylation is more effective in enhancing the reactivity of low rank coals. In the second phase of studies, the major findings were as follows: 1. Liquefaction reactivity increases with increasing level of alkylation for both hydroliquefaction and co-processing reaction conditions. 2. the increase in reactivity found for O-alkylated Wyodak subbituminous coal is caused by chemical changes at phenolic and carboxylic functional sites. 3. O-methylation of Wyodak subbituminous coal reduced the apparent activation energy for liquefaction of this coal.

  14. Reduced alcohol intake and reward associated with impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST

    DEFF Research Database (Denmark)

    Karlsson, Rose-Marie; Adermark, Louise; Molander, Anna

    2012-01-01

    mice with a deletion of GLAST to test this prediction. WT and GLAST KO mice were tested for alcohol consumption using two-bottle free-choice drinking. Alcohol reward was evaluated using conditioned place preference (CPP). Sensitivity to depressant alcohol effects was tested using the accelerating...... rotarod, alcohol-induced hypothermia, and loss of righting reflex. Extracellular glutamate was measured using microdialysis, and striatal slice electrophysiology was carried out to examine plasticity of the cortico-striatal pathway as a model system in which adaptations to the constitutive GLAST deletion...... deletion of GLAST unexpectedly results in markedly reduced alcohol consumption and preference, associated with markedly reduced alcohol reward. Endocannabinoid signaling appears to be down-regulated upstream of the CB1 receptor as a result of the GLAST deletion, and is a candidate mechanism behind...

  15. Rutin as a Mediator of Lipid Metabolism and Cellular Signaling Pathways Interactions in Fibroblasts Altered by UVA and UVB Radiation

    Directory of Open Access Journals (Sweden)

    Agnieszka Gęgotek

    2017-01-01

    Full Text Available Background. Rutin is a natural nutraceutical that is a promising compound for the prevention of UV-induced metabolic changes in skin cells. The aim of this study was to examine the effects of rutin on redox and endocannabinoid systems, as well as proinflammatory and proapoptotic processes, in UV-irradiated fibroblasts. Methods. Fibroblasts exposed to UVA and UVB radiation were treated with rutin. The activities and levels of oxidants/antioxidants and endocannabinoid system components, as well as lipid, DNA, and protein oxidation products, and the proinflammatory and pro/antiapoptotic proteins expression were measured. Results. Rutin reduced UV-induced proinflammatory response and ROS generation and enhanced the activity/levels of antioxidants (SOD, GSH-Px, vitamin E, GSH, and Trx. Rutin also normalized UV-induced Nrf2 expression. Its biological activity prevented changes in the levels of the lipid mediators: MDA, 4-HNE, and endocannabinoids, as well as the endocannabinoid receptors CB1/2, VR1, and GPR55 expression. Furthermore, rutin prevented the protein modifications (tyrosine derivatives formation in particular and decreased the levels of the proapoptotic markers—caspase-3 and cytochrome c. Conclusion. Rutin prevents UV-induced inflammation and redox imbalance at protein and transcriptional level which favors lipid, protein, and DNA protection. In consequence rutin regulates endocannabinoid system and apoptotic balance.

  16. A calpain-2 selective inhibitor enhances learning & memory by prolonging ERK activation.

    Science.gov (United States)

    Liu, Yan; Wang, Yubin; Zhu, Guoqi; Sun, Jiandong; Bi, Xiaoning; Baudry, Michel

    2016-06-01

    While calpain-1 activation is required for LTP induction by theta burst stimulation (TBS), calpain-2 activation limits its magnitude during the consolidation period. A selective calpain-2 inhibitor applied either before or shortly after TBS enhanced the degree of potentiation. In the present study, we tested whether the selective calpain-2 inhibitor, Z-Leu-Abu-CONH-CH2-C6H3 (3, 5-(OMe)2 (C2I), could enhance learning and memory in wild-type (WT) and calpain-1 knock-out (C1KO) mice. We first showed that C2I could reestablish TBS-LTP in hippocampal slices from C1KO mice, and this effect was blocked by PD98059, an inhibitor of ERK. TBS resulted in PTEN degradation in hippocampal slices from both WT and C1KO mice, and C2I treatment blocked this effect in both mouse genotypes. Systemic injection of C2I 30 min before training in the fear-conditioning paradigm resulted in a biphasic dose-response curve, with low doses enhancing and high doses inhibiting freezing behavior. The difference between the doses needed to enhance and inhibit learning matches the difference in concentrations producing inhibition of calpain-2 and calpain-1. A low dose of C2I also restored normal learning in a novel object recognition task in C1KO mice. Levels of SCOP, a ERK phosphatase known to be cleaved by calpain-1, were decreased in dorsal hippocampus early but not late following training in WT mice; C2I treatment did not affect the early decrease in SCOP levels but prevented its recovery at the later time-point and prolonged ERK activation. The results indicate that calpain-2 activation limits the extent of learning, an effect possibly due to temporal limitation of ERK activation, as a result of SCOP synthesis induced by calpain-2-mediated PTEN degradation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. An HPLC tracing of the enhancer regulation in selected discrete brain areas of food-deprived rats.

    Science.gov (United States)

    Miklya, I; Knoll, B; Knoll, J

    2003-05-09

    The recent discovery of the enhancer regulation in the mammalian brain brought a different perspective to the brain-organized realization of goal-oriented behavior, which is the quintessence of plastic behavioral descriptions such as drive or motivation. According to this new approach, 'drive' means that special endogenous enhancer substances enhance the impulse-propagation-mediated release of transmitters in a proper population of enhancer-sensitive neurons, and keep these neurons in the state of enhanced excitability until the goal is reached. However, to reach any goal needs the participation of the catecholaminergic machinery, the engine of the brain. We developed a method to detect the specific enhancer effect of synthetic enhancer substances [(-)-deprenyl, (-)-PPAP, (-)-BPAP] by measuring the release of transmitters from freshly isolated selected discrete brain areas (striatum, substantia nigra, tuberculum olfactorium, locus coeruleus, raphe) by the aid of HPLC with electrochemical detection. To test the validity of the working hypothesis that in any form of goal-seeking behavior the catecholaminergic and serotonergic neurons work on a higher activity level, we compared the amount of norepinephrine, dopamine, and serotonin released from selected discrete brain areas isolated from the brain of sated and food-deprived rats. Rats were deprived of food for 48 and 72 hours, respectively, and the state of excitability of their catecholaminergic and serotonergic neurons in comparison to that of sated rats was measured. We tested the orienting-searching reflex activity of the rats in a special open field, isolated thereafter selected discrete brain areas and measured the release of norepinephrine, dopamine, and serotonin from the proper tissue samples into the organ bath. The orienting-searching reflex activity of the rats increased proportionally to the time elapsed from the last feed and the amount of dopamine released from the striatum, substantia nigra and

  18. Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum

    Directory of Open Access Journals (Sweden)

    Ana ePalomino

    2014-03-01

    Full Text Available Growing awareness of cerebellar involvement in addiction is based on the cerebellum’s intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression (CB1 receptors and enzymes that produce (DAGLα/β and NAPE-PLD and degrade (MAGL and FAAH eCB were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system (glutamate synthesizing enzymes LGA and KGA, mGluR3/5 metabotropic receptors, and NR1/2A/2B/2C-NMDA and GluR1/2/3/4-AMPA ionotropic receptor subunits and the gene expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-AG production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and glutamate systems. Repeated cocaine results in normalization of glutamate receptor expression, although sustained changes in eCB is observed. We suggest that cocaine-induced alterations to cerebellar eCB should be considered when analyzing the adaptations imposed by psychostimulants that

  19. Engineering DNA Backbone Interactions Results in TALE Scaffolds with Enhanced 5-Methylcytosine Selectivity.

    Science.gov (United States)

    Rathi, Preeti; Witte, Anna; Summerer, Daniel

    2017-11-08

    Transcription activator-like effectors (TALEs) are DNA major-groove binding proteins widely used for genome targeting. TALEs contain an N-terminal region (NTR) and a central repeat domain (CRD). Repeats of the CRD selectively recognize each one DNA nucleobase, offering programmability. Moreover, repeats with selectivity for 5-methylcytosine (5mC) and its oxidized derivatives can be designed for analytical applications. However, both TALE domains also nonspecifically interact with DNA phosphates via basic amino acids. To enhance the 5mC selectivity of TALEs, we aimed to decrease the nonselective binding energy of TALEs. We substituted basic amino acids with alanine in the NTR and identified TALE mutants with increased selectivity. We then analysed conserved, DNA phosphate-binding KQ diresidues in CRD repeats and identified further improved mutants. Combination of mutations in the NTR and CRD was highly synergetic and resulted in TALE scaffolds with up to 4.3-fold increased selectivity in genomic 5mC analysis via affinity enrichment. Moreover, transcriptional activation in HEK293T cells by a TALE-VP64 construct based on this scaffold design exhibited a 3.5-fold increased 5mC selectivity. This provides perspectives for improved 5mC analysis and for the 5mC-conditional control of TALE-based editing constructs in vivo.

  20. Feature-size dependent selective edge enhancement of x-ray images

    International Nuclear Information System (INIS)

    Herman, S.

    1988-01-01

    Morphological filters are nonlinear signal transformations that operate on a picture directly in the space domain. Such filters are based on the theory of mathematical morphology previously formulated. The filt4er being presented here features a ''mask'' operator (called a ''structuring element'' in some of the literature) which is a function of the two spatial coordinates x and y. The two basic mathematical operations are called ''masked erosion'' and ''masked dilation''. In the case of masked erosion the mask is passed over the input image in a raster pattern. At each position of the mask, the pixel values under the mask are multiplied by the mask pixel values. Then the output pixel value, located at the center position of the mask,is set equal to the minimum of the product of the mask and input values. Similarity, for masked dilation, the output pixel value is the maximum of the product of the input and the mask pixel values. The two basic processes of dilation and erosion can be used to construct the next level of operations the ''positive sieve'' (also called ''opening'') and the ''negative sieve'' (''closing''). The positive sieve modifies the peaks in the image whereas the negative sieve works on image valleys. The positive sieve is implemented by passing the output of the masked erosion step through the masked dilation function. The negative sieve reverses this procedure, using a dilation followed by an erosion. Each such sifting operator is characterized by a ''hole size''. It will be shown that the choice of hole size will select the range of pixel detail sizes which are to be enhanced. The shape of the mask will govern the shape of the enhancement. Finally positive sifting is used to enhance positive-going (peak) features, whereas negative enhances the negative-going (valley) landmarks

  1. Hoxa2 Selectively Enhances Meis Binding to Change a Branchial Arch Ground State

    Science.gov (United States)

    Amin, Shilu; Donaldson, Ian J.; Zannino, Denise A.; Hensman, James; Rattray, Magnus; Losa, Marta; Spitz, François; Ladam, Franck; Sagerström, Charles; Bobola, Nicoletta

    2015-01-01

    Summary Hox transcription factors (TFs) are essential for vertebrate development, but how these evolutionary conserved proteins function in vivo remains unclear. Because Hox proteins have notoriously low binding specificity, they are believed to bind with cofactors, mainly homeodomain TFs Pbx and Meis, to select their specific targets. We mapped binding of Meis, Pbx, and Hoxa2 in the branchial arches, a series of segments in the developing vertebrate head. Meis occupancy is largely similar in Hox-positive and -negative arches. Hoxa2, which specifies second arch (IIBA) identity, recognizes a subset of Meis prebound sites that contain Hox motifs. Importantly, at these sites Meis binding is strongly increased. This enhanced Meis binding coincides with active enhancers, which are linked to genes highly expressed in the IIBA and regulated by Hoxa2. These findings show that Hoxa2 operates as a tissue-specific cofactor, enhancing Meis binding to specific sites that provide the IIBA with its anatomical identity. PMID:25640223

  2. Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

    Science.gov (United States)

    Speed, Haley E; Masiulis, Irene; Gibson, Jay R; Powell, Craig M

    2015-01-01

    A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C) of Neuroligin 3 (NLGN3R451C) is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I) imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs) onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs) from parvalbumin-positive (PV) or somatostatin-positive (SOM) interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at interneurons

  3. Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

    Directory of Open Access Journals (Sweden)

    Haley E Speed

    Full Text Available A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C of Neuroligin 3 (NLGN3R451C is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs from parvalbumin-positive (PV or somatostatin-positive (SOM interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at

  4. A Novel Selective Inverse Agonist of the CB2 Receptor as a Radiolabeled Tool Compound for Kinetic Binding Studies.

    Science.gov (United States)

    Martella, Andrea; Sijben, Huub; Rufer, Arne C; Grether, Uwe; Fingerle, Juergen; Ullmer, Christoph; Hartung, Thomas; IJzerman, Adriaan P; van der Stelt, Mario; Heitman, Laura H

    2017-10-01

    The endocannabinoid system, and in particular the cannabinoid type 2 receptor (CB2R), raised the interest of many medicinal chemistry programs for its therapeutic relevance in several (patho)physiologic processes. However, the physico-chemical properties of tool compounds for CB2R (e.g., the radioligand [ 3 H]CP55,940) are not optimal, despite the research efforts in developing effective drugs to target this system. At the same time, the importance of drug-target binding kinetics is growing since the kinetic binding profile of a ligand may provide important insights for the resulting in vivo efficacy. In this context we synthesized and characterized [ 3 H]RO6957022, a highly selective CB2R inverse agonist, as a radiolabeled tool compound. In equilibrium and kinetic binding experiments [ 3 H]RO6957022 showed high affinity for human CB2R with fast association ( k on ) and moderate dissociation ( k off ) kinetics. To demonstrate the robustness of [ 3 H]RO6957022 binding, affinity studies were carried out for a wide range of CB2R reference ligands, spanning the range of full, partial, and inverse agonists. Finally, we used [ 3 H]RO6957022 to study the kinetic binding profiles (i.e., k on and k off values) of selected synthetic and endogenous (i.e., 2-arachidonoylglycerol, anandamide, and noladin ether) CB2R ligands by competition association experiments. All tested ligands, and in particular the endocannabinoids, displayed distinct kinetic profiles, shedding more light on their mechanism of action and the importance of association rates in the determination of CB2R affinity. Altogether, this study shows that the use of a novel tool compound, i.e., [ 3 H]RO6957022, can support the development of novel ligands with a repertoire of kinetic binding profiles for CB2R. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  5. Enhanced fluidity liquid chromatography of inulin fructans using ternary solvent strength and selectivity gradients.

    Science.gov (United States)

    Bennett, Raffeal; Olesik, Susan V

    2018-01-25

    The value of exploring selectivity and solvent strength ternary gradients in enhanced fluidity liquid chromatography (EFLC) is demonstrated for the separation of inulin-type fructans from chicory. Commercial binary pump systems for supercritical fluid chromatography only allow for the implementation of ternary solvent strength gradients which can be restrictive for the separation of polar polymeric analytes. In this work, a custom system was designed to extend the capability of EFLC to allow tuning of selectivity or solvent strength in ternary gradients. Gradient profiles were evaluated using the Berridge function (RF 1 ), normalized resolution product (NRP), and gradient peak capacity (P c ). Selectivity gradients provided the separation of more analytes over time. The RF 1 function showed favor to selectivity gradients with comparable P c to that of solvent strength gradients. NRP did not strongly correlate with P c or RF 1 score. EFLC with the hydrophilic interaction chromatography, HILIC, separation mode was successfully employed to separate up to 47 fructan analytes in less than 25 min using a selectivity gradient. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning

    Science.gov (United States)

    Brown, Holden D.; Amodeo, Dionisio A.; Sweeney, John A.; Ragozzino, Michael E.

    2011-01-01

    Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally-biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 minutes prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with a SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally-biased response pattern or a learned choice pattern. PMID:22219222

  7. Is Visual Selective Attention in Deaf Individuals Enhanced or Deficient? The Case of the Useful Field of View

    Science.gov (United States)

    Dye, Matthew W. G.; Hauser, Peter C.; Bavelier, Daphne

    2009-01-01

    Background Early deafness leads to enhanced attention in the visual periphery. Yet, whether this enhancement confers advantages in everyday life remains unknown, as deaf individuals have been shown to be more distracted by irrelevant information in the periphery than their hearing peers. Here, we show that, in a complex attentional task, a performance advantage results for deaf individuals. Methodology/Principal Findings We employed the Useful Field of View (UFOV) which requires central target identification concurrent with peripheral target localization in the presence of distractors – a divided, selective attention task. First, the comparison of deaf and hearing adults with or without sign language skills establishes that deafness and not sign language use drives UFOV enhancement. Second, UFOV performance was enhanced in deaf children, but only after 11 years of age. Conclusions/Significance This work demonstrates that, following early auditory deprivation, visual attention resources toward the periphery slowly get augmented to eventually result in a clear behavioral advantage by pre-adolescence on a selective visual attention task. PMID:19462009

  8. SELECTION AND TREATMENT OF STRIPPER GAS WELLS FOR PRODUCTION ENHANCEMENT, MOCANE-LAVERNE FIELD, OKLAHOMA

    Energy Technology Data Exchange (ETDEWEB)

    Scott Reeves; Buckley Walsh

    2003-08-01

    In 1996, Advanced Resources International (ARI) began performing R&D targeted at enhancing production and reserves from natural gas fields. The impetus for the effort was a series of field R&D projects in the early-to-mid 1990's, in eastern coalbed methane and gas shales plays, where well remediation and production enhancement had been successfully demonstrated. As a first step in the R&D effort, an assessment was made of the potential for restimulation to provide meaningful reserve additions to the U.S. gas resource base, and what technologies were needed to do so. That work concluded that: (1) A significant resource base did exist via restimulation (multiples of Tcf). (2) The greatest opportunities existed in non-conventional plays where completion practices were (relatively) complex and technology advancement was rapid. (3) Accurate candidate selection is the greatest single factor that contributes to a successful restimulation program. With these findings, a field-oriented program targeted at tight sand formations was initiated to develop and demonstrate successful candidate recognition technology. In that program, which concluded in 2001, nine wells were restimulated in the Green River, Piceance and East Texas basins, which in total added 2.9 Bcf of reserves at an average cost of $0.26/Mcf. In addition, it was found that in complex and heterogeneous reservoirs (such as tight sand formations), candidate selection procedures should involve a combination of fundamental engineering and advanced pattern recognition approaches, and that simple statistical methods for identifying candidate wells are not effective. In mid-2000, the U.S. Department of Energy (DOE) awarded ARI an R&D contract to determine if the methods employed in that project could also be applied to stripper gas wells. In addition, the ability of those approaches to identify more general production enhancement opportunities (beyond only restimulation), such as via artificial lift and compression

  9. A multi-phase approach to select new wine yeast strains with enhanced fermentative fitness and glutathione production.

    Science.gov (United States)

    Bonciani, Tommaso; De Vero, Luciana; Mezzetti, Francesco; Fay, Justin C; Giudici, Paolo

    2018-03-01

    The genetic improvement of winemaking yeasts is a virtually infinite process, as the design of new strains must always cope with varied and ever-evolving production contexts. Good wine yeasts must feature both good primary traits, which are related to the overall fermentative fitness of the strain, and secondary traits, which provide accessory features augmenting its technological value. In this context, the superiority of "blind," genetic improvement techniques, as those based on the direct selection of the desired phenotype without prior knowledge of the genotype, was widely proven. Blind techniques such as adaptive evolution strategies were implemented for the enhancement of many traits of interest in the winemaking field. However, these strategies usually focus on single traits: this possibly leads to genetic tradeoff phenomena, where the selection of enhanced secondary traits might lead to sub-optimal primary fermentation traits. To circumvent this phenomenon, we applied a multi-step and strongly directed genetic improvement strategy aimed at combining a strong fermentative aptitude (primary trait) with an enhanced production of glutathione (secondary trait). We exploited the random genetic recombination associated to a library of 69 monosporic clones of strain UMCC 855 (Saccharomyces cerevisiae) to search for new candidates possessing both traits. This was achieved by consecutively applying three directional selective criteria: molybdate resistance (1), fermentative aptitude (2), and glutathione production (3). The strategy brought to the selection of strain 21T2-D58, which produces a high concentration of glutathione, comparable to that of other glutathione high-producers, still with a much greater fermentative aptitude.

  10. Enhancing the mathematical properties of new haplotype homozygosity statistics for the detection of selective sweeps.

    Science.gov (United States)

    Garud, Nandita R; Rosenberg, Noah A

    2015-06-01

    Soft selective sweeps represent an important form of adaptation in which multiple haplotypes bearing adaptive alleles rise to high frequency. Most statistical methods for detecting selective sweeps from genetic polymorphism data, however, have focused on identifying hard selective sweeps in which a favored allele appears on a single haplotypic background; these methods might be underpowered to detect soft sweeps. Among exceptions is the set of haplotype homozygosity statistics introduced for the detection of soft sweeps by Garud et al. (2015). These statistics, examining frequencies of multiple haplotypes in relation to each other, include H12, a statistic designed to identify both hard and soft selective sweeps, and H2/H1, a statistic that conditional on high H12 values seeks to distinguish between hard and soft sweeps. A challenge in the use of H2/H1 is that its range depends on the associated value of H12, so that equal H2/H1 values might provide different levels of support for a soft sweep model at different values of H12. Here, we enhance the H12 and H2/H1 haplotype homozygosity statistics for selective sweep detection by deriving the upper bound on H2/H1 as a function of H12, thereby generating a statistic that normalizes H2/H1 to lie between 0 and 1. Through a reanalysis of resequencing data from inbred lines of Drosophila, we show that the enhanced statistic both strengthens interpretations obtained with the unnormalized statistic and leads to empirical insights that are less readily apparent without the normalization. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Content dependent selection of image enhancement parameters for mobile displays

    Science.gov (United States)

    Lee, Yoon-Gyoo; Kang, Yoo-Jin; Kim, Han-Eol; Kim, Ka-Hee; Kim, Choon-Woo

    2011-01-01

    Mobile devices such as cellular phones and portable multimedia player with capability of playing terrestrial digital multimedia broadcasting (T-DMB) contents have been introduced into consumer market. In this paper, content dependent image quality enhancement method for sharpness and colorfulness and noise reduction is presented to improve perceived image quality on mobile displays. Human visual experiments are performed to analyze viewers' preference. Relationship between the objective measures and the optimal values of image control parameters are modeled by simple lookup tables based on the results of human visual experiments. Content dependent values of image control parameters are determined based on the calculated measures and predetermined lookup tables. Experimental results indicate that dynamic selection of image control parameters yields better image quality.

  12. Genetic Selection to Enhance Animal Welfare Using Meat Inspection Data from Slaughter Plants.

    Science.gov (United States)

    Mathur, Pramod K; Vogelzang, Roos; Mulder, Herman A; Knol, Egbert F

    2018-01-24

    Animal health and welfare are monitored during meat inspection in many slaughter plants around the world. Carcasses are examined by meat inspectors and remarks are made with respect to different diseases, injuries, and other abnormalities. This is a valuable data resource for disease prevention and enhancing animal welfare, but it is rarely used for this purpose. Records on carcass remarks on 140,375 finisher pigs were analyzed to investigate the possibility of genetic selection to reduce the risk of the most prevalent diseases and indicators of suboptimal animal welfare. As part of this, effects of some non-genetic factors such as differences between farms, sexes, and growth rates were also examined. The most frequent remarks were pneumonia (15.4%), joint disorders (9.8%), pleuritis (4.7%), pericarditis (2.3%), and liver lesions (2.2%). Joint disorders were more frequent in boars than in gilts. There were also significant differences between farms. Pedigree records were available for 142,324 pigs from 14 farms and were used for genetic analysis. Heritability estimates for pneumonia, pleuritis, pericarditis, liver lesions, and joint disorders were 0.10, 0.09, 0.14, 0.24, and 0.17 on the liability scale, respectively, suggesting the existence of substantial genetic variation. This was further confirmed though genome wide associations using deregressed breeding values as phenotypes. The genetic correlations between these remarks and finishing traits were small but mostly negative, suggesting the possibility of enhancing pig health and welfare simultaneously with genetic improvement in finishing traits. A selection index based on the breeding values for these traits and their economic values was developed. This index is used to enhance animal welfare in pig farms.

  13. Selective enhancement and verification of woody biomass digestibility as a denitrification carbon source.

    Science.gov (United States)

    Hu, Rongting; Zheng, Xilai; Xin, Jia; Sun, Zhaoyue; Zheng, Tianyuan

    2017-11-01

    The denitrification efficiency of woody biomass as carbon source is low because of its poor carbon availability. In this study, representative poplar sawdust was pretreated with lime and peracetic acid to enhance the biomass digestibility to different degrees; sawdust was then mixed with soil to investigate its denitrification efficiency. Under controllable conditions (25-95°C, 12-24h, varying dosages), sawdust digestibility (characterized by reducing sugar yield) was selectively enhanced 1.0-21.8 times over that of the raw sawdust (28.8mgeq.glucoseg -1 dry biomass). This increase was mainly attributed to the removal of lignin from the biomass. As a carbon source, the sawdust (digestibility enhanced by 5.4 times) increased the nitrate removal rate by 4.7 times, without N 2 O emission. However, the sawdust with high digestibility (12.6 or 18.0 times), despite releasing more dissolved organic carbon (DOC), did not exhibit further increase in denitrification efficiency, and emitted N 2 O. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Tip-Selective Growth of Silver on Gold Nanostars for Surface-Enhanced Raman Scattering.

    Science.gov (United States)

    Zhang, Weiqing; Liu, Jie; Niu, Wenxin; Yan, Heng; Lu, Xianmao; Liu, Bin

    2018-04-19

    Nanogaps as "hot spots" with highly localized surface plasmon can generate ultrastrong electromagnetic fields. Superior to the exterior nanogaps obtained via aggregation and self-assembly, interior nanogaps within Au and Ag nanostructures give stable and reproducible surface-enhanced Raman scattering (SERS) signals. However, the synthesis of nanostructures with interior hot spots is still challenging because of the lack of high-yield strategies and clear design principles. Herein, gold-silver nanoclusters (Au-Ag NCs) with multiple interior hot spots were fabricated as SERS platforms via selective growth of Ag nanoparticles on the tips of Au nanostars (Au NSs). Furthermore, the interior gap sizes of Au-Ag NCs can be facilely tuned by changing the amount of AgNO 3 used. Upon 785 nm excitation, single Au-Ag NC 350 exhibits 43-fold larger SERS enhancement factor and the optimal signal reproducibility relative to single Au NS. The SERS enhancement factors and signal reproducibility of Au-Ag NCs increase with the decrease of gap sizes. Collectively, the Au-Ag NCs could serve as a flexible, reproducible, and active platform for SERS investigation.

  15. Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB₂R selective benzimidazoles reveal unexpected intrinsic properties.

    Science.gov (United States)

    Nimczick, Martin; Pemp, Daniela; Darras, Fouad H; Chen, Xinyu; Heilmann, Jörg; Decker, Michael

    2014-08-01

    The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB₂R) of the endocannabinoid system (ECS) are described. Therefore, two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized. Changes of the parent structure at these positions have a crucial effect on the potency and efficacy of the ligands. However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Uncoupling of sarcoplasmic reticulum Ca²⁺-ATPase by N-arachidonoyl dopamine. Members of the endocannabinoid family as thermogenic drugs

    DEFF Research Database (Denmark)

    Mahmmoud, Yasser Ahmed; Gaster, Michel

    2013-01-01

    BACKGROUND AND PURPOSE: The sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) plays a role in thermogenesis. The exogenous compound capsaicin increased SERCA-mediated ATP hydrolysis not coupled to Ca²⁺ transport. Here, we have sought to identify endogenous compounds that may function as SERCA uncoupling...... agents. EXPERIMENTAL APPROACH: Using isolated SR vesicles from rabbits, we have screened for endogenous compounds that uncouple SERCA. We have also studied their ability to deplete cytoplasmic ATP from human skeletal muscle cells in culture. KEY RESULTS: Studies on SR vesicles showed that the endogenous......, regardless of the presence of glucose. CONCLUSIONS AND IMPLICATIONS: NADA is an endogenous molecule that may function as SERCA uncoupling agent in vivo. Members of the endocannabinoid family exert concerted actions on several Ca²⁺-handling proteins. Uncoupling of SERCA by exogenous compounds could be a novel...

  17. The Effect of Vocabulary Self-Selection Strategy and Input Enhancement Strategy on the Vocabulary Knowledge of Iranian EFL Learners

    Science.gov (United States)

    Masoudi, Golfam

    2017-01-01

    The present study was designed to investigate empirically the effect of Vocabulary Self-Selection strategy and Input Enhancement strategy on the vocabulary knowledge of Iranian EFL Learners. After taking a diagnostic pretest, both experimental groups enrolled in two classes. Learners who practiced Vocabulary Self-Selection were allowed to…

  18. On-the-fly selection of cell-specific enhancers, genes, miRNAs and proteins across the human body using SlideBase

    DEFF Research Database (Denmark)

    Ienasescu, Hans-Ioan; Li, Kang; Andersson, Robin

    2016-01-01

    Genomics consortia have produced large datasets profiling the expression of genes, micro-RNAs, enhancers and more across human tissues or cells. There is a need for intuitive tools to select subsets of such data that is the most relevant for specific studies. To this end, we present Slide...... for individual cell types/tissues, producing sets of genes, enhancers etc. which satisfy these constraints. Changes in slider settings result in simultaneous changes in the selected sets, updated in real time. SlideBase is linked to major databases from genomics consortia, including FANTOM, GTEx, The Human...

  19. Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond.

    Science.gov (United States)

    Cani, P D; Geurts, L; Matamoros, S; Plovier, H; Duparc, T

    2014-09-01

    The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short-chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  20. Natural Aphrodisiacs-A Review of Selected Sexual Enhancers.

    Science.gov (United States)

    West, Elizabeth; Krychman, Michael

    2015-10-01

    The Food and Drug Administration defines an aphrodisiac drug product as "any product that bears labeling claims that it will arouse or increase sexual desire, or that it will improve sexual performance." Presently, there are no approved medications for the treatment of lowered desire for women, and many opt for "natural" products. The aim of this article was to review the most popular and currently used aphrodisiac products marketed in the United States. The safety and efficacy of animal- and plant-based aphrodisiacs, vitamins and minerals, and popular over-the-counter combination supplements have been reviewed. An English PubMed literature search was performed using the key words "sexuality," "sex," "aphrodisiac," and "sexual enhancer." Approximately 50 articles were reviewed by the authors. The authors used relevant case series, case-controlled, and randomized clinical trial data. Products were evaluated based on the quality of research, and their known efficacy and safety considerations. Products with low risk and potential benefit for sexual response based on prior research studies were highlighted. Research has demonstrated that the risks of yohimbine, Spanish fly, mad honey, and Bufo toad may outweigh any benefit, and these products should be avoided. Other products, such as Maca, Tribulus, Ginkgo, and ginseng, have limited but emerging data. Randomized clinical trial data are often lacking, but future research should be performed to further elucidate the efficacy and safety of these products. Future randomized clinical trials are warranted before health care practitioners can recommend most aphrodisiac products. There remain some medical concerns with drug interactions, purity, reliability, and safety. West E and Krychman M. Natural aphrodisiacs-A review of selected sexual enhancers.. Copyright © 2015 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

  1. High Performance Enhancement-Mode AlGaN/GaN MIS-HEMT with Selective Fluorine Treatment

    Directory of Open Access Journals (Sweden)

    Chao Yang

    2015-01-01

    Full Text Available A novel enhancement-mode (E-mode Metal-Insulator-Semiconductor- (MIS- HEMT with selective fluorine ion (F− treatment is proposed and its mechanism is investigated. The HEMT features the Selective F− treatment both in the AlGaN channel region and in the thick passivation layer between the gate and drain (SFCP-MIS-HEMT. First, the F− in the passivation layer not only extends the depletion region and thus enhances the average electric field (E-field between the gate and drain by the assisted depletion effect but also reduces the E-field peak at the gate end, leading to a higher breakdown voltage (BV. Second, in the AlGaN channel region, the F− region realizes the E-mode and the region without F− maintains a high drain current (ID. Third, MIS structure suppresses the gate leakage current, increasing the gate swing voltage and the BV. Compared with a MIS-HEMT with F− treatment in whole channel (FC-MIS-HEMT, SFCP-MIS-HEMT increases the BV by 46% and the saturation drain current (ID,sat by 28%.

  2. Prenatal cannabis exposure - The "first hit" to the endocannabinoid system.

    Science.gov (United States)

    Richardson, Kimberlei A; Hester, Allison K; McLemore, Gabrielle L

    As more states and countries legalize medical and/or adult recreational marijuana use, the incidences of prenatal cannabis exposure (PCE) will likely increase. While young people increasingly view marijuana as innocuous, marijuana preparations have been growing in potency in recent years, potentially creating global clinical, public health, and workforce concerns. Unlike fetal alcohol spectrum disorder, there is no phenotypic syndrome associated with PCE. There is also no preponderance of evidence that PCE causes lifelong cognitive, behavioral, or functional abnormalities, and/or susceptibility to subsequent addiction. However, there is compelling circumstantial evidence, based on the principles of teratology and fetal malprogramming, suggesting that pregnant women should refrain from smoking marijuana. The usage of marijuana during pregnancy perturbs the fetal endogenous cannabinoid signaling system (ECSS), which is present and active from the early embryonic stage, modulating neurodevelopment and continuing this role into adulthood. The ECSS is present in virtually every brain structure and organ system, and there is also evidence that this system is important in the regulation of cardiovascular processes. Endocannabinoids (eCBs) undergird a broad spectrum of processes, including the early stages of fetal neurodevelopment and uterine implantation. Delta-9-tetrahydrocannabinol (THC), the psychoactive chemical in cannabis, enters maternal circulation, and readily crosses the placental membrane. THC binds to CB receptors of the fetal ECSS, altering neurodevelopment and possibly rewiring ECSS circuitry. In this review, we discuss the Double-Hit Hypothesis as it relates to PCE. We contend that PCE, similar to a neurodevelopmental teratogen, delivers the first hit to the ECSS, which is compromised in such a way that a second hit (i.e., postnatal stressors) will precipitate the emergence of a specific phenotype. In summary, we conclude that perturbations of the

  3. The enhancement of radiosensitivity by celecoxib, selective cyclooxygenase-2 inhibitor, on human cancer cells expressing differential levels of cyclooxygenase-2

    International Nuclear Information System (INIS)

    Pyo, Hong Ryull; Shin, You Keun; Kim, Hyun Seok; Seong, Jin Sil; Suh, Chang Ok; Kim, Gwi Eon

    2003-01-01

    To investigate the modulation of radiosensitivity by celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on cancer cells over- and under-expressing COX-2. A clonogenic radiation survival analysis was performed on A549 human lung and MCF-7 human breast cancer cell lines incubated in both 1 and 10% fetal bovine serum (FBS) containing media. The apoptosis in both cell lines was measured after treatment with radiation and/or celecoxib. Celecoxib enhanced the radiation sensitivity of the A549 cells in the medium containing the 10% FBS, with radiation enhancement ratios of 1.58 and 1.81 respectively, at surviving fractions of 0.1, with 30 μ M and 50 μ M celecoxib. This enhanced radiosensitivity disappeared in the medium containing the 1% FBS. Celecoxib did not change the radiation sensitivity of the MCF-7 cells in either media. The induction of apoptosis by celecoxib and radiation was not synergistic in either cell line. Celecoxib, a selective COX-2 inhibitor, preferentially enhanced the effect of radiation on COX-2 over-expressing cancer cells compared to the cells with a low expression, and this effect disappeared on incubation of the cells during drug treatment in the medium with suboptimal serum concentration. Apoptosis did not appear to be the underlying mechanism of this radiation enhancement effect due to celecoxib on the A549 cells. These findings suggest radiosensitization by a selective COX-2 inhibitor is COX-2 dependent

  4. Differences in the endocannabinoid system of sperm from fertile and infertile men.

    Directory of Open Access Journals (Sweden)

    Sheena E M Lewis

    Full Text Available Male infertility is a major cause of problems for many couples in conceiving a child. Recently, lifestyle pastimes such as alcohol, tobacco and marijuana have been shown to have further negative effects on male reproduction. The endocannabinoid system (ECS, mainly through the action of anandamide (AEA and 2-arachidonoylglycerol (2-AG at cannabinoid (CB(1, CB(2 and vanilloid (TRPV1 receptors, plays a crucial role in controlling functionality of sperm, with a clear impact on male reproductive potential. Here, sperm from fertile and infertile men were used to investigate content (through LC-ESI-MS, mRNA (through quantitative RT-PCR, protein (through Western Blotting and ELISA expression, and functionality (through activity and binding assays of the main metabolic enzymes of AEA and 2-AG (NAPE-PLD and FAAH, for AEA; DAGL and MAGL for 2-AG, as well as of their binding receptors CB(1, CB(2 and TRPV1. Our findings show a marked reduction of AEA and 2-AG content in infertile seminal plasma, paralleled by increased degradation: biosynthesis ratios of both substances in sperm from infertile versus fertile men. In addition, TRPV1 binding was detected in fertile sperm but was undetectable in infertile sperm, whereas that of CB(1 and CB(2 receptors was not statistically different in the two groups. In conclusion, this study identified unprecedented alterations of the ECS in infertile sperm, that might impact on capacitation and acrosome reaction, and hence fertilization outcomes. These alterations might also point to new biomarkers to determine male reproductive defects, and identify distinct ECS elements as novel targets for therapeutic exploitation of ECS-oriented drugs to treat male fertility problems.

  5. Video enhancement : content classification and model selection

    NARCIS (Netherlands)

    Hu, H.

    2010-01-01

    The purpose of video enhancement is to improve the subjective picture quality. The field of video enhancement includes a broad category of research topics, such as removing noise in the video, highlighting some specified features and improving the appearance or visibility of the video content. The

  6. Visual Input Enhances Selective Speech Envelope Tracking in Auditory Cortex at a ‘Cocktail Party’

    Science.gov (United States)

    Golumbic, Elana Zion; Cogan, Gregory B.; Schroeder, Charles E.; Poeppel, David

    2013-01-01

    Our ability to selectively attend to one auditory signal amidst competing input streams, epitomized by the ‘Cocktail Party’ problem, continues to stimulate research from various approaches. How this demanding perceptual feat is achieved from a neural systems perspective remains unclear and controversial. It is well established that neural responses to attended stimuli are enhanced compared to responses to ignored ones, but responses to ignored stimuli are nonetheless highly significant, leading to interference in performance. We investigated whether congruent visual input of an attended speaker enhances cortical selectivity in auditory cortex, leading to diminished representation of ignored stimuli. We recorded magnetoencephalographic (MEG) signals from human participants as they attended to segments of natural continuous speech. Using two complementary methods of quantifying the neural response to speech, we found that viewing a speaker’s face enhances the capacity of auditory cortex to track the temporal speech envelope of that speaker. This mechanism was most effective in a ‘Cocktail Party’ setting, promoting preferential tracking of the attended speaker, whereas without visual input no significant attentional modulation was observed. These neurophysiological results underscore the importance of visual input in resolving perceptual ambiguity in a noisy environment. Since visual cues in speech precede the associated auditory signals, they likely serve a predictive role in facilitating auditory processing of speech, perhaps by directing attentional resources to appropriate points in time when to-be-attended acoustic input is expected to arrive. PMID:23345218

  7. Structure-selective hot-spot Raman enhancement for direct identification and detection of trace penicilloic acid allergen in penicillin.

    Science.gov (United States)

    Zhang, Liying; Jin, Yang; Mao, Hui; Zheng, Lei; Zhao, Jiawei; Peng, Yan; Du, Shuhu; Zhang, Zhongping

    2014-08-15

    Trace penicilloic acid allergen frequently leads to various fatal immune responses to many patients, but it is still a challenge to directly discriminate and detect its residue in penicillin by a chemosensing way. Here, we report that silver-coated gold nanoparticles (Au@Ag NPs) exhibit a structure-selective hot-spot Raman enhancement capability for direct identification and detection of trace penicilloic acid in penicillin. It has been demonstrated that penicilloic acid can very easily link Au@Ag NPs together by its two carboxyl groups, locating itself spontaneously at the interparticle of Au@Ag NPs to form strong Raman hot-spot. At the critical concentration inducing the nanoparticle aggregation, Raman-enhanced effect of penicilloic acid is ~60,000 folds higher than that of penicillin. In particular, the selective Raman enhancement to the two carboxyl groups makes the peak of carboxyl group at C6 of penicilloic acid appear as a new Raman signal due to the opening of β-lactam ring of penicillin. The surface-enhanced Raman scattering (SERS) nanoparticle sensor reaches a sensitive limit lower than the prescribed 1.0‰ penicilloic acid residue in penicillin. The novel strategy to examine allergen is more rapid, convenient and inexpensive than the conventional separation-based assay methods. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Enhanced A3 adenosine receptor selectivity of multivalent nucleoside-dendrimer conjugates

    Directory of Open Access Journals (Sweden)

    Shainberg Asher

    2008-10-01

    Full Text Available Abstract Background An approach to use multivalent dendrimer carriers for delivery of nucleoside signaling molecules to their cell surface G protein-coupled receptors (GPCRs was recently introduced. Results A known adenosine receptor (AR agonist was conjugated to polyamidoamine (PAMAM dendrimer carriers for delivery of the intact covalent conjugate to on the cell surface. Depending on the linking moiety, multivalent conjugates of the N6-chain elongated functionalized congener ADAC (N6-[4-[[[4-[[[(2-aminoethylamino]carbonyl]methyl]anilino]carbonyl]methyl]phenyl]-adenosine achieved unanticipated high selectivity in binding to the cytoprotective human A3 AR, a class A GPCR. The key to this selectivity of > 100-fold in both radioreceptor binding (Ki app = 2.4 nM and functional assays (EC50 = 1.6 nM in inhibition of adenylate cyclase was maintaining a free amino group (secondary in an amide-linked chain. Attachment of neutral amide-linked chains or thiourea-containing chains preserved the moderate affinity and efficacy at the A1 AR subtype, but there was no selectivity for the A3 AR. Since residual amino groups on dendrimers are associated with cytotoxicity, the unreacted terminal positions of this A3 AR-selective G2.5 dendrimer were present as carboxylate groups, which had the further benefit of increasing water-solubility. The A3 AR selective G2.5 dendrimer was also visualized binding the membrane of cells expressing the A3 receptor but did not bind cells that did not express the receptor. Conclusion This is the first example showing that it is feasible to modulate and even enhance the pharmacological profile of a ligand of a GPCR based on conjugation to a nanocarrier and the precise structure of the linking group, which was designed to interact with distal extracellular regions of the 7 transmembrane-spanning receptor. This ligand tool can now be used in pharmacological models of tissue rescue from ischemia and to probe the existence of A3 AR

  9. Selective Attention Enhances Beta-Band Cortical Oscillation to Speech under "Cocktail-Party" Listening Conditions.

    Science.gov (United States)

    Gao, Yayue; Wang, Qian; Ding, Yu; Wang, Changming; Li, Haifeng; Wu, Xihong; Qu, Tianshu; Li, Liang

    2017-01-01

    Human listeners are able to selectively attend to target speech in a noisy environment with multiple-people talking. Using recordings of scalp electroencephalogram (EEG), this study investigated how selective attention facilitates the cortical representation of target speech under a simulated "cocktail-party" listening condition with speech-on-speech masking. The result shows that the cortical representation of target-speech signals under the multiple-people talking condition was specifically improved by selective attention relative to the non-selective-attention listening condition, and the beta-band activity was most strongly modulated by selective attention. Moreover, measured with the Granger Causality value, selective attention to the single target speech in the mixed-speech complex enhanced the following four causal connectivities for the beta-band oscillation: the ones (1) from site FT7 to the right motor area, (2) from the left frontal area to the right motor area, (3) from the central frontal area to the right motor area, and (4) from the central frontal area to the right frontal area. However, the selective-attention-induced change in beta-band causal connectivity from the central frontal area to the right motor area, but not other beta-band causal connectivities, was significantly correlated with the selective-attention-induced change in the cortical beta-band representation of target speech. These findings suggest that under the "cocktail-party" listening condition, the beta-band oscillation in EEGs to target speech is specifically facilitated by selective attention to the target speech that is embedded in the mixed-speech complex. The selective attention-induced unmasking of target speech may be associated with the improved beta-band functional connectivity from the central frontal area to the right motor area, suggesting a top-down attentional modulation of the speech-motor process.

  10. Human bone marrow mesenchymal stem cells secrete endocannabinoids that stimulate in vitro hematopoietic stem cell migration effectively comparable to beta-adrenergic stimulation.

    Science.gov (United States)

    Köse, Sevil; Aerts-Kaya, Fatima; Köprü, Çağla Zübeyde; Nemutlu, Emirhan; Kuşkonmaz, Barış; Karaosmanoğlu, Beren; Taşkıran, Ekim Zihni; Altun, Belgin; Uçkan Çetinkaya, Duygu; Korkusuz, Petek

    2018-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a well-known hematopoietic stem cell (HSC)-mobilizing agent used in both allogeneic and autologous transplantation. However, a proportion of patients or healthy donors fail to mobilize a sufficient number of cells. New mobilization agents are therefore needed. Endocannabinoids (eCBs) are endogenous lipid mediators generated in the brain and peripheral tissues and activate the cannabinoid receptors CB1 and CB2. We suggest that eCBs may act as mobilizers of HSCs from the bone marrow (BM) under stress conditions as beta-adrenergic receptors (Adrβ). This study demonstrates that BM mesenchymal stem cells (MSCs) secrete anandamide (AEA) and 2-arachidonylglycerol (2-AG) and the peripheral blood (PB) and BM microenvironment contain AEA and 2-AG. 2-AG levels are significantly higher in PB of the G-CSF-treated group compared with BM plasma. BM mononuclear cells (MNCs) and CD34 + HSCs express CB1, CB2, and Adrβ subtypes. CD34 + HSCs had higher CB1 and CB2 receptor expression in G-CSF-untreated and G-CSF-treated groups compared with MSCs. MNCs but not MSCs expressed CB1 and CB2 receptors based on qRT-PCR and flow cytometry. AEA- and 2-AG-stimulated HSC migration was blocked by eCB receptor antagonists in an in vitro migration assay. In conclusion, components of the eCB system and their interaction with Adrβ subtypes were demonstrated on HSCs and MSCs of G-CSF-treated and G-CSF-untreated healthy donors in vitro, revealing that eCBs might be potential candidates to enhance or facilitate G-CSF-mediated HSC migration under stress conditions in a clinical setting. Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  11. Integrated basic treatment of activated carbon for enhanced CO{sub 2} selectivity

    Energy Technology Data Exchange (ETDEWEB)

    Adelodun, Adedeji Adebukola; Jo, Young-Min, E-mail: ymjo@khu.ac.kr

    2013-12-01

    We attempted the use of three chemical agents viz nitric acid (HN), calcium nitrate (CaN) and calcium ethanoate (CaEt) to achieve enhanced CO{sub 2} selective adsorption by activated carbon (AC). In dry phase treatment, microporous coconut shell-based carbon (CS) exhibits higher CO{sub 2} capacity than coal-based. However, upon wet-phase pre-treatment, modified CS samples showed lesser CO{sub 2} adsorption efficiency. Surface characterization with X-ray photoelectron spectroscopy confirms the presence of calcium and amine species on the samples with integrated treatment (A-CaN). These samples recorded the highest low-level CO{sub 2} capture despite calcinated CaEt-doped samples (C-CaEt) showing the highest value for pure and high level CO{sub 2} adsorption capacities. The slope and linearity values of isobaric desorption were used to estimate the proportion of CO{sub 2} chemisorbed and heterogeneity of the adsorbents’ surfaces respectively. Consequently, integrated basic impregnation provides the most efficient adsorbents for selective adsorption of both indoor and outdoor CO{sub 2} levels.

  12. Is rheumatoid arthritis a consequence of natural selection for enhanced tuberculosis resistance?

    Science.gov (United States)

    Mobley, James L

    2004-01-01

    Although the bubonic plague or "Black Death" is notorious for the toll it took on the population of Europe in the middle ages, another epidemic, the "White Death" of tuberculosis is responsible for millions of deaths worldwide over the past 300 years. With one in four deaths due to tuberculosis in Western Europe and the United States in the 19th century, this disease undoubtedly acted as a powerful genetic selective force. The epidemiology of modern day rheumatoid arthritis (RA) is strikingly similar to the epidemiology of tuberculosis 100-200 years ago, suggesting the possibility that genetic factors that enhanced survival in tuberculosis epidemics are now influencing susceptibility to RA. Recent advances in the analysis of genetic polymorphisms associated with disease have identified several genes linked to RA susceptibility that encode proteins involved in the immune response to Mycobacterium tuberculosis infection, including TNF-alpha, NRAMP1, PARP-1, HLA-DRB1, and PADI4. These results suggest that rheumatoid arthritis, and possibly other autoimmune diseases, are modern day manifestations of the genetic selective pressure exerted by tuberculosis epidemics of the recent past.

  13. Process and analytical studies of enhanced low severity co-processing using selective coal pretreatment. Final technical report

    Energy Technology Data Exchange (ETDEWEB)

    Baldwin, R.M.; Miller, R.L.

    1991-12-01

    The findings in the first phase were as follows: 1. Both reductive (non-selective) alkylation and selective oxygen alkylation brought about an increase in liquefaction reactivity for both coals. 2. Selective oxygen alkylation is more effective in enhancing the reactivity of low rank coals. In the second phase of studies, the major findings were as follows: 1. Liquefaction reactivity increases with increasing level of alkylation for both hydroliquefaction and co-processing reaction conditions. 2. the increase in reactivity found for O-alkylated Wyodak subbituminous coal is caused by chemical changes at phenolic and carboxylic functional sites. 3. O-methylation of Wyodak subbituminous coal reduced the apparent activation energy for liquefaction of this coal.

  14. The administration of endocannabinoid uptake inhibitors OMDM-2 or VDM-11 promotes sleep and decreases extracellular levels of dopamine in rats.

    Science.gov (United States)

    Murillo-Rodríguez, Eric; Palomero-Rivero, Marcela; Millán-Aldaco, Diana; Di Marzo, Vincenzo

    2013-01-17

    The family of the endocannabinoid system comprises endogenous lipids (such as anandamide [ANA]), receptors (CB(1)/CB(2) cannabinoid receptors), metabolic enzymes (fatty acid amide hydrolase [FAAH]) and a putative membrane transporter (anandamide membrane transporter [AMT]). Although the role of ANA, FAAH or the CB(1) cannabinoid receptor in sleep modulation has been reported, the effects of the inhibition of AMT on sleep remain unclear. In the present study, we show that microdialysis perfusion in rats of AMT inhibitors, (9Z)-N-[1-((R)-4-hydroxbenzyl)-2-hydroxyethyl]-9-octadecenamide (OMDM-2) or N-(4-hydroxy-2-methylphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (VDM-11; 10, 20 or 30 μM; each compound) delivered into the paraventricular thalamic nucleus (PVA) increased sleep and decreased waking. In addition, the infusion of compounds reduced the extracellular levels of dopamine collected from nucleus accumbens. Taken together, these findings illustrate a critical role of AMT in sleep modulation. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Cholinergic enhancement modulates neural correlates of selective attention and emotional processing.

    Science.gov (United States)

    Bentley, Paul; Vuilleumier, Patrik; Thiel, Christiane M; Driver, Jon; Dolan, Raymond J

    2003-09-01

    Neocortical cholinergic afferents are proposed to influence both selective attention and emotional processing. In a study of healthy adults we used event-related fMRI while orthogonally manipulating attention and emotionality to examine regions showing effects of cholinergic modulation by the anticholinesterase physostigmine. Either face or house pictures appeared at task-relevant locations, with the alternative picture type at irrelevant locations. Faces had either neutral or fearful expressions. Physostigmine increased relative activity within the anterior fusiform gyrus for faces at attended, versus unattended, locations, but decreased relative activity within the posterolateral occipital cortex for houses in attended, versus unattended, locations. A similar pattern of regional differences in the effect of physostigmine on cue-evoked responses was also present in the absence of stimuli. Cholinergic enhancement augmented the relative neuronal response within the middle fusiform gyrus to fearful faces, whether at attended or unattended locations. By contrast, physostigmine influenced responses in the orbitofrontal, intraparietal and cingulate cortices to fearful faces when faces occupied task-irrelevant locations. These findings suggest that acetylcholine may modulate both selective attention and emotional processes through independent, region-specific effects within the extrastriate cortex. Furthermore, cholinergic inputs to the frontoparietal cortex may influence the allocation of attention to emotional information.

  16. Epigenetic mechanisms associated with addiction-related behavioural effects of nicotine and/or cocaine: implication of the endocannabinoid system.

    Science.gov (United States)

    Hayase, Tamaki

    2017-10-01

    The addictive use of nicotine (NC) and cocaine (COC) continues to be a major public health problem, and their combined use has been reported, particularly during adolescence. In neural plasticity, commonly induced by NC and COC, as well as behavioural plasticity related to the use of these two drugs, the involvement of epigenetic mechanisms, in which the reversible regulation of gene expression occurs independently of the DNA sequence, has recently been reported. Furthermore, on the basis of intense interactions with the target neurotransmitter systems, the endocannabinoid (ECB) system has been considered pivotal for eliciting the effects of NC or COC. The combined use of marijuana with NC and/or COC has also been reported. This article presents the addiction-related behavioural effects of NC and/or COC, based on the common behavioural/neural plasticity and combined use of NC/COC, and reviews the interacting role of the ECB system. The epigenetic processes inseparable from the effects of NC and/or COC (i.e. DNA methylation, histone modifications and alterations in microRNAs) and the putative therapeutic involvement of the ECB system at the epigenetic level are also discussed.

  17. Effects of centrally administered endocannabinoids and opioids on orofacial pain perception in rats.

    Science.gov (United States)

    Zubrzycki, Marek; Janecka, Anna; Liebold, Andreas; Ziegler, Mechthild; Zubrzycka, Maria

    2017-11-01

    Endocannabinoids and opioids play a vital role in mediating pain-induced analgesia. The specific effects of these compounds within the orofacial region are largely unknown. In this study, we tried to determine whether an increase in cannabinoid and opioid concentration in the CSF affects impulse transmission between the motor centres localized in the vicinity of the third and fourth cerebral ventricles. The study objectives were realized on rats using a method that allows the recording of the amplitude of evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation. The amplitude of ETJ was a measure of the effect of neurotransmitters on neural structures. Perfusion of cerebral ventricles with anandamide (AEA), endomorphin-2 (EM-2), URB597, an inhibitor of fatty acid amide hydrolase (FAAH) and JZL195, a dual inhibitor of FAAH and monoacylglycerol lipase (MAGL) reduced the ETJ amplitude. The antinociceptive effect of AEA, EM-2, URB597 and JZL195 was blocked by CB 1 receptor antagonist, AM251 and by μ receptor-antagonist, β-funaltrexamine. In contrast to AEA, 2-arachidonoylglycerol alone did not decrease ETJ amplitude. We demonstrated that in the orofacial area, analgesic activity is modulated by AEA and that EM-2-induced antinociception was mediated by μ and CB 1 receptors. The action of AEA and EM-2 is tightly regulated by FAAH and FAAH/MAGL, by preventing the breakdown of endogenous cannabinoids in regions where they are produced on demand. Therefore, the current findings support the therapeutic potential of FAAH and FAAH/MAGL inhibitors as novel pharmacotherapeutic agents for orofacial pain. © 2017 The British Pharmacological Society.

  18. Enhanced permeability, selectivity, and antifouling ability of CNTs/Al2O3 membrane under electrochemical assistance.

    Science.gov (United States)

    Fan, Xinfei; Zhao, Huimin; Liu, Yanming; Quan, Xie; Yu, Hongtao; Chen, Shuo

    2015-02-17

    Membrane filtration provides effective solutions for removing contaminants, but achieving high permeability, good selectivity, and antifouling ability remains a great challenge for existing membrane filtration technologies. In this work, membrane filtration coupled with electrochemistry has been developed to enhance the filtration performance of a CNTs/Al2O3 membrane. The as-prepared CNTs/Al2O3 membrane, obtained by coating interconnected CNTs on an Al2O3 substrate, presented good pore-size tunability, mechanical stability, and electroconductivity. For the removal of a target (silica spheres as a probe) with a size comparable to the membrane pore size, the removal efficiency and flux at +1.5 V were 1.1 and 1.5 times higher, respectively, than those without electrochemical assistance. Moreover, the membrane also exhibited a greatly enhanced removal efficiency for contaminants smaller than the membrane pores, providing enhancements of 4 orders of magnitude and a factor of 5.7 for latex particles and phenol, respectively. These results indicated that both the permeability and the selectivity of CNTs/Al2O3 membranes can be significantly improved by electrochemical assistance, which was further confirmed by the removal of natural organic matter (NOM). The permeate flux and NOM removal efficiency at +1.5 V were about 1.6 and 3.0 times higher, respectively, than those without electrochemical assistance. In addition, the lost flux of the fouled membrane was almost completely recovered by an electrochemically assisted backwashing process.

  19. Selective Use of the Mother Tongue to Enhance Students’ English Learning Processes...Beyond the Same Assumptions

    Directory of Open Access Journals (Sweden)

    Luis Fernando Cuartas Alvarez

    2014-04-01

    Full Text Available This article reports the results of an action-research project that examines enhancing students’ English learning processes through the selective use of their mother tongues with the aim of overcoming their reluctant attitudes toward learning English in the classroom. This study involves forty ninth-graders from an all-girls public school in Medellin, Colombia. The data gathered included field notes, questionnaires, and participants’ focus group interviews. The findings show that the mother tongue plays an important role in students’ English learning processes by fostering students’ affective, motivational, cognitive, and attitudinal aspects. Thus, the mother tongue serves as the foothold for further advances in learning English when used selectively.

  20. Improvement of selected strains through gamma irradiation for enhanced lipolytic potential

    International Nuclear Information System (INIS)

    Iftikhar, T.; Mubashir, N.; Hussain, Y.; Abbas, S.Q.; Ashraf, I.

    2010-01-01

    The purpose of the present investigation was to enhance the production of industrially important enzyme lipase by subjecting the wild lipase producing fungal strains i.e. Aspergillus niger, Rhizopus microsporus and Penicillium atrovenetum to various doses of gamma irradiation (20, 40, 60, 80, 100, 120, 140 and 160 Gy). The isolation and lipolytic activity of selected mutant derived strains is described in this paper. Among all the mutants tested, MBL-5 obtained at 140Gy of Aspergillus niger strain showed highest extracellular lipase activity (13.75 +- 0.15 U mL/sup -1/) while MBL-1 Rhizopus microsporus at the rate 20Gy showed the lowest activity i.e., 1.06 +- 0.11 U mL/sup -1/. A range of pH 3, 5, 7, 9 and 11 was used to check the lipolytic potential of various mutants along with their wild type. It was observed that MBL-5 (Aspergillus niger) and MBL-2 (Rhizopus microsporus) showed enhanced extracellular lipase activity at pH 11 while MBL-3 (Penicillium atrovenetum) showed the highest extracellular lipase activity 22.53 +- 0.21 U mL/sup -1/ at pH 9. It indicates a possible role for the MBL-2, MBL-3 and MBL-5 mutant strains in the detergent industry for the development of eco-friendly technologies. (author)

  1. Selective Attention Enhances Beta-Band Cortical Oscillation to Speech under “Cocktail-Party” Listening Conditions

    Science.gov (United States)

    Gao, Yayue; Wang, Qian; Ding, Yu; Wang, Changming; Li, Haifeng; Wu, Xihong; Qu, Tianshu; Li, Liang

    2017-01-01

    Human listeners are able to selectively attend to target speech in a noisy environment with multiple-people talking. Using recordings of scalp electroencephalogram (EEG), this study investigated how selective attention facilitates the cortical representation of target speech under a simulated “cocktail-party” listening condition with speech-on-speech masking. The result shows that the cortical representation of target-speech signals under the multiple-people talking condition was specifically improved by selective attention relative to the non-selective-attention listening condition, and the beta-band activity was most strongly modulated by selective attention. Moreover, measured with the Granger Causality value, selective attention to the single target speech in the mixed-speech complex enhanced the following four causal connectivities for the beta-band oscillation: the ones (1) from site FT7 to the right motor area, (2) from the left frontal area to the right motor area, (3) from the central frontal area to the right motor area, and (4) from the central frontal area to the right frontal area. However, the selective-attention-induced change in beta-band causal connectivity from the central frontal area to the right motor area, but not other beta-band causal connectivities, was significantly correlated with the selective-attention-induced change in the cortical beta-band representation of target speech. These findings suggest that under the “cocktail-party” listening condition, the beta-band oscillation in EEGs to target speech is specifically facilitated by selective attention to the target speech that is embedded in the mixed-speech complex. The selective attention-induced unmasking of target speech may be associated with the improved beta-band functional connectivity from the central frontal area to the right motor area, suggesting a top-down attentional modulation of the speech-motor process. PMID:28239344

  2. Selectively Plasmon-Enhanced Second-Harmonic Generation from Monolayer Tungsten Diselenide on Flexible Substrates

    KAUST Repository

    Wang, Zhuo

    2018-01-04

    Monolayer two-dimensional transition metal dichalcogenides (2D TMDCs) exhibit promising characteristics in miniaturized nonlinear optical frequency converters, due to their inversion asymmetry and large second-order nonlinear susceptibility. However, these materials usually have a very short light interaction lengths with the pump laser because they are atomically thin, such that second-harmonic generation (SHG) is generally inefficient. In this paper, we fabricate a judiciously structured 150-nm-thick planar surface consisting of monolayer tungsten diselenide and sub-20-nm-wide gold trenches on flexible substrates, reporting ~7000-fold SHG enhancement without peak broadening or background in the spectra as compared to WSe2 on as-grown sapphire substrates. Our proof-of-concept experiment yields effective second-order nonlinear susceptibility of 2.1 × 104 pm/V. Three orders of magnitude enhancement is maintained with pump wavelength ranging from 800 nm to 900 nm, breaking the limitation of narrow pump wavelength range for cavity-enhanced SHG. In addition, SHG amplitude can be dynamically controlled via selective excitation of the lateral gap plasmon by rotating the laser polarization. Such fully open, flat and ultrathin profile enables a great variety of functional samples with high SHG from one patterned silicon substrate, favoring scalable production of nonlinear converters. The surface accessibility also enables integration with other optical components for information processing in an ultrathin and flexible form.

  3. Selectively Plasmon-Enhanced Second-Harmonic Generation from Monolayer Tungsten Diselenide on Flexible Substrates

    KAUST Repository

    Wang, Zhuo; Dong, Zhaogang; Zhu, Hai; Jin, Lei; Chiu, Ming-Hui; Li, Lain-Jong; Xu, Qing-Hua; Eda, Goki; Maier, Stefan A.; Wee, Andrew T. S.; Qiu, Cheng-Wei; Yang, Joel K.W.

    2018-01-01

    Monolayer two-dimensional transition metal dichalcogenides (2D TMDCs) exhibit promising characteristics in miniaturized nonlinear optical frequency converters, due to their inversion asymmetry and large second-order nonlinear susceptibility. However, these materials usually have a very short light interaction lengths with the pump laser because they are atomically thin, such that second-harmonic generation (SHG) is generally inefficient. In this paper, we fabricate a judiciously structured 150-nm-thick planar surface consisting of monolayer tungsten diselenide and sub-20-nm-wide gold trenches on flexible substrates, reporting ~7000-fold SHG enhancement without peak broadening or background in the spectra as compared to WSe2 on as-grown sapphire substrates. Our proof-of-concept experiment yields effective second-order nonlinear susceptibility of 2.1 × 104 pm/V. Three orders of magnitude enhancement is maintained with pump wavelength ranging from 800 nm to 900 nm, breaking the limitation of narrow pump wavelength range for cavity-enhanced SHG. In addition, SHG amplitude can be dynamically controlled via selective excitation of the lateral gap plasmon by rotating the laser polarization. Such fully open, flat and ultrathin profile enables a great variety of functional samples with high SHG from one patterned silicon substrate, favoring scalable production of nonlinear converters. The surface accessibility also enables integration with other optical components for information processing in an ultrathin and flexible form.

  4. Development of Selectable Marker-Free Transgenic Rice Plants with Enhanced Seed Tocopherol Content through FLP/FRT-Mediated Spontaneous Auto-Excision.

    Science.gov (United States)

    Woo, Hee-Jong; Qin, Yang; Park, Soo-Yun; Park, Soon Ki; Cho, Yong-Gu; Shin, Kong-Sik; Lim, Myung-Ho; Cho, Hyun-Suk

    2015-01-01

    Development of marker-free transgenic plants is a technical alternative for avoiding concerns about the safety of selectable marker genes used in genetically modified (GM) crops. Here, we describe the construction of a spontaneous self-excision binary vector using an oxidative stress-inducible modified FLP/FRT system and its successful application to produce marker-free transgenic rice plants with enhanced seed tocopherol content. To generate selectable marker-free transgenic rice plants, we constructed a binary vector using the hpt selectable marker gene and the rice codon-optimized FLP (mFLP) gene under the control of an oxidative stress-inducible promoter between two FRT sites, along with multiple cloning sites for convenient cloning of genes of interest. Using this pCMF binary vector with the NtTC gene, marker-free T1 transgenic rice plants expressing NtTC were produced by Agrobacterium-mediated stable transformation using hygromycin as a selective agent, followed by segregation of selectable marker genes. Furthermore, α-, γ-, and total tocopherol levels were significantly increased in seeds of the marker-free transgenic TC line compared with those of wild-type plants. Thus, this spontaneous auto-excision system, incorporating an oxidative stress-inducible mFLP/FRT system to eliminate the selectable marker gene, can be easily adopted and used to efficiently generate marker-free transgenic rice plants. Moreover, nutritional enhancement of rice seeds through elevation of tocopherol content coupled with this marker-free strategy may improve human health and public acceptance of GM rice.

  5. Effects of Choice Architecture and Chef-Enhanced Meals on the Selection and Consumption of Healthier School Foods

    Science.gov (United States)

    Cohen, Juliana F.W.; Richardson, Scott A.; Cluggish, Sarah A.; Parker, Ellen; Catalano, Paul J.; Rimm, Eric B.

    2015-01-01

    IMPORTANCE Little is known about the long-term effect of a chef-enhanced menu on healthier food selection and consumption in school lunchrooms. In addition, it remains unclear if extended exposure to other strategies to promote healthier foods (eg, choice architecture) also improves food selection or consumption. OBJECTIVE To evaluate the short- and long-term effects of chef-enhanced meals and extended exposure to choice architecture on healthier school food selection and consumption. DESIGN, SETTING, AND PARTICIPANTS A school-based randomized clinical trial was conducted during the 2011–2012 school year among 14 elementary and middle schools in 2 urban, low-income school districts (intent-to-treat analysis). Included in the study were 2638 students in grades 3 through 8 attending participating schools (38.4%of eligible participants). INTERVENTIONS Schools were first randomized to receive a professional chef to improve school meal palatability (chef schools) or to a delayed intervention (control group). To assess the effect of choice architecture (smart café), all schools after 3 months were then randomized to the smart café intervention or to the control group. MAIN OUTCOMES AND MEASURES School food selection was recorded, and consumption was measured using plate waste methods. RESULTS After 3 months, vegetable selection increased in chef vs control schools (odds ratio [OR], 1.75; 95% CI, 1.36–2.24), but there was no effect on the selection of other components or on meal consumption. After long-term or extended exposure to the chef or smart café intervention, fruit selection increased in the chef (OR, 3.08; 95% CI, 2.23–4.25), smart café (OR, 1.45; 95% CI, 1.13–1.87), and chef plus smart café (OR, 3.10; 95% CI, 2.26–4.25) schools compared with the control schools, and consumption increased in the chef schools (OR, 0.17; 95% CI, 0.03–0.30 cups/d). Vegetable selection increased in the chef (OR, 2.54; 95% CI, 1.83–3.54), smart café (OR, 1.91; 95

  6. Reductions in Circulating Endocannabinoid Levels in Individuals with Post-Traumatic Stress Disorder Following Exposure to the World Trade Center Attacks

    Science.gov (United States)

    Hill, Matthew N.; Bierer, Linda M.; Makotkine, Iouri; Golier, Julia A.; Galea, Sandro; McEwen, Bruce S.; Hillard, Cecilia J.; Yehuda, Rachel

    2013-01-01

    Endocannabinoid (eCB) signaling has been identified as a modulator of adaptation to stress, and is integral to basal and stress-induced glucocorticoid regulation. Furthermore, interactions between eCBs and glucocorticoids have been shown to be necessary for the regulation of emotional memories, suggesting that eCB function may relate to the development of post-traumatic stress disorder (PTSD). To examine this, plasma eCBs were measured in a sample (n=46) drawn from a population-based cohort selected for physical proximity to the World Trade Center (WTC) at the time of the 9/11 attacks. Participants received a structured diagnostic interview and were grouped according to whether they met diagnostic criteria for PTSD (no PTSD, n=22; lifetime diagnosis of PTSD = 24). eCB content (2-arachidonoylglycerol (2-AG) and anandamide (AEA)) and cortisol were measured from 8 a.m. plasma samples. Circulating 2-AG content was significantly reduced among individuals meeting diagnostic criteria for PTSD. The effect of reduced 2-AG content in PTSD remained significant after controlling for the stress of exposure to the WTC collapse, gender, depression and alcohol abuse. There were no significant group differences for AEA or cortisol levels; however, across the whole sample AEA levels positively correlated with circulating cortisol, and AEA levels exhibited a negative relationship with the degree of intrusive symptoms within the PTSD sample. This report shows that PTSD is associated with a reduction in circulating levels of the eCB 2-AG. Given the role of 2-AG in the regulation of the stress response, these data support the hypothesis that deficient eCB signaling may be a component of the glucocorticoid dysregulation associated with PTSD. The negative association between AEA levels and intrusive symptoms is consistent with animal data indicating that reductions in AEA promote retention of aversive emotional memories. Future work will aim to replicate these findings and extend their

  7. Enhanced selective removal of Cu(II) from aqueous solution by novel polyethylenimine-functionalized ion imprinted hydrogel: Behaviors and mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jingjing [State Key Laboratory of Pollutant Control and Resource Reuse, Nanjing 210023 (China); School of the Environment, Nanjing University, Nanjing 210023 (China); Li, Zhengkui, E-mail: zhkuili@nju.edu.cn [State Key Laboratory of Pollutant Control and Resource Reuse, Nanjing 210023 (China); School of the Environment, Nanjing University, Nanjing 210023 (China)

    2015-12-30

    Highlights: • A novel ion-imprinted poly(polyethylenimine/hydroxyethyl acrylate) hydrogel was synthesized. • The prepared hydrogel enhanced the selectivity of Cu(II) removal. • The material had high adsorption capacity and excellent regeneration property for copper. • The adsorption mechanism was the chelate interaction between functional groups and Cu(II) ions. - Abstract: A novel polyethylenimine-functionalized ion-imprinted hydrogel (Cu(II)-p(PEI/HEA)) was newly synthesized by {sup 60}Co-γ-induced polymerization for the selective removal of Cu(II) from aqueous solution. The adsorption performances including the adsorption capacity and selectivity of the novel hydrogel were much better than those of similar adsorbents reported. The hydrogel was characterized via scanning electron microscope, transmission electron microscopy, Fourier transform infrared spectra, thermal gravimetric analysis and X-ray photoelectron spectroscopy to determine the structure and mechanisms. The adsorption process was pH and temperature sensitive, better fitted to pseudo-second-order equation, and was Langmuir monolayer adsorption. The maximum adsorption capacity for Cu(II) was 40.00 mg/g. The selectivity coefficients of ion-imprinted hydrogel for Cu(II)/Pb(II), Cu(II)/Cd(II) and Cu(II)/Ni(II) were 55.09, 107.47 and 63.12, respectively, which were 3.93, 4.25 and 3.53 times greater than those of non-imprinted hydrogel, respectively. Moreover, the adsorption capacity of Cu(II)-p(PEI/HEA) could still keep more than 85% after four adsorption–desorption cycles. Because of such enhanced selective removal performance and excellent regeneration property, Cu(II)-p(PEI/HEA) is a promising adsorbent for the selective removal of copper ions from wastewater.

  8. Selective sensitivity enhancement in FT-NMR

    International Nuclear Information System (INIS)

    Farrar, T.C.

    1987-01-01

    In this article the basic two-spin nuclear magnetic resonance (NMR) experiment and the new sensitivity enhancement experiments are reviewed. In part two of this two-part series an overview of two-dimensional NMR experiments will be presented. Part two will appear in the June 1 issue of Analytical Chemistry

  9. Mutagenic Effects of Ribavirin on Hepatitis E Virus—Viral Extinction versus Selection of Fitness-Enhancing Mutations

    Directory of Open Access Journals (Sweden)

    Daniel Todt

    2016-10-01

    Full Text Available Hepatitis E virus (HEV, an important agent of viral hepatitis worldwide, can cause severe courses of infection in pregnant women and immunosuppressed patients. To date, HEV infections can only be treated with ribavirin (RBV. Major drawbacks of this therapy are that RBV is not approved for administration to pregnant women and that the virus can acquire mutations, which render the intra-host population less sensitive or even resistant to RBV. One of the proposed modes of action of RBV is a direct mutagenic effect on viral genomes, inducing mismatches and subsequent nucleotide substitutions. These transition events can drive the already error-prone viral replication beyond an error threshold, causing viral population extinction. In contrast, the expanded heterogeneous viral population can facilitate selection of mutant viruses with enhanced replication fitness. Emergence of these mutant viruses can lead to therapeutic failure. Consequently, the onset of RBV treatment in chronically HEV-infected individuals can result in two divergent outcomes: viral extinction versus selection of fitness-enhanced viruses. Following an overview of RNA viruses treated with RBV in clinics and a summary of the different antiviral modes of action of this drug, we focus on the mutagenic effect of RBV on HEV intrahost populations, and how HEV is able to overcome lethal mutagenesis.

  10. Mutagenic Effects of Ribavirin on Hepatitis E Virus-Viral Extinction versus Selection of Fitness-Enhancing Mutations.

    Science.gov (United States)

    Todt, Daniel; Walter, Stephanie; Brown, Richard J P; Steinmann, Eike

    2016-10-13

    Hepatitis E virus (HEV), an important agent of viral hepatitis worldwide, can cause severe courses of infection in pregnant women and immunosuppressed patients. To date, HEV infections can only be treated with ribavirin (RBV). Major drawbacks of this therapy are that RBV is not approved for administration to pregnant women and that the virus can acquire mutations, which render the intra-host population less sensitive or even resistant to RBV. One of the proposed modes of action of RBV is a direct mutagenic effect on viral genomes, inducing mismatches and subsequent nucleotide substitutions. These transition events can drive the already error-prone viral replication beyond an error threshold, causing viral population extinction. In contrast, the expanded heterogeneous viral population can facilitate selection of mutant viruses with enhanced replication fitness. Emergence of these mutant viruses can lead to therapeutic failure. Consequently, the onset of RBV treatment in chronically HEV-infected individuals can result in two divergent outcomes: viral extinction versus selection of fitness-enhanced viruses. Following an overview of RNA viruses treated with RBV in clinics and a summary of the different antiviral modes of action of this drug, we focus on the mutagenic effect of RBV on HEV intrahost populations, and how HEV is able to overcome lethal mutagenesis.

  11. Development of Selectable Marker-Free Transgenic Rice Plants with Enhanced Seed Tocopherol Content through FLP/FRT-Mediated Spontaneous Auto-Excision.

    Directory of Open Access Journals (Sweden)

    Hee-Jong Woo

    Full Text Available Development of marker-free transgenic plants is a technical alternative for avoiding concerns about the safety of selectable marker genes used in genetically modified (GM crops. Here, we describe the construction of a spontaneous self-excision binary vector using an oxidative stress-inducible modified FLP/FRT system and its successful application to produce marker-free transgenic rice plants with enhanced seed tocopherol content. To generate selectable marker-free transgenic rice plants, we constructed a binary vector using the hpt selectable marker gene and the rice codon-optimized FLP (mFLP gene under the control of an oxidative stress-inducible promoter between two FRT sites, along with multiple cloning sites for convenient cloning of genes of interest. Using this pCMF binary vector with the NtTC gene, marker-free T1 transgenic rice plants expressing NtTC were produced by Agrobacterium-mediated stable transformation using hygromycin as a selective agent, followed by segregation of selectable marker genes. Furthermore, α-, γ-, and total tocopherol levels were significantly increased in seeds of the marker-free transgenic TC line compared with those of wild-type plants. Thus, this spontaneous auto-excision system, incorporating an oxidative stress-inducible mFLP/FRT system to eliminate the selectable marker gene, can be easily adopted and used to efficiently generate marker-free transgenic rice plants. Moreover, nutritional enhancement of rice seeds through elevation of tocopherol content coupled with this marker-free strategy may improve human health and public acceptance of GM rice.

  12. RIP INPUT TABLES FROM WAPDEG FOR LA DESIGN SELECTION: ENHANCED DESIGN ALTERNATIVE V

    International Nuclear Information System (INIS)

    K. Mon

    1999-01-01

    The purpose of this calculation is to document (1) the Waste Package Degradation (WAPDEG) version 3.09 (CRWMS M and O 1998b, Software Routine Report for WAPDEG (Version 3.09)) simulations used to analyze degradation and failure of 2-cm thick titanium grade 7 corrosion resistant material (CRM) drip shields (that are placed over waste packages composed of a 2-cm thick Alloy 22 corrosion resistant material (CRM) as the outer barrier and an unspecified material to provide structural support as the inner barrier) as well as degradation and failure of the waste packages themselves, and (2) post-processing of these results into tables of drip shield/waste package degradation time histories suitable for use as input into the Integrated Probabilistic Simulator for Environmental Systems (RIP) version 5.19.01 (Golder Associates 1998) computer code. Performance credit of the inner barrier material is not taken in this calculation. This calculation supports Performance Assessment analysis of the License Application Design Selection (LADS) Enhanced Design Alternative V. Additional details concerning the Enhanced Design Alternative V are provided in a Design Input Request (CRWMS M and O 1999e, Design Input Request for LADS Phase II EDA Evaluations, Item 3)

  13. Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

    Science.gov (United States)

    Navarro, Gemma; Borroto-Escuela, Dasiel; Angelats, Edgar; Etayo, Íñigo; Reyes-Resina, Irene; Pulido-Salgado, Marta; Rodríguez-Pérez, Ana I; Canela, Enric I; Saura, Josep; Lanciego, José Luis; Labandeira-García, José Luis; Saura, Carlos A; Fuxe, Kjell; Franco, Rafael

    2018-01-01

    Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB 1 and CB 2 receptors, which may form heteromeric complexes (CB 1 -CB 2 Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoid receptors in resting and LPS/IFN-γ-activated microglia. In activated microglia mRNA transcripts increased (2 fold for CB 1 and circa 20 fold for CB 2 ), whereas receptor levels were similar for CB 1 and markedly upregulated for CB 2 ; CB 1 -CB 2 Hets were also upregulated. Unlike in resting cells, CB 2 receptors became robustly coupled to G i in activated cells, in which CB 1 -CB 2 Hets mediated a potentiation effect. Hence, resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß 1-42 ). Microglial activation markers were detected in the striatum of a Parkinson's disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APP Sw,Ind ) mice, a transgenic Alzheimer's disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APP Sw,Ind and in cells from control animals activated using LPS plus IFN-γ. Expression of CB 1 -CB 2 Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB 1 -CB 2 Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB 1 -CB 2 heteroreceptor complex in activated microglia have potential as targets in the

  14. High Selectivity Oxygen Delignification

    Energy Technology Data Exchange (ETDEWEB)

    Lucian A. Lucia

    2005-11-15

    Project Objective: The objectives of this project are as follows: (1) Examine the physical and chemical characteristics of a partner mill pre- and post-oxygen delignified pulp and compare them to lab generated oxygen delignified pulps; (2) Apply the chemical selectivity enhancement system to the partner pre-oxygen delignified pulps under mill conditions (with and without any predetermined amounts of carryover) to determine how efficiently viscosity is preserved, how well selectivity is enhanced, if strength is improved, measure any yield differences and/or bleachability differences; and (3) Initiate a mill scale oxygen delignification run using the selectivity enhancement agent, collect the mill data, analyze it, and propose any future plans for implementation.

  15. Assessment of chronic thromboembolic pulmonary hypertension by three-dimensional contrast-enhanced MR angiography - comparison with selective intraarterial DSA

    International Nuclear Information System (INIS)

    Kreitner, K.F.; Ley, S.; Kauczor, H.U.; Kalden, P.; Pitton, M.B.; Thelen, M.; Mayer, E.; Laub, G.

    2000-01-01

    Purpose: This study compares contrast-enhanced 3D-MR angiography (MRA) of the pulmonary arteries with selective intraarterial DSA in patients with chronic thromboembolic pulmonary hypertension. Materials and methods: 20 patients preoperatively underwent a contrast-enhanced 3D-MRA of the pulmonary arteries at 1.5 T using the phased-array body coil. For MRA, we used a 3D-Flash-sequence after bolus timing. 2 radiologists analyzed the acquired image material in consensus with respect to the detection of central thromboembolic material and the visualization of the pulmonary arterial tree. Finally, the MR angiograms were compared with selective DSA images using surgical findings as the definitive standard. Results: MRA demonstrated central thromboembolic material, vessel cut-offs and abnormal proximal-to-distal tapering in all patients. Compared to DSA, MRA depicted the pulmonary vessels up to the segmental level in all cases, it was inferior to DSA in delineation of the subsegmental arteries (sensitivity 87%, specificity 100%). The central beginning of the thromboembolic occlusions seen at MRA corresponded to the beginning of the deobliteration procedure during pulmonary thromboendarterectomy in every case. (orig.) [de

  16. Gadofosveset-enhanced MR angiography of the pedal arteries in patients with diabetes mellitus and comparison with selective intraarterial DSA

    International Nuclear Information System (INIS)

    Roehrl, Boris; Kunz, Rainer Peter; Oberholzer, Katja; Pitton, Michael Bernhard; Dueber, Christoph; Kreitner, Karl-Friedrich; Neufang, Achim

    2009-01-01

    To compare gadofosveset-enhanced magnetic resonance angiography (MRA) of the pedal vasculature with selective intraarterial DSA. Eighteen patients with PAOD and type II diabetes were prospectively examined at 1.5 T. For contrast enhancement, 0.03 mmol/kg body weight gadofosveset was used. MR imaging consisted of dynamic and of high-resolution steady-state imaging. Selective digital subtraction angiography (DSA) was performed within 5 days and served as standard of reference. Image analysis was done by two observers. There were no differences between MRA and DSA regarding overall image quality. First-pass MRA detected significantly more patent vessel segments than did DSA (P < 0.001, kappa = 0.46). Interobserver agreement of MRA was very good with respect to the detection of patent vessel segments and the assessment of hemodynamically relevant stenoses (kappa = 0.97 and 0.89, respectively). Steady-state imaging depicted significantly more patent metatarsal arteries than did dynamic imaging, and delineated inflammatory complications including osteomyelitis, soft-tissue abscesses, and fistulas related to the diabetic foot. Gadofosveset-enhanced MRA of the pedal vasculature proved to be superior to DSA. It offered a long imaging time window, and allowed for better depiction of the pedal outflow. Steady-state imaging delineated inflammatory complications associated with the diabetic foot. (orig.)

  17. Gadofosveset-enhanced MR angiography of the pedal arteries in patients with diabetes mellitus and comparison with selective intraarterial DSA

    Energy Technology Data Exchange (ETDEWEB)

    Roehrl, Boris; Kunz, Rainer Peter; Oberholzer, Katja; Pitton, Michael Bernhard; Dueber, Christoph; Kreitner, Karl-Friedrich [Johannes Gutenberg University Mainz, Department of Diagnostic and Interventional Radiology, Mainz (Germany); Neufang, Achim [Johannes Gutenberg University Mainz, Department of Cardiothoracic and Vascular Surgery, Mainz (Germany)

    2009-12-15

    To compare gadofosveset-enhanced magnetic resonance angiography (MRA) of the pedal vasculature with selective intraarterial DSA. Eighteen patients with PAOD and type II diabetes were prospectively examined at 1.5 T. For contrast enhancement, 0.03 mmol/kg body weight gadofosveset was used. MR imaging consisted of dynamic and of high-resolution steady-state imaging. Selective digital subtraction angiography (DSA) was performed within 5 days and served as standard of reference. Image analysis was done by two observers. There were no differences between MRA and DSA regarding overall image quality. First-pass MRA detected significantly more patent vessel segments than did DSA (P < 0.001, kappa = 0.46). Interobserver agreement of MRA was very good with respect to the detection of patent vessel segments and the assessment of hemodynamically relevant stenoses (kappa = 0.97 and 0.89, respectively). Steady-state imaging depicted significantly more patent metatarsal arteries than did dynamic imaging, and delineated inflammatory complications including osteomyelitis, soft-tissue abscesses, and fistulas related to the diabetic foot. Gadofosveset-enhanced MRA of the pedal vasculature proved to be superior to DSA. It offered a long imaging time window, and allowed for better depiction of the pedal outflow. Steady-state imaging delineated inflammatory complications associated with the diabetic foot. (orig.)

  18. M13 Bacteriophage/Silver Nanowire Surface-Enhanced Raman Scattering Sensor for Sensitive and Selective Pesticide Detection.

    Science.gov (United States)

    Koh, Eun Hye; Mun, ChaeWon; Kim, ChunTae; Park, Sung-Gyu; Choi, Eun Jung; Kim, Sun Ho; Dang, Jaejeung; Choo, Jaebum; Oh, Jin-Woo; Kim, Dong-Ho; Jung, Ho Sang

    2018-03-28

    A surface-enhanced Raman scattering (SERS) sensor comprising silver nanowires (AgNWs) and genetically engineered M13 bacteriophages expressing a tryptophan-histidine-tryptophan (WHW) peptide sequence (BPWHW) was fabricated by simple mixing of BPWHW and AgNW solutions, followed by vacuum filtration onto a glass-fiber filter paper (GFFP) membrane. The AgNWs stacked on the GFFP formed a high density of SERS-active hot spots at the points of nanowire intersections, and the surface-coated BPWHW functioned as a bioreceptor for selective pesticide detection. The BPWHW-functionalized AgNW (BPWHW/AgNW) sensor was characterized by scanning electron microscopy, confocal scanning fluorescence microscopy, atomic force microscopy, and Fourier transform infrared spectroscopy. The Raman signal enhancement and the selective pesticide SERS detection properties of the BPWHW/AgNW sensor were investigated in the presence of control substrates such as wild-type M13 bacteriophage-decorated AgNWs (BPWT/AgNW) and undecorated AgNWs (AgNW). The BPWHW/AgNW sensor exhibited a significantly higher capture capability for pesticides, especially paraquat (PQ), than the control SERS substrates, and it also showed a relatively higher selectivity for PQ than for other bipyridylium pesticides such as diquat and difenzoquat. Furthermore, as a field application test, PQ was detected on the surface of PQ-pretreated apple peels, and the results demonstrated the feasibility of using a paper-based SERS substrate for on-site residual pesticide detection. The developed M13 bacteriophage-functionalized AgNW SERS sensor might be applicable for the detection of various pesticides and chemicals through modification of the M13 bacteriophage surface peptide sequence.

  19. Solid-State NMR on bacterial cells: selective cell wall signal enhancement and resolution improvement using dynamic nuclear polarization

    International Nuclear Information System (INIS)

    Takahashi, Hiroki; Bardet, Michel; De Paepe, Gael; Hediger, Sabine; Ayala, Isabel; Simorre, Jean-Pierre

    2013-01-01

    Dynamic nuclear polarization (DNP) enhanced solid-state nuclear magnetic resonance (NMR) has recently emerged as a powerful technique for the study of material surfaces. In this study, we demonstrate its potential to investigate cell surface in intact cells. Using Bacillus subtilis bacterial cells as an example, it is shown that the polarizing agent 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL) has a strong binding affinity to cell wall polymers (peptidoglycan). This particular interaction is thoroughly investigated with a systematic study on extracted cell wall materials, disrupted cells, and entire cells, which proved that TOTAPOL is mainly accumulating in the cell wall. This property is used on one hand to selectively enhance or suppress cell wall signals by controlling radical concentrations and on the other hand to improve spectral resolution by means of a difference spectrum. Comparing DNP-enhanced and conventional solid-state NMR, an absolute sensitivity ratio of 24 was obtained on the entire cell sample. This important increase in sensitivity together with the possibility of enhancing specifically cell wall signals and improving resolution really opens new avenues for the use of DNP-enhanced solid-state NMR as an on-cell investigation tool. (authors)

  20. Solid-state NMR on bacterial cells: selective cell wall signal enhancement and resolution improvement using dynamic nuclear polarization.

    Science.gov (United States)

    Takahashi, Hiroki; Ayala, Isabel; Bardet, Michel; De Paëpe, Gaël; Simorre, Jean-Pierre; Hediger, Sabine

    2013-04-03

    Dynamic nuclear polarization (DNP) enhanced solid-state nuclear magnetic resonance (NMR) has recently emerged as a powerful technique for the study of material surfaces. In this study, we demonstrate its potential to investigate cell surface in intact cells. Using Bacillus subtilis bacterial cells as an example, it is shown that the polarizing agent 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL) has a strong binding affinity to cell wall polymers (peptidoglycan). This particular interaction is thoroughly investigated with a systematic study on extracted cell wall materials, disrupted cells, and entire cells, which proved that TOTAPOL is mainly accumulating in the cell wall. This property is used on one hand to selectively enhance or suppress cell wall signals by controlling radical concentrations and on the other hand to improve spectral resolution by means of a difference spectrum. Comparing DNP-enhanced and conventional solid-state NMR, an absolute sensitivity ratio of 24 was obtained on the entire cell sample. This important increase in sensitivity together with the possibility of enhancing specifically cell wall signals and improving resolution really opens new avenues for the use of DNP-enhanced solid-state NMR as an on-cell investigation tool.

  1. Oxytocin increases attention to the eyes and selectively enhances self-reported affective empathy for fear.

    Science.gov (United States)

    Hubble, Kelly; Daughters, Katie; Manstead, Antony S R; Rees, Aled; Thapar, Anita; van Goozen, Stephanie H M

    2017-11-01

    Oxytocin (OXT) has previously been implicated in a range of prosocial behaviors such as trust and emotion recognition. Nevertheless, recent studies have questioned the evidence for this link. In addition, there has been relatively little conclusive research on the effect of OXT on empathic ability and such studies as there are have not examined the mechanisms through which OXT might affect empathy, or whether OXT selectively facilitates empathy for specific emotions. In the current study, we used eye-tracking to assess attention to socially relevant information while participants viewed dynamic, empathy-inducing video clips, in which protagonists expressed sadness, happiness, pain or fear. In a double-blind, within-subjects, randomized control trial, 40 healthy male participants received 24 IU intranasal OXT or placebo in two identical experimental sessions, separated by a 2-week interval. OXT led to an increase in time spent fixating upon the eye-region of the protagonist's face across emotions. OXT also selectively enhanced self-reported affective empathy for fear, but did not affect cognitive or affective empathy for other emotions. Nevertheless, there was no positive relationship between eye-gaze patterns and affective empathy, suggesting that although OXT influences eye-gaze and may enhance affective empathy for fear, these two systems are independent. Future studies need to further examine the effect of OXT on eye-gaze to fully ascertain whether this can explain the improvements in emotional behavior. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Adaptive enhancement of optical fringe patterns by selective reconstruction using FABEMD algorithm and Hilbert spiral transform.

    Science.gov (United States)

    Trusiak, Maciej; Patorski, Krzysztof; Wielgus, Maciej

    2012-10-08

    Presented method for fringe pattern enhancement has been designed for processing and analyzing low quality fringe patterns. It uses a modified fast and adaptive bidimensional empirical mode decomposition (FABEMD) for the extraction of bidimensional intrinsic mode functions (BIMFs) from an interferogram. Fringe pattern is then selectively reconstructed (SR) taking the regions of selected BIMFs with high modulation values only. Amplitude demodulation and normalization of the reconstructed image is conducted using the spiral phase Hilbert transform (HS). It has been tested using computer generated interferograms and real data. The performance of the presented SR-FABEMD-HS method is compared with other normalization techniques. Its superiority, potential and robustness to high fringe density variations and the presence of noise, modulation and background illumination defects in analyzed fringe patterns has been corroborated.

  3. Creaming enhancement in a liter scale ultrasonic reactor at selected transducer configurations and frequencies.

    Science.gov (United States)

    Juliano, Pablo; Temmel, Sandra; Rout, Manoj; Swiergon, Piotr; Mawson, Raymond; Knoerzer, Kai

    2013-01-01

    Recent research has shown that high frequency ultrasound (0.4-3 MHz), can enhance milkfat separation in small scale systems able to treat only a few milliliters of sample. In this work, the effect of ultrasonic standing waves on milkfat creaming was studied in a 6L reactor and the influence of different frequencies and transducer configurations in direct contact with the fluid was investigated. A recombined coarse milk emulsion with fat globules stained with oil-red-O dye was selected for the separation trials. Runs were performed with one or two transducers placed in vertical (parallel or perpendicular) and horizontal positions (at the reactor base) at 0.4, 1 and/or 2 MHz (specific energy 8.5 ± 0.6 kJ/kg per transducer). Creaming behavior was assessed by measuring the thickness of the separated cream layer. Other methods supporting this assessment included the measurement of fat content, backscattering, particle size distribution, and microscopy of samples taken at the bottom and top of the reactor. Most efficient creaming was found after treatment at 0.4 MHz in single and double vertical transducer configurations. Among these configurations, a higher separation rate was obtained when sonicating at 0.4 MHz in a vertical perpendicular double transducer setup. The horizontal transducer configuration promoted creaming at 2 MHz only. Fat globule size increase was observed when creaming occurred. This research highlights the potential for enhanced separation of milkfat in larger scale systems from selected transducer configurations in contact with a dairy emulsion, or emulsion splitting in general. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Enhancement of collective immunity in Tokyo metropolitan area by selective vaccination against an emerging influenza pandemic.

    Directory of Open Access Journals (Sweden)

    Masaya M Saito

    Full Text Available Vaccination is a preventive measure against influenza that does not require placing restrictions on social activities. However, since the stockpile of vaccine that can be prepared before the arrival of an emerging pandemic strain is generally quite limited, one has to select priority target groups to which the first stockpile is distributed. In this paper, we study a simulation-based priority target selection method with the goal of enhancing the collective immunity of the whole population. To model the region in which the disease spreads, we consider an urban area composed of suburbs and central areas connected by a single commuter train line. Human activity is modelled following an agent-based approach. The degree to which collective immunity is enhanced is judged by the attack rate in unvaccinated people. The simulation results show that if students and office workers are given exclusive priority in the first three months, the attack rate can be reduced from [Formula: see text] in the baseline case down to 1-2%. In contrast, random vaccination only slightly reduces the attack rate. It should be noted that giving preference to active social groups does not mean sacrificing those at high risk, which corresponds to the elderly in our simulation model. Compared with the random administration of vaccine to all social groups, this design successfully reduces the attack rate across all age groups.

  5. An enhanced PSO-DEFS based feature selection with biometric authentication for identification of diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Umarani Balakrishnan

    2016-11-01

    Full Text Available Recently, automatic diagnosis of diabetic retinopathy (DR from the retinal image is the most significant research topic in the medical applications. Diabetic macular edema (DME is the major reason for the loss of vision in patients suffering from DR. Early identification of the DR enables to prevent the vision loss and encourage diabetic control activities. Many techniques are developed to diagnose the DR. The major drawbacks of the existing techniques are low accuracy and high time complexity. To overcome these issues, this paper proposes an enhanced particle swarm optimization-differential evolution feature selection (PSO-DEFS based feature selection approach with biometric authentication for the identification of DR. Initially, a hybrid median filter (HMF is used for pre-processing the input images. Then, the pre-processed images are embedded with each other by using least significant bit (LSB for authentication purpose. Simultaneously, the image features are extracted using convoluted local tetra pattern (CLTrP and Tamura features. Feature selection is performed using PSO-DEFS and PSO-gravitational search algorithm (PSO-GSA to reduce time complexity. Based on some performance metrics, the PSO-DEFS is chosen as a better choice for feature selection. The feature selection is performed based on the fitness value. A multi-relevance vector machine (M-RVM is introduced to classify the 13 normal and 62 abnormal images among 75 images from 60 patients. Finally, the DR patients are further classified by M-RVM. The experimental results exhibit that the proposed approach achieves better accuracy, sensitivity, and specificity than the existing techniques.

  6. Mice Expressing a "Hyper-Sensitive" Form of the Cannabinoid Receptor 1 (CB1 Are Neither Obese Nor Diabetic.

    Directory of Open Access Journals (Sweden)

    David J Marcus

    Full Text Available Multiple lines of evidence implicate the endocannabinoid signaling system in the modulation of metabolic disease. Genetic or pharmacological inactivation of CB1 in rodents leads to reduced body weight, resistance to diet-induced obesity, decreased intake of highly palatable food, and increased energy expenditure. Cannabinoid agonists stimulate feeding in rodents and increased levels of endocannabinoids can disrupt lipid metabolism. Therefore, the hypothesis that sustained endocannabinoid signaling can lead to obesity and diabetes was examined in this study using S426A/S430A mutant mice expressing a desensitization-resistant CB1 receptor. These mice display exaggerated and prolonged responses to acute administration of phytocannabinoids, synthetic cannabinoids, and endocannabinoids. As a consequence these mice represent a novel model for determining the effect of enhanced endocannabinoid signaling on metabolic disease. S426A/S430A mutants consumed equivalent amounts of both high fat (45% and low fat (10% chow control diet compared to wild-type littermate controls. S426A/S430A mutants and wild-type mice fed either high or low fat control diet displayed similar fasting blood glucose levels and normal glucose clearance following a 2 g/kg glucose challenge. Furthermore, S426A/S430A mutants and wild-type mice consumed similar amounts of chow following an overnight fast. While both THC and JZL195 significantly increased food intake two hours after injection, this increase was similar between the S426A/S430A mutant and wildtype control mice Our results indicate that S426A/S430A mutant mice expressing the desensitization-resistant form of CB1 do not exhibit differences in body weight, food intake, glucose homeostasis, or re-feeding following a fast.

  7. Modifying Memory: Selectively Enhancing and Updating Personal Memories for a Museum Tour by Reactivating Them

    Science.gov (United States)

    St. Jacques, Peggy L.; Schacter, Daniel L.

    2013-01-01

    Memory can be modified when reactivated, but little is known about how the properties and extent of reactivation can selectively affect subsequent memory. We developed a novel museum paradigm to directly investigate reactivation-induced plasticity for personal memories. Participants reactivated memories triggered by photos taken from a camera they wore during a museum tour and made relatedness judgments on novel photos taken from a different tour of the same museum. Subsequent recognition memory for events at the museum was better for memories that were highly reactivated (i.e., the retrieval cues during reactivation matched the encoding experience) than for memories that were reactivated at a lower level (i.e., the retrieval cues during reactivation mismatched the encoding experience), but reactivation also increased false recognition of photographs depicting stops that were not experienced during the museum tour. Reactivation thus enables memories to be selectively enhanced and distorted via updating, thereby supporting the dynamic and flexible nature of memory. PMID:23406611

  8. ADRA2B deletion variant selectively predicts stress-induced enhancement of long-term memory in females.

    Science.gov (United States)

    Zoladz, Phillip R; Kalchik, Andrea E; Hoffman, Mackenzie M; Aufdenkampe, Rachael L; Lyle, Sarah M; Peters, David M; Brown, Callie M; Cadle, Chelsea E; Scharf, Amanda R; Dailey, Alison M; Wolters, Nicholas E; Talbot, Jeffery N; Rorabaugh, Boyd R

    2014-10-01

    Clarifying the mechanisms that underlie stress-induced alterations of learning and memory may lend important insight into susceptibility factors governing the development of stress-related psychological disorders, such as post-traumatic stress disorder (PTSD). Previous work has shown that carriers of the ADRA2B Glu(301)-Glu(303) deletion variant exhibit enhanced emotional memory, greater amygdala responses to emotional stimuli and greater intrusiveness of traumatic memories. We speculated that carriers of this deletion variant might also be more vulnerable to stress-induced enhancements of long-term memory, which would implicate the variant as a possible susceptibility factor for traumatic memory formation. One hundred and twenty participants (72 males, 48 females) submerged their hand in ice cold (stress) or warm (no stress) water for 3min. Immediately afterwards, they studied a list of 42 words varying in emotional valence and arousal and then completed an immediate free recall test. Twenty-four hours later, participants' memory for the word list was examined via free recall and recognition assessments. Stressed participants exhibiting greater heart rate responses to the stressor had enhanced recall on the 24-h assessment. Importantly, this enhancement was independent of the emotional nature of the learned information. In contrast to previous work, we did not observe a general enhancement of memory for emotional information in ADRA2B deletion carriers. However, stressed female ADRA2B deletion carriers, particularly those exhibiting greater heart rate responses to the stressor, did demonstrate greater recognition memory than all other groups. Collectively, these findings implicate autonomic mechanisms in the pre-learning stress-induced enhancement of long-term memory and suggest that the ADRA2B deletion variant may selectively predict stress effects on memory in females. Such findings lend important insight into the physiological mechanisms underlying stress

  9. Enhanced phosphate selectivity from wastewater using copper-loaded chelating resin functionalized with polyethylenimine.

    Science.gov (United States)

    An, Byungryul; Nam, Juhee; Choi, Jae-Woo; Hong, Seok-Won; Lee, Sang-Hyup

    2013-11-01

    In water and wastewater, phosphate is considered a critical contaminant due to cause algae blooms and eutrophication. To meet the stringent regulation of phosphate in water, a new commercial chelating resin functionalized with polyethylenimine was tested for phosphate removal by loading Cu(2+) and Fe(2+)/Fe(3+) to enhance selectivity for phosphate. Batch and column experiments showed that CR20-Cu exhibited high selectivity for phosphate over other strong anions such as sulfate. The average binary phosphate/nitrate and phosphate/sulfate factors for CR20-Cu were calculated to be 7.3 and 4.8, respectively, which were more than 0.97 and 0.22 for a commercial anion exchanger (AMP16). The optimal pH for the phosphate removal efficiency was determined to be 7. According to the fixed-bed column test, the breakthrough sequence for multiple ions was HPO4(2-)>SO4(2-)>NO3(-)>Cl(-). Saturated CR20-Cu can be regenerated using 4% NaCl at pH 7. More than 95% of the phosphate from CR20-Cu was recovered, and the phosphate uptake capacity for CR20-Cu was not reduced after 7 regeneration cycles. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. A Selection Method for Power Generation Plants Used for Enhanced Geothermal Systems (EGS

    Directory of Open Access Journals (Sweden)

    Kaiyong Hu

    2016-07-01

    Full Text Available As a promising and advanced technology, enhanced geothermal systems (EGS can be used to generate electricity using deep geothermal energy. In order to better utilize the EGS to produce electricity, power cycles’ selection maps are generated for people to choose the best system based on the geofluids’ temperature and dryness conditions. Optimizations on double-flash system (DF, flash-organic Rankine cycle system (FORC, and double-flash-organic Rankine cycle system (DFORC are carried out, and the single-flash (SF system is set as a reference system. The results indicate that each upgraded system (DF, FORC, and DFORC can produce more net power output compared with the SF system and can reach a maximum net power output under a given geofluid condition. For an organic Rankine cycle (ORC using R245fa as working fluid, the generated selection maps indicate that using the FORC system can produce more power than using other power cycles when the heat source temperature is below 170 °C. Either DF or DFORC systems could be an option if the heat source temperature is above 170 °C, but the DF system is more attractive under a relatively lower geofluid’s dryness and a higher temperature condition.

  11. Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M4 PAM VU0467154.

    Science.gov (United States)

    Gould, Robert W; Grannan, Michael D; Gunter, Barak W; Ball, Jacob; Bubser, Michael; Bridges, Thomas M; Wess, Jurgen; Wood, Michael W; Brandon, Nicholas J; Duggan, Mark E; Niswender, Colleen M; Lindsley, Craig W; Conn, P Jeffrey; Jones, Carrie K

    2018-01-01

    Although selective activation of the M 1 muscarinic acetylcholine receptor (mAChR) subtype has been shown to improve cognitive function in animal models of neuropsychiatric disorders, recent evidence suggests that enhancing M 4 mAChR function can also improve memory performance. Positive allosteric modulators (PAMs) targeting the M 4 mAChR subtype have shown therapeutic potential for the treatment of multiple symptoms observed in schizophrenia, including positive and cognitive symptoms when assessed in acute preclinical dosing paradigms. Since the cholinergic system has been implicated in multiple stages of learning and memory, we evaluated the effects of repeated dosing with the highly selective M 4 PAM VU0467154 on either acquisition and/or consolidation of learning and memory when dosed alone or after pharmacologic challenge with the N-methyl-d-aspartate subtype of glutamate receptors (NMDAR) antagonist MK-801. MK-801 challenge represents a well-documented preclinical model of NMDAR hypofunction that is thought to underlie some of the positive and cognitive symptoms observed in schizophrenia. In wildtype mice, 10-day, once-daily dosing of VU0467154 either prior to, or immediately after daily testing enhanced the rate of learning in a touchscreen visual pairwise discrimination task; these effects were absent in M 4 mAChR knockout mice. Following a similar 10-day, once-daily dosing regimen of VU0467154, we also observed 1) improved acquisition of memory in a cue-mediated conditioned freezing paradigm, 2) attenuation of MK-801-induced disruptions in the acquisition of memory in a context-mediated conditioned freezing paradigm and 3) reversal of MK-801-induced hyperlocomotion. Comparable efficacy and plasma and brain concentrations of VU0467154 were observed after repeated dosing as those previously reported with an acute, single dose administration of this M 4 PAM. Together, these studies are the first to demonstrate that cognitive enhancing and antipsychotic

  12. The Cannabinoid System and Pain

    Science.gov (United States)

    Woodhams, Stephen G.; Chapman, Victoria; Finn, David P.; Hohmann, Andrea G.; Neugebauer, Volker

    2018-01-01

    Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1 receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain. PMID:28625720

  13. Postsynaptic Depolarization Enhances GABA Drive to Dorsomedial Hypothalamic Neurons through Somatodendritic Cholecystokinin Release.

    Science.gov (United States)

    Crosby, Karen M; Baimoukhametova, Dinara V; Bains, Jaideep S; Pittman, Quentin J

    2015-09-23

    Somatodendritically released peptides alter synaptic function through a variety of mechanisms, including autocrine actions that liberate retrograde transmitters. Cholecystokinin (CCK) is a neuropeptide expressed in neurons in the dorsomedial hypothalamic nucleus (DMH), a region implicated in satiety and stress. There are clear demonstrations that exogenous CCK modulates food intake and neuropeptide expression in the DMH, but there is no information on how endogenous CCK alters synaptic properties. Here, we provide the first report of somatodendritic release of CCK in the brain in male Sprague Dawley rats. CCK is released from DMH neurons in response to repeated postsynaptic depolarizations, and acts in an autocrine fashion on CCK2 receptors to enhance postsynaptic NMDA receptor function and liberate the retrograde transmitter, nitric oxide (NO). NO subsequently acts presynaptically to enhance GABA release through a soluble guanylate cyclase-mediated pathway. These data provide the first demonstration of synaptic actions of somatodendritically released CCK in the hypothalamus and reveal a new form of retrograde plasticity, depolarization-induced potentiation of inhibition. Significance statement: Somatodendritic signaling using endocannabinoids or nitric oxide to alter the efficacy of afferent transmission is well established. Despite early convincing evidence for somatodendritic release of neurohypophysial peptides in the hypothalamus, there is only limited evidence for this mode of release for other peptides. Here, we provide the first evidence for somatodendritic release of the satiety peptide cholecystokinin (CCK) in the brain. We also reveal a new form of synaptic plasticity in which postsynaptic depolarization results in enhancement of inhibition through the somatodendritic release of CCK. Copyright © 2015 the authors 0270-6474/15/3513160-11$15.00/0.

  14. DNA abasic site-selective enhancement of sanguinarine fluorescence with a large emission shift.

    Directory of Open Access Journals (Sweden)

    Fei Wu

    Full Text Available Small molecules that can specifically bind to a DNA abasic site (AP site have received much attention due to their importance in DNA lesion identification, drug discovery, and sensor design. Herein, the AP site binding behavior of sanguinarine (SG, a natural alkaloid, was investigated. In aqueous solution, SG has a short-wavelength alkanolamine emission band and a long-wavelength iminium emission band. At pH 8.3, SG experiences a fluorescence quenching for both bands upon binding to fully matched DNAs without the AP site, while the presence of the AP site induces a strong SG binding and the observed fluorescence enhancement for the iminium band are highly dependent on the nucleobases flanking the AP site, while the alkanolamine band is always quenched. The bases opposite the AP site also exert some modifications on the SG's emission behavior. It was found that the observed quenching for DNAs with Gs and Cs flanking the AP site is most likely caused by electron transfer between the AP site-bound excited-state SG and the nearby Gs. However, the flanking As and Ts that are not easily oxidized favor the enhanced emission. This AP site-selective enhancement of SG fluorescence accompanies a band conversion in the dominate emission from the alkanolamine to iminium band thus with a large emission shift of about 170 nm. Absorption spectra, steady-state and transient-state fluorescence, DNA melting, and electrolyte experiments confirm that the AP site binding of SG occurs and the stacking interaction with the nearby base pairs is likely to prevent the converted SG iminium form from contacting with water that is thus emissive when the AP site neighbors are bases other than guanines. We expect that this fluorophore would be developed as a promising AP site binder having a large emission shift.

  15. Selective enhancement of main olfactory input to the medial amygdala by GnRH.

    Science.gov (United States)

    Blake, Camille Bond; Meredith, Michael

    2010-03-04

    In male hamsters mating behavior is dependent on chemosensory input from the main olfactory and vomeronasal systems, whose central pathways contain cell bodies and fibers of gonadotropin-releasing hormone (GnRH) neurons. In sexually naive males, vomeronasal organ removal (VNX), but not main olfactory lesions, impairs mating behavior. Intracerebroventricular (i.c.v.)-GnRH restores mating in sexually naive VNX males and enhances medial amygdala (Me) immediate-early gene activation by chemosensory stimulation. In sexually experienced males, VNX does not impair mating and i.c.v.-GnRH suppresses Me activation. Thus, the main olfactory system is sufficient for mating in experienced-VNX males, but not in naive-VNX males. We investigated the possibility that GnRH enhances main olfactory input to the amygdala in naive-VNX males using i.c.v.-GnRH and pharmacological stimulation (bicuculline/D,L-homocysteic acid mixture) of the main olfactory bulb (MOB). In sexually naive intact males there was a robust increase of Fos protein expression in the anteroventral medial amygdala (MeAv) with MOB stimulation, but no effect of GnRH. There was no effect of stimulation or GnRH in posterodorsal medial amygdala (MePd). In naive-VNX animals, GnRH increased Fos in MeAv and MePv. Only combined MOB stimulation and i.c.v.-GnRH produced a significant increase in Fos in the dorsal (reproduction-related) portion of MeP (MePd). When the animals were sexually experienced before VNX, a condition in which GnRH does not enhance mating, i.c.v.-GnRH combined with MOB stimulation suppressed Fos expression in MePd. This suggests a more selective effect of GnRH on olfactory input in MePd than elsewhere in medial amygdala of VNX males. 2009 Elsevier B.V. All rights reserved.

  16. Inhibition of monoacylglycerol lipase (MAGL) enhances cue-induced reinstatement of nicotine-seeking behavior in mice.

    Science.gov (United States)

    Trigo, Jose M; Le Foll, Bernard

    2016-05-01

    Tobacco smoking is still a major population health issue. The endocannabinoid system has been shown to control drug-seeking behaviors. There are two main endocannabinoids: anandamide degraded by fatty acid amide hydrolase (FAAH) and 2-arachidonoylglycerol (2-AG) degraded by monoacylglycerol lipase (MAGL). The role of MAGL has only been explored recently, and so far, no study have been performed to evaluate the effects of MAGL inhibitor on nicotine reinforcing properties and cue-induced reinstatement of nicotine seeking. Here, we investigated the effects of the MAGL inhibitor JZL184 on nicotine self-administration under fixed and progressive-ratio schedules of reinforcement and on cue-induced reinstatement of nicotine seeking in mice. We also evaluated the effects of JZL184 on food self-administration for possible non-specific effects. JZL184 (0, 8, and 16 mg/kg) did not affect food taking, nicotine taking, or motivation for nicotine. MAGL inhibition by JZL184 (16 mg/kg) increased reinstatement of previously extinguished nicotine seeking induced by presentation of nicotine-associated cues, but did not produce reinstatement on its own. This study implicates involvement of 2-AG in nicotine-seeking behaviors.

  17. Longevity enhances selection of environmental sex determination.

    Science.gov (United States)

    Bull, J J; Bulmer, M G

    1989-12-01

    Environmental sex determination (ESD) is a mechanism in which an individual develops as male or female largely in response to some environmental effect experienced early in life. Its forms range from sex determination by egg incubation temperature in reptiles to sex determination of photoperiod in amphipods. Previous theoretical work as suggested that ESD is favored by natural selection if the fitness consequences of the early environmental experience differ for males and females, so that an individual benefits by being male under some conditions and female under others. A drawback of ESD is that it enables climatic changes to influence the population sex ratio, and such fluctuations select against ESD. This study employed numerical analyses to investigate the balance between these two opposing forces. The negative impact of climatic fluctuations appears to depend greatly on species longevity: substantial between-year fluctuations are of little consequence in selecting against ESD in long-lived species because annual sex ratio fluctuations tend to cancel and thus alter the total population sex ratio only slightly. Thus, if a species is sufficiently long-lived, extreme ESD can be maintained despite only a weak advantage. This result offers one explanation for the failure to demonstrate an advantage for the extreme forms of ESD observed in reptiles.

  18. ENHANCEMENTS TO NATURAL ATTENUATION: SELECTED CASE STUDIES

    Energy Technology Data Exchange (ETDEWEB)

    Vangelas, K; W. H. Albright, W; E. S. Becvar, E; C. H. Benson, C; T. O. Early, T; E. Hood, E; P. M. Jardine, P; M. Lorah, M; E. Majche, E; D. Major, D; W. J. Waugh, W; G. Wein, G; O. R. West, O

    2007-05-15

    In 2003 the US Department of Energy (DOE) embarked on a project to explore an innovative approach to remediation of subsurface contaminant plumes that focused on introducing mechanisms for augmenting natural attenuation to achieve site closure. Termed enhanced attenuation (EA), this approach has drawn its inspiration from the concept of monitored natural attenuation (MNA).

  19. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects

    Directory of Open Access Journals (Sweden)

    Eva M Marco

    2011-10-01

    Full Text Available Public concern on mental health has noticeably increased given the high prevalence of neuropsychiatric disorders. Cognition and emotionality are the most affected functions in neuropsychiatric disorders, i.e. anxiety disorders, depression and schizophrenia. In this review, most relevant literature on the role of the endocannabinoid (eCB system in neuropsychiatric disorders will be presented. Evidence from clinical and animal studies is provided for the participation of CB1 and CB2 receptors (CB1R and CB2R in the above mentioned neuropsychiatric disorders. CBRs are crucial in some of the emotional and cognitive impairments reported, although more research is required to understand the specific role of the eCB system in neuropsychiatric disorders. Cannabidiol (CBD, the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders. Although further studies are needed, recent studies indicate that CBD therapeutic effects may partially depend on facilitation of eCB-mediated neurotransmission. Last but not least, this review includes recent findings on the role of the eCB system in eating disorders. A deregulation of the eCB system has been proposed to be in the bases of several neuropsychiatric disorders, including eating disorders. Cannabis consumption has been related to the appearance of psychotic symptoms and schizophrenia. In contrast, the pharmacological manipulation of this eCB system has been proposed as a potential strategy for the treatment of anxiety disorders, depression, and anorexia nervosa. In conclusion, the eCB system plays a critical role in psychiatry; however, detrimental consequences of manipulating this endogenous system cannot be underestimated over the potential and promising perspectives of its therapeutic manipulation.

  20. Harm reduction-the cannabis paradox

    Directory of Open Access Journals (Sweden)

    Melamede Robert

    2005-09-01

    Full Text Available Abstract This article examines harm reduction from a novel perspective. Its central thesis is that harm reduction is not only a social concept, but also a biological one. More specifically, evolution does not make moral distinctions in the selection process, but utilizes a cannabis-based approach to harm reduction in order to promote survival of the fittest. Evidence will be provided from peer-reviewed scientific literature that supports the hypothesis that humans, and all animals, make and use internally produced cannabis-like products (endocannabinoids as part of the evolutionary harm reduction program. More specifically, endocannabinoids homeostatically regulate all body systems (cardiovascular, digestive, endocrine, excretory, immune, nervous, musculo-skeletal, reproductive. Therefore, the health of each individual is dependant on this system working appropriately.

  1. Selective Memories: Infants' Encoding Is Enhanced in Selection via Suppression

    Science.gov (United States)

    Markant, Julie; Amso, Dima

    2013-01-01

    The present study examined the hypothesis that inhibitory visual selection mechanisms play a vital role in memory by limiting distractor interference during item encoding. In Experiment 1a we used a modified spatial cueing task in which 9-month-old infants encoded multiple category exemplars in the contexts of an attention orienting mechanism…

  2. Hydrogen Oxidation-Selective Electrocatalysis by Fine Tuning of Pt Ensemble Sites to Enhance the Durability of Automotive Fuel Cells.

    Science.gov (United States)

    Yun, Su-Won; Park, Shin-Ae; Kim, Tae-June; Kim, Jun-Hyuk; Pak, Gi-Woong; Kim, Yong-Tae

    2017-02-08

    A simple, inexpensive approach is proposed for enhancing the durability of automotive proton exchange membrane fuel cells by selective promotion of the hydrogen oxidation reaction (HOR) and suppression of the oxygen reduction reaction (ORR) at the anode in startup/shutdown events. Dodecanethiol forms a self-assembled monolayer (SAM) on the surface of Pt particles, thus decreasing the number of Pt ensemble sites. Interestingly, by controlling the dodecanethiol concentration during SAM formation, the number of ensemble sites can be precisely optimized such that it is sufficient for the HOR but insufficient for the ORR. Thus, a Pt surface with an SAM of dodecanethiol clearly effects HOR-selective electrocatalysis. Clear HOR selectivity is demonstrated in unit cell tests with the actual membrane electrode assembly, as well as in an electrochemical three-electrode setup with a thin-film rotating disk electrode configuration. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Enhancement of Selection, Bubble and Insertion Sorting Algorithm

    OpenAIRE

    Muhammad Farooq Umar; Ehsan Ullah Munir; Shafqat Ali Shad; Muhammad Wasif Nisar

    2014-01-01

    In everyday life there is a large amount of data to arrange because sorting removes any ambiguities and make the data analysis and data processing very easy, efficient and provides with cost less effort. In this study a set of improved sorting algorithms are proposed which gives better performance and design idea. In this study five new sorting algorithms (Bi-directional Selection Sort, Bi-directional bubble sort, MIDBiDirectional Selection Sort, MIDBidirectional bubble sort and linear insert...

  4. Effects of choice architecture and chef-enhanced meals on the selection and consumption of healthier school foods: a randomized clinical trial.

    Science.gov (United States)

    Cohen, Juliana F W; Richardson, Scott A; Cluggish, Sarah A; Parker, Ellen; Catalano, Paul J; Rimm, Eric B

    2015-05-01

    Little is known about the long-term effect of a chef-enhanced menu on healthier food selection and consumption in school lunchrooms. In addition, it remains unclear if extended exposure to other strategies to promote healthier foods (eg, choice architecture) also improves food selection or consumption. To evaluate the short- and long-term effects of chef-enhanced meals and extended exposure to choice architecture on healthier school food selection and consumption. A school-based randomized clinical trial was conducted during the 2011-2012 school year among 14 elementary and middle schools in 2 urban, low-income school districts (intent-to-treat analysis). Included in the study were 2638 students in grades 3 through 8 attending participating schools (38.4% of eligible participants). Schools were first randomized to receive a professional chef to improve school meal palatability (chef schools) or to a delayed intervention (control group). To assess the effect of choice architecture (smart café), all schools after 3 months were then randomized to the smart café intervention or to the control group. School food selection was recorded, and consumption was measured using plate waste methods. After 3 months, vegetable selection increased in chef vs control schools (odds ratio [OR], 1.75; 95% CI, 1.36-2.24), but there was no effect on the selection of other components or on meal consumption. After long-term or extended exposure to the chef or smart café intervention, fruit selection increased in the chef (OR, 3.08; 95% CI, 2.23-4.25), smart café (OR, 1.45; 95% CI, 1.13-1.87), and chef plus smart café (OR, 3.10; 95% CI, 2.26-4.25) schools compared with the control schools, and consumption increased in the chef schools (OR, 0.17; 95% CI, 0.03-0.30 cups/d). Vegetable selection increased in the chef (OR, 2.54; 95% CI, 1.83-3.54), smart café (OR, 1.91; 95% CI, 1.46-2.50), and chef plus smart café schools (OR, 7.38, 95% CI, 5.26-10.35) compared with the control schools

  5. Highly selective and sensitive detection of Cu2+ with lysine enhancing bovine serum albumin modified-carbon dots fluorescent probe.

    Science.gov (United States)

    Liu, Jia-Ming; Lin, Li-ping; Wang, Xin-Xing; Lin, Shao-Qin; Cai, Wen-Lian; Zhang, Li-Hong; Zheng, Zhi-Yong

    2012-06-07

    Based on the ability of lysine (Lys) to enhance the fluorescence intensity of bovine serum albumin modified-carbon dots (CDs-BSA) to decrease surface defects and quench fluorescence of the CDs-BSA-Lys system in the presence of Cu(2+) under conditions of phosphate buffer (PBS, pH = 5.0) at 45 °C for 10 min, a sensitive Lys enhancing CDs-BSA fluorescent probe was designed. The environment-friendly, simple, rapid, selective and sensitive fluorescent probe has been utilized to detect Cu(2+) in hair and tap water samples and it achieved consistent results with those obtained by inductively coupled plasma mass spectroscopy (ICP-MS). The mechanism of the proposed assay for the detection of Cu(2+) is discussed.

  6. Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

    Science.gov (United States)

    Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

    2015-02-01

    A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on

  7. Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back

    Directory of Open Access Journals (Sweden)

    Roberto Coccurello

    2018-04-01

    Full Text Available Palatable food can be seductive and hedonic eating can become irresistible beyond hunger and negative consequences. This is witnessed by the subtle equilibrium between eating to provide energy intake for homeostatic functions, and reward-induced overeating. In recent years, considerable efforts have been devoted to study neural circuits, and to identify potential factors responsible for the derangement of homeostatic eating toward hedonic eating and addiction-like feeding behavior. Here, we examined recent literature on “old” and “new” players accountable for reward-induced overeating and possible liability to eating addiction. Thus, the role of midbrain dopamine is positioned at the intersection between selected hormonal signals involved in food reward information processing (namely, leptin, ghrelin, and insulin, and lipid-derived neural mediators such as endocannabinoids. The impact of high fat palatable food and dietary lipids on endocannabinoid formation is reviewed in its pathogenetic potential for the derangement of feeding homeostasis. Next, endocannabinoid signaling that regulates synaptic plasticity is discussed as a key mechanism acting both at hypothalamic and mesolimbic circuits, and affecting both dopamine function and interplay between leptin and ghrelin signaling. Outside the canonical hypothalamic feeding circuits involved in energy homeostasis and the notion of “feeding center,” we focused on lateral hypothalamus as neural substrate able to confront food-associated homeostatic information with food salience, motivation to eat, reward-seeking, and development of compulsive eating. Thus, the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry is reexamined in order to interrogate the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling. We suggested a pivotal role for endocannabinoids in food reward processing within the lateral hypothalamus, and for orexin

  8. Biotechnological approaches to enhance salidroside, rosin and its derivatives production in selected Rhodiola spp. in vitro cultures.

    Science.gov (United States)

    Grech-Baran, Marta; Sykłowska-Baranek, Katarzyna; Pietrosiuk, Agnieszka

    Rhodiola (Crassulaceae) an arctic-alpine plant, is extensively used in traditional folk medicine in Asian and European countries. A number of investigations have demonstrated that Rhodiola preparations exhibit adaptogenic, neuroprotective, anti-tumour, cardioprotective, and anti-depressant effects. The main compounds responsible for these activities are believed to be salidroside, rosin and its derivatives which became the target of biotechnological investigations. This review summarizes the results of the diverse biotechnological approaches undertaken to enhance the production of salidroside, rosin and its derivatives in callus, cell suspension and organ in vitro cultures of selected Rhodiola species.

  9. Enzastaurin (LY317615), a Protein Kinase C Beta Selective Inhibitor, Enhances Antiangiogenic Effect of Radiation

    International Nuclear Information System (INIS)

    Willey, Christopher D.; Xiao Dakai; Tu Tianxiang; Kim, Kwang Woon; Moretti, Luigi; Niermann, Kenneth J.; Tawtawy, Mohammed N.; Quarles, Chad C. Ph.D.; Lu Bo

    2010-01-01

    Purpose: Angiogenesis has generated interest in oncology because of its important role in cancer growth and progression, particularly when combined with cytotoxic therapies, such as radiotherapy. Among the numerous pathways influencing vascular growth and stability, inhibition of protein kinase B(Akt) or protein kinase C(PKC) can influence tumor blood vessels within tumor microvasculature. Therefore, we wanted to determine whether PKC inhibition could sensitize lung tumors to radiation. Methods and Materials: The combination of the selective PKCβ inhibitor Enzastaurin (ENZ, LY317615) and ionizing radiation were used in cell culture and a mouse model of lung cancer. Lung cancer cell lines and human umbilical vascular endothelial cells (HUVEC) were examined using immunoblotting, cytotoxic assays including cell proliferation and clonogenic assays, and Matrigel endothelial tubule formation. In vivo, H460 lung cancer xenografts were examined for tumor vasculature and proliferation using immunohistochemistry. Results: ENZ effectively radiosensitizes HUVEC within in vitro models. Furthermore, concurrent ENZ treatment of lung cancer xenografts enhanced radiation-induced destruction of tumor vasculature and proliferation by IHC. However, tumor growth delay was not enhanced with combination treatment compared with either treatment alone. Analysis of downstream effectors revealed that HUVEC and the lung cancer cell lines differed in their response to ENZ and radiation such that only HUVEC demonstrate phosphorylated S6 suppression, which is downstream of mTOR. When ENZ was combined with the mTOR inhibitor, rapamycin, in H460 lung cancer cells, radiosensitization was observed. Conclusion: PKC appears to be crucial for angiogenesis, and its inhibition by ENZ has potential to enhance radiotherapy in vivo.

  10. alpha7 Nicotinic acetylcholine receptor knockout selectively enhances ethanol-, but not beta-amyloid-induced neurotoxicity.

    Science.gov (United States)

    de Fiebre, Nancyellen C; de Fiebre, Christopher M

    2005-01-03

    The alpha7 subtype of nicotinic acetylcholine receptor (nAChR) has been implicated as a potential site of action for two neurotoxins, ethanol and the Alzheimer's disease related peptide, beta-amyloid. Here, we utilized primary neuronal cultures of cerebral cortex from alpha7 nAChR null mutant mice to examine the role of this receptor in modulating the neurotoxic properties of subchronic, "binge" ethanol and beta-amyloid. Knockout of the alpha7 nAChR gene selectively enhanced ethanol-induced neurotoxicity in a gene dosage-related fashion. Susceptibility of cultures to beta-amyloid induced toxicity, however, was unaffected by alpha7 nAChR gene null mutation. Further, beta-amyloid did not inhibit the binding of the highly alpha7-selective radioligand, [(125)I]alpha-bungarotoxin. On the other hand, in studies in Xenopus oocytes ethanol efficaciously inhibited alpha7 nAChR function. These data suggest that alpha7 nAChRs modulate the neurotoxic effects of binge ethanol, but not the neurotoxicity produced by beta-amyloid. It is hypothesized that inhibition of alpha7 nAChRs by ethanol provides partial protection against the neurotoxic properties of subchronic ethanol.

  11. The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation

    Directory of Open Access Journals (Sweden)

    Murphy Niamh

    2012-04-01

    observed an age-related decrease in LTP in the dentate gyrus which was partially restored in URB597-treated aged rats. The data suggest that enhancement of levels of endocannabinoids in the brain by URB597 has beneficial effects on synaptic function, perhaps by modulating microglial activation.

  12. Holotransferrin enhances selective anticancer activity of artemisinin against human hepatocellular carcinoma cells.

    Science.gov (United States)

    Deng, Xiao-rong; Liu, Zhao-xia; Liu, Feng; Pan, Lei; Yu, He-ping; Jiang, Jin-ping; Zhang, Jian-jun; Liu, Li; Yu, Jun

    2013-12-01

    Artemisinin, also termed qinghaosu, is extracted from the traditional Chinese medicine artemesia annua L. (the blue-green herb) in the early 1970s, which has been confirmed for effectively treating malaria. Additionally, emerging data prove that artemisinin exhibits anti-cancer effects against many types of cancers such as leukemia, melanoma, etc. Artemisinin becomes cytotoxic in the presence of ferrous iron. Since iron influx is high in cancer cells, artemisinin and its analogs selectively kill cancer cells with increased intracellular iron concentrations. This study is aimed to investigate the selective inhibitory effects of artemisinin on SMMC-7721 cells in vitro and determine the effect of holotransferrin, which increases the concentration of ferrous iron in cancer cells, combined with artemisinin on the anticancer activity. MTT assay was used for assessing the proliferation of SMMC-7721 cells treated with artemisinin. The induction of apoptosis and inhibition of colony formation in SMMC-7721 cells treated with artemisinin were determined by TdT-mediated dUTP nick end labeling (TUNEL) and colony formation assay, respectively. The results showed that artemisinin at various concentrations significantly inhibited growth, colony formation and cell viability of SMMC-7721 cells (P<0.05), likely due to induction of apoptosis of SMMC-7721 cells. Of interest, it was found that incubation of artemisinin combined with holotransferrin sensitized the growth inhibitory effect of artemisinin on SMMC-7721 cells (P<0.01). Our data suggest that treatment with artemisinin leads to inhibition of viability and proliferation, and apoptosis of SMMC-7721 cells. Furthermore, we observed that holotransferrin significantly enhanced the anti-cancer activity of artemisinin. This study may provide a potential therapeutic choice for liver cancer.

  13. RIP Input Tables From Wapdeg For LA Design Selection: Enhanced Design Alternative IIIb

    International Nuclear Information System (INIS)

    K.G. Mon; K.G. Mast; J.H. Lee

    1999-01-01

    The purpose of this calculation is to document the Waste Package Degradation (WAPDEG) version 3.09 (CRWMS M and O 1998b. 'Software Routine Report for WAPDEG' (Version 3.09)) simulations used to analyze degradation and failure of 2-cm thick titanium grade 7 corrosion resistant material (CRM) drip shields as well as degradation and failure of the waste packages over which they are placed. The waste packages are composed of two corrosion resistant materials (CRM) barriers. The outer barrier is composed of 2 cm of Alloy 22 and the inner barrier is composed of 1.5 cm of titanium grade 7. The WAPDEG simulation results are post-processed into tables of drip shield/waste package degradation time histories suitable for use as input into the Integrated Probabilistic Simulator for Environmental Systems (RIP) version 5.19.01 (Golder Associates 1998) computer code. This calculation supports Performance Assessment analysis of the License Application Design Selection (LADS) Enhanced Design Alternative IIIb

  14. A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice.

    Science.gov (United States)

    Bilkei-Gorzo, Andras; Albayram, Onder; Draffehn, Astrid; Michel, Kerstin; Piyanova, Anastasia; Oppenheimer, Hannah; Dvir-Ginzberg, Mona; Rácz, Ildiko; Ulas, Thomas; Imbeault, Sophie; Bab, Itai; Schultze, Joachim L; Zimmer, Andreas

    2017-06-01

    The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ 9 -tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.

  15. Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer's disease and Less Well-Known Diseases.

    Science.gov (United States)

    Paez, Juan A; Campillo, Nuria E

    2018-02-25

    The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer's disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. An application of zeta potential method for the selection of nano-fluids to enhance IVR capability

    International Nuclear Information System (INIS)

    Pham Quynh Trang; Kim, Tae Il; Chang, Soon Heung

    2009-01-01

    In-vessel Retention (IVR) is one of the key severe accident management strategies that have been applied currently for advanced light water reactors such as APR1000 or APR1400. The concept of IVR consists of external cooling of the reactor vessel by flooding the reactor cavity to remove the decay heat from the molten core through the lower head of the vessel. However, the heat removal process is limited by the occurrence of critical heat flux (CHF) at the reactor vessel outer surface that may lead to a sharp increase of local temperature, damaging the integrity of the reactor vessel. In order to obtain higher power of nuclear reactors and to assure the achievement of the IVR capability during accident conditions, an enhancement of CHF at the outer surface of the vessel is required. The potential use of nano-fluids to increase the CHF is among the main IVR enhancing approaches. In this study, Al 2 O 3 and CNT nano-fluids with different concentrations have been used as the potential coolant to enhance IVR capabilities. The dispersion stability of the nano-fluids was verified by zeta potential measurements. The results showed effects of time, concentration and pH on the stability of nanofluids. Three types of nano-fluids were selected as the candidates to apply for the IVR. A series of experiments have been performed in this study to understand the pool-boiling critical heat flux behavior on downward facing surfaces submerged in a pool of nano-fluids at very low concentration. The inclination angle was changed from horizontal to vertical to investigate the effect of orientation on CHF enhancement which is needed for the application in IVR

  17. (-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain.

    Science.gov (United States)

    Knoll, J; Yoneda, F; Knoll, B; Ohde, H; Miklya, I

    1999-12-01

    1. The brain constituents beta-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain ('catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (-)Deprenyl (Selegiline) and (-)1-phenyl-2-propylaminopentane [(-)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property. 2. By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (-)1-(benzofuran-2-yl)-2-propylaminopentane [(-)BPAP] was selected as a potential follower of (-)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain. 3. (-)BPAP significantly enhanced in 0.18 micromol 1(-1) concentration the impulse propagation mediated release of [(3)H]-noradrenaline and [(3)H]-dopamine and in 36 nmol 1(-1) concentration the release of [(3)H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10(-12) - 10(-14) M (-)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of beta-amyloid in 10(-14) M concentration. In rats (-)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 microg kg(-1) s.c. In the shuttle box, (-)BPAP in rats was about 130 times more potent than (-)deprenyl in antagonizing tetrabenazine induced inhibition of performance.

  18. Motivation of medical students: selection by motivation or motivation by selection.

    Science.gov (United States)

    Wouters, Anouk; Croiset, Gerda; Galindo-Garre, Francisca; Kusurkar, Rashmi A

    2016-01-29

    Medical schools try to implement selection procedures that will allow them to select the most motivated students for their programs. Though there is a general feeling that selection stimulates student motivation, conclusive evidence for this is lacking. The current study aims to use the perspective of Self-determination Theory (SDT) of motivation as a lens to examine how medical students' motivation differs in relation to different selection procedures. The hypotheses were that 1) selected students report higher strength and autonomous motivation than non-selected students, and 2) recently selected students report higher strength and autonomous motivation than non-selected students and students who were selected longer ago. First- (Y1) and fourth-year (Y4) medical students in the six-year regular programme and first-year students in the four-year graduate entry programme (GE) completed questionnaires measuring motivation strength and type (autonomous-AM, controlled-CM). Scores were compared between students admitted based on selection, lottery or top pre-university GPA (top GPA) using ANCOVAs. Selected students' answers on open-ended questions were analysed using inductive thematic analysis to identify reasons for changes in motivation. The response rate was 61.4 % (n = 357). Selected students (Y1, Y4 and GE) reported a significantly higher strength of motivation than non-selected students (Y1 and Y4 lottery and top GPA) (p motivation as they felt autonomous, competent and that they belonged to a special group. These reported reasons are in alignment with the basic psychological needs described by Self-Determination Theory as important in enhancing autonomous motivation. A comprehensive selection procedure, compared to less demanding admission procedures, does not seem to yield a student population which stands out in terms of autonomous motivation. The current findings indicate that selection might temporarily enhance students' motivation. The mechanism

  19. Replica Node Detection Using Enhanced Single Hop Detection with Clonal Selection Algorithm in Mobile Wireless Sensor Networks

    Directory of Open Access Journals (Sweden)

    L. S. Sindhuja

    2016-01-01

    Full Text Available Security of Mobile Wireless Sensor Networks is a vital challenge as the sensor nodes are deployed in unattended environment and they are prone to various attacks. One among them is the node replication attack. In this, the physically insecure nodes are acquired by the adversary to clone them by having the same identity of the captured node, and the adversary deploys an unpredictable number of replicas throughout the network. Hence replica node detection is an important challenge in Mobile Wireless Sensor Networks. Various replica node detection techniques have been proposed to detect these replica nodes. These methods incur control overheads and the detection accuracy is low when the replica is selected as a witness node. This paper proposes to solve these issues by enhancing the Single Hop Detection (SHD method using the Clonal Selection algorithm to detect the clones by selecting the appropriate witness nodes. The advantages of the proposed method include (i increase in the detection ratio, (ii decrease in the control overhead, and (iii increase in throughput. The performance of the proposed work is measured using detection ratio, false detection ratio, packet delivery ratio, average delay, control overheads, and throughput. The implementation is done using ns-2 to exhibit the actuality of the proposed work.

  20. Enhanced selective removal of Cu(II) from aqueous solution by novel polyethylenimine-functionalized ion imprinted hydrogel: Behaviors and mechanisms.

    Science.gov (United States)

    Wang, Jingjing; Li, Zhengkui

    2015-12-30

    A novel polyethylenimine-functionalized ion-imprinted hydrogel (Cu(II)-p(PEI/HEA)) was newly synthesized by (60)Co-γ-induced polymerization for the selective removal of Cu(II) from aqueous solution. The adsorption performances including the adsorption capacity and selectivity of the novel hydrogel were much better than those of similar adsorbents reported. The hydrogel was characterized via scanning electron microscope, transmission electron microscopy, Fourier transform infrared spectra, thermal gravimetric analysis and X-ray photoelectron spectroscopy to determine the structure and mechanisms. The adsorption process was pH and temperature sensitive, better fitted to pseudo-second-order equation, and was Langmuir monolayer adsorption. The maximum adsorption capacity for Cu(II) was 40.00 mg/g. The selectivity coefficients of ion-imprinted hydrogel for Cu(II)/Pb(II), Cu(II)/Cd(II) and Cu(II)/Ni(II) were 55.09, 107.47 and 63.12, respectively, which were 3.93, 4.25 and 3.53 times greater than those of non-imprinted hydrogel, respectively. Moreover, the adsorption capacity of Cu(II)-p(PEI/HEA) could still keep more than 85% after four adsorption-desorption cycles. Because of such enhanced selective removal performance and excellent regeneration property, Cu(II)-p(PEI/HEA) is a promising adsorbent for the selective removal of copper ions from wastewater. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes

    International Nuclear Information System (INIS)

    Newsom-Davis, J.; Willcox, N.; Calder, L.

    1981-01-01

    We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 10 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responder's thymic cells, irradiated to abrogate antibody production and suppression (P<0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlated with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P<0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases

  2. Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Newsom-Davis, J.; Willcox, N.; Calder, L.

    1981-11-26

    We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 10 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responder's thymic cells, irradiated to abrogate antibody production and suppression (P<0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlated with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P<0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases.

  3. Lack of association of genetic variants in genes of the endocannabinoid system with anorexia nervosa

    Directory of Open Access Journals (Sweden)

    Herpertz-Dahlmann Beate

    2008-11-01

    Full Text Available Abstract Background Several lines of evidence indicate that the central cannabinoid receptor 1 (CNR1 as well as the major endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH, N-acylethanolamine-hydrolyzing acid amidase (NAAA and monoglyceride lipase (MGLL are implicated in mediating the orexigenic effects of cannabinoids. The aim of this study was to analyse whether nucleotide sequence variations in the CNR1, FAAH, NAAA and MGLL genes are associated with anorexia nervosa (AN. Methods We analysed the association of a previously described (AATn repeat in the 3' flanking region of CNR1 as well as a total of 15 single nucleotide polymorphisms (SNPs representative of regions with restricted haplotype diversity in CNR1, FAAH, NAAA or MGLL in up to 91 German AN trios (patient with AN and both biological parents using the transmission-disequilibrium-test (TDT. One SNP was additionally analysed in an independent case-control study comprising 113 patients with AN and 178 normal weight controls. Genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, ARMS-PCR or using 3730xl capillary sequencers. Results The TDT revealed no evidence for association for any of the SNPs or the (AATn repeat with AN (all two-sided uncorrected p-values > 0.05. The lowest p-value of 0.11 was detected for the A-allele of the CNR1 SNP rs1049353 for which the transmission rate was 59% (95% confidence interval 47%...70%. Further genotyping of rs1049353 in 113 additional independent patients with AN and 178 normal weight controls could not substantiate the initial trend for association (p = 1.00. Conclusion As we found no evidence for an association of genetic variation in CNR1, FAAH, NAAA and MGLL with AN, we conclude that genetic variations in these genes do not play a major role in the etiology of AN in our study groups.

  4. Layered double hydroxide-enhanced luminescence in a Fenton-like system for selective sensing of cobalt in Hela cells

    Science.gov (United States)

    Yu, Mei; Yuan, Zhiqin; Lu, Chao

    2017-09-01

    This work presented a facile and eco-friendly method for the determination of cobalt ions (Co(II)) in living cells based on layered double hydroxides (Mg-Al CO3-LDHs) enhanced chemiluminescence (CL) emission of a Co(II)-hydrogen peroxide-sodium hydroxide system. The enhanced CL emission was attributed to the large specific surface area of Mg-Al CO3-LDHs, which facilitates the generation of an excited-stated intermediate. The proposed method displayed high selectivity toward Co(II) over other metal ions. Under the optimal conditions, the increased CL intensity showed a linear response versus Co(II) concentration in the range of 5.0-1000 nM with a detection limit of 3.7 nM (S/N = 3). The relative standard deviation for nine repeated measurements of 100 nM Co(II) was 3.2%. Furthermore, the proposed method was successfully applied to detect Co(II) in living cell samples, and the results were agreed with those obtained by the standard ICP-MS method.

  5. Enhancing the Durability and Carrier Selectivity of Perovskite Solar Cells Using a Blend Interlayer.

    Science.gov (United States)

    Sin, Dong Hun; Jo, Sae Byeok; Lee, Seung Goo; Ko, Hyomin; Kim, Min; Lee, Hansol; Cho, Kilwon

    2017-05-31

    A mechanically and thermally stable and electron-selective ZnO/CH 3 NH 3 PbI 3 interface is created via hybridization of a polar insulating polymer, poly(ethylene glycol) (PEG), into ZnO nanoparticles (NPs). PEG successfully passivates the oxygen defects on ZnO and prevents direct contact between CH 3 NH 3 PbI 3 and defects on ZnO. A uniform CH 3 NH 3 PbI 3 film is formed on a soft ZnO:PEG layer after dispersion of the residual stress from the volume expansion during CH 3 NH 3 PbI 3 conversion. PEG also increases the work of adhesion of the CH 3 NH 3 PbI 3 film on the ZnO:PEG layer and holds the CH 3 NH 3 PbI 3 film with hydrogen bonding. Furthermore, PEG tailors the interfacial electronic structure of ZnO, reducing the electron affinity of ZnO. As a result, a selective electron-collection cathode is formed with a reduced electron affinity and a deep-lying valence band of ZnO, which significantly enhances the carrier lifetime (473 μs) and photovoltaic performance (15.5%). The mechanically and electrically durable ZnO:PEG/CH 3 NH 3 PbI 3 interface maintains the sustainable performance of the solar cells over 1 year. A soft and durable cathodic interface via PEG hybridization in a ZnO layer is an effective strategy toward flexible electronics and commercialization of the perovskite solar cells.

  6. Sustained selective attention to competing amplitude-modulations in human auditory cortex.

    Science.gov (United States)

    Riecke, Lars; Scharke, Wolfgang; Valente, Giancarlo; Gutschalk, Alexander

    2014-01-01

    Auditory selective attention plays an essential role for identifying sounds of interest in a scene, but the neural underpinnings are still incompletely understood. Recent findings demonstrate that neural activity that is time-locked to a particular amplitude-modulation (AM) is enhanced in the auditory cortex when the modulated stream of sounds is selectively attended to under sensory competition with other streams. However, the target sounds used in the previous studies differed not only in their AM, but also in other sound features, such as carrier frequency or location. Thus, it remains uncertain whether the observed enhancements reflect AM-selective attention. The present study aims at dissociating the effect of AM frequency on response enhancement in auditory cortex by using an ongoing auditory stimulus that contains two competing targets differing exclusively in their AM frequency. Electroencephalography results showed a sustained response enhancement for auditory attention compared to visual attention, but not for AM-selective attention (attended AM frequency vs. ignored AM frequency). In contrast, the response to the ignored AM frequency was enhanced, although a brief trend toward response enhancement occurred during the initial 15 s. Together with the previous findings, these observations indicate that selective enhancement of attended AMs in auditory cortex is adaptive under sustained AM-selective attention. This finding has implications for our understanding of cortical mechanisms for feature-based attentional gain control.

  7. Sustained Selective Attention to Competing Amplitude-Modulations in Human Auditory Cortex

    Science.gov (United States)

    Riecke, Lars; Scharke, Wolfgang; Valente, Giancarlo; Gutschalk, Alexander

    2014-01-01

    Auditory selective attention plays an essential role for identifying sounds of interest in a scene, but the neural underpinnings are still incompletely understood. Recent findings demonstrate that neural activity that is time-locked to a particular amplitude-modulation (AM) is enhanced in the auditory cortex when the modulated stream of sounds is selectively attended to under sensory competition with other streams. However, the target sounds used in the previous studies differed not only in their AM, but also in other sound features, such as carrier frequency or location. Thus, it remains uncertain whether the observed enhancements reflect AM-selective attention. The present study aims at dissociating the effect of AM frequency on response enhancement in auditory cortex by using an ongoing auditory stimulus that contains two competing targets differing exclusively in their AM frequency. Electroencephalography results showed a sustained response enhancement for auditory attention compared to visual attention, but not for AM-selective attention (attended AM frequency vs. ignored AM frequency). In contrast, the response to the ignored AM frequency was enhanced, although a brief trend toward response enhancement occurred during the initial 15 s. Together with the previous findings, these observations indicate that selective enhancement of attended AMs in auditory cortex is adaptive under sustained AM-selective attention. This finding has implications for our understanding of cortical mechanisms for feature-based attentional gain control. PMID:25259525

  8. Mice expressing a "hyper-sensitive" form of the CB1 cannabinoid receptor (CB1 show modestly enhanced alcohol preference and consumption.

    Directory of Open Access Journals (Sweden)

    David J Marcus

    Full Text Available We recently characterized S426A/S430A mutant mice expressing a desensitization-resistant form of the CB1 receptor. These mice display an enhanced response to endocannabinoids and ∆9-THC. In this study, S426A/S430A mutants were used as a novel model to test whether ethanol consumption, morphine dependence, and reward for these drugs are potentiated in mice with a "hyper-sensitive" form of CB1. Using an unlimited-access, two-bottle choice, voluntary drinking paradigm, S426A/S430A mutants exhibit modestly increased intake and preference for low (6% but not higher concentrations of ethanol. S426A/S430A mutants and wild-type mice show similar taste preference for sucrose and quinine, exhibit normal sensitivity to the hypothermic and ataxic effects of ethanol, and have normal blood ethanol concentrations following administration of ethanol. S426A/S430A mutants develop robust conditioned place preference for ethanol (2 g/kg, morphine (10 mg/kg, and cocaine (10 mg/kg, demonstrating that drug reward is not changed in S426A/S430A mutants. Precipitated morphine withdrawal is also unchanged in opioid-dependent S426A/S430A mutant mice. Although ethanol consumption is modestly changed by enhanced CB1 signaling, reward, tolerance, and acute sensitivity to ethanol and morphine are normal in this model.

  9. Biodegradation Resistance and Bioactivity of Hydroxyapatite Enhanced Mg-Zn Composites via Selective Laser Melting.

    Science.gov (United States)

    Shuai, Cijun; Zhou, Yuanzhuo; Yang, Youwen; Feng, Pei; Liu, Long; He, Chongxian; Zhao, Mingchun; Yang, Sheng; Gao, Chengde; Wu, Ping

    2017-03-17

    Mg-Zn alloys have attracted great attention as implant biomaterials due to their biodegradability and biomechanical compatibility. However, their clinical application was limited due to the too rapid degradation. In the study, hydroxyapatite (HA) was incorporated into Mg-Zn alloy via selective laser melting. Results showed that the degradation rate slowed down due to the decrease of grain size and the formation of protective layer of bone-like apatite. Moreover, the grain size continually decreased with increasing HA content, which was attributed to the heterogeneous nucleation and increased number of nucleation particles in the process of solidification. At the same time, the amount of bone-like apatite increased because HA could provide favorable areas for apatite nucleation. Besides, HA also enhanced the hardness due to the fine grain strengthening and second phase strengthening. However, some pores occurred owing to the agglomerate of HA when its content was excessive, which decreased the biodegradation resistance. These results demonstrated that the Mg-Zn/HA composites were potential implant biomaterials.

  10. Interaction Between the Cannabinoid and Vanilloid Systems on Anxiety in Male Rats

    Directory of Open Access Journals (Sweden)

    Nafiseh Faraji

    2017-03-01

    Conclusion: Acute neuropharmacological blockade of the TRPV1 receptor or stimulation of the CB1 receptor produced an anxiolytic effect. It seems that antagonism of the vanilloid system modulates cannabinoid outputs that increase the anxiolytic effect. TRPV1 antagonism may alter endocannabinoids production, which in turn enhances anxiolytic effect. These results suggest interaction of two systems or sharing some signaling pathways that affect anxiety expression.

  11. Production enhancement partnerships -- successful business arrangements

    International Nuclear Information System (INIS)

    Coble, L.; Weitzel, K.; Attai, L.; Gray, K.

    1995-01-01

    Production enhancement projects are creating changes in business relationships between oil and gas and service companies. The most successful projects are building partnerships. Service companies are being asked to share the risk while supplying services to enhance well performance. Risk sharing creates common project objectives and requires the service company's involvement in initial project planning, job design, and reservoir understanding. Service work compensation is based on well or field performance improvement as a result of the treatment(s). This paper presents an integrated approach to the selection and prioritization of well candidates for production enhancement jobs or treatments. Special emphasis is placed on reservoir understanding using field reviews and/or extensive reservoir description studies to provide the essential information for well candidate selection and the best return on investment. Processes are illustrated and discussion gives the data requirements and techniques used to select and prioritize well candidates. Field examples demonstrate the techniques, critical factors, and appropriate software used by geoscience and field operations teams to maximize benefits from production enhancement projects

  12. Exploring the chemical enhancement for surface-enhanced Raman scattering with Au bowtie nanoantennas

    International Nuclear Information System (INIS)

    Fromm, David P.; Sundaramurthy, Arvind; Kinkhabwala, Anika; Schuck, P. James; Kino, Gordon S.; Moerner, W.E.

    2006-01-01

    Single metallic bowtie nanoantennas provide a controllable environment for surface-enhanced Raman scattering (SERS) of adsorbed molecules. Bowties have experimentally measured electromagnetic enhancements, enabling estimation of chemical enhancement for both the bulk and the few-molecule regime. Strong fluctuations of selected Raman lines imply that a small number of p-mercaptoaniline molecules on a single bowtie show chemical enhancement >10 7 , much larger than previously believed, likely due to charge transfer between the Au surface and the molecule. This chemical sensitivity of SERS has significant implications for ultra-sensitive detection of single molecules

  13. Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents

    International Nuclear Information System (INIS)

    Kim, Jae Ho; Kim, Sang Hie; Kolozsvary, A.

    1995-01-01

    The purpose of this investigation was to demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents. Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses or irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation. The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 μg/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 ± 0.1 and 1.3 ± 0.1, respectively. Exposure of cells to 10 μg/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 ± 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone. An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors. 25 refs., 6 figs

  14. Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae Ho; Kim, Sang Hie; Kolozsvary, A. [Henry Ford Hospital, Detroit, MI (United States)] [and others

    1995-11-01

    The purpose of this investigation was to demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents. Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses or irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation. The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 {mu}g/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 {plus_minus} 0.1 and 1.3 {plus_minus} 0.1, respectively. Exposure of cells to 10 {mu}g/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 {plus_minus} 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone. An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors. 25 refs., 6 figs.

  15. Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents

    International Nuclear Information System (INIS)

    Jae, Ho Kim; Sang, Hie Kim; Kolozsvary, Andrew; Brown, Stephen L.; Ok, Bae Kim; Freytag, Svend O.

    1995-01-01

    Purpose: To demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents. Methods and Materials: Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses of irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation. Results: The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 μg/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 ± 0.1 and 1.3 ± 0.1, respectively. Exposure of cells to 10 μg/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 ± 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone. Conclusion: An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors

  16. Inactivation of Anandamide Signaling: A Continuing Debate

    Directory of Open Access Journals (Sweden)

    Wael E. Houssen

    2010-10-01

    Full Text Available Since the first endocannabinoid anandamide was identified in 1992, extensive research has been conducted to characterize the elements of the tightly controlled endocannabinoid signaling system. While it was established that the activity of endocannabinoids are terminated by a two-step process that includes cellular uptake and degradation, there is still a continuing debate about the mechanistic role of these processes in inactivating anandamide signals.

  17. Mice expressing a “hyper-sensitive” form of the CB1 cannabinoid receptor (CB1) show modestly enhanced alcohol preference and consumption

    Science.gov (United States)

    Gonek, Maciej; Zee, Michael L.; Farnsworth, Jill C.; Amin, Randa A.; Andrews, Mary-Jeanette; Davis, Brian J.; Mackie, Ken; Morgan, Daniel J.

    2017-01-01

    We recently characterized S426A/S430A mutant mice expressing a desensitization-resistant form of the CB1 receptor. These mice display an enhanced response to endocannabinoids and ∆9-THC. In this study, S426A/S430A mutants were used as a novel model to test whether ethanol consumption, morphine dependence, and reward for these drugs are potentiated in mice with a “hyper-sensitive” form of CB1. Using an unlimited-access, two-bottle choice, voluntary drinking paradigm, S426A/S430A mutants exhibit modestly increased intake and preference for low (6%) but not higher concentrations of ethanol. S426A/S430A mutants and wild-type mice show similar taste preference for sucrose and quinine, exhibit normal sensitivity to the hypothermic and ataxic effects of ethanol, and have normal blood ethanol concentrations following administration of ethanol. S426A/S430A mutants develop robust conditioned place preference for ethanol (2 g/kg), morphine (10 mg/kg), and cocaine (10 mg/kg), demonstrating that drug reward is not changed in S426A/S430A mutants. Precipitated morphine withdrawal is also unchanged in opioid-dependent S426A/S430A mutant mice. Although ethanol consumption is modestly changed by enhanced CB1 signaling, reward, tolerance, and acute sensitivity to ethanol and morphine are normal in this model. PMID:28426670

  18. Enhancement of Thermal Stability and Selectivity by Introducing Aminotriazine Comonomer to Poly(Octadecyl Acrylate-Grafted Silica as Chromatography Matrix

    Directory of Open Access Journals (Sweden)

    Abul K. Mallik

    2018-02-01

    Full Text Available This paper introduces a poly(octadecyl acrylate (pODA-based organic phase on silica, which is assisted by 2-vinyl-4,6-diamino-1,3,5-triazine (AT, for a chromatography stationary phase. The ODA-AT copolymer grafting onto silica surface was characterized by elemental analysis, FT-IR spectroscopy, scanning electron microscopy, thermo gravimetric analysis and differential scanning calorimeter (DSC. An endothermic peak top of the copolymer-grafted silica was increased to 46 °C from 38 °C, which was a peak top of pODA homopolymer. For high performance liquid chromatography (HPLC application, the molecular selectivity increased with an increase in the AT contents of the ODA-AT copolymer as organic phase. The co-existence of an aminotriazine moiety in the copolymer promoted side-chain ordering of the poly(octadecyl moiety, thus enhancing molecular planarity selectivity for PAHs in reversed-phase liquid chromatography.

  19. Dendritic spikes amplify the synaptic signal to enhance detection of motion in a simulation of the direction-selective ganglion cell.

    Directory of Open Access Journals (Sweden)

    Michael J Schachter

    2010-08-01

    Full Text Available The On-Off direction-selective ganglion cell (DSGC in mammalian retinas responds most strongly to a stimulus moving in a specific direction. The DSGC initiates spikes in its dendritic tree, which are thought to propagate to the soma with high probability. Both dendritic and somatic spikes in the DSGC display strong directional tuning, whereas somatic PSPs (postsynaptic potentials are only weakly directional, indicating that spike generation includes marked enhancement of the directional signal. We used a realistic computational model based on anatomical and physiological measurements to determine the source of the enhancement. Our results indicate that the DSGC dendritic tree is partitioned into separate electrotonic regions, each summing its local excitatory and inhibitory synaptic inputs to initiate spikes. Within each local region the local spike threshold nonlinearly amplifies the preferred response over the null response on the basis of PSP amplitude. Using inhibitory conductances previously measured in DSGCs, the simulation results showed that inhibition is only sufficient to prevent spike initiation and cannot affect spike propagation. Therefore, inhibition will only act locally within the dendritic arbor. We identified the role of three mechanisms that generate directional selectivity (DS in the local dendritic regions. First, a mechanism for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null side of the cell's dendritic tree and weakens it on the preferred side. Second, spatially offset postsynaptic inhibition generates robust DS in the isolated dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently necessary because it is more robust across the dendritic tree. The pre- and postsynaptic mechanisms together can overcome the local intrinsic DS. These local dendritic mechanisms can perform independent nonlinear computations to make a decision, and there could be analogous mechanisms within

  20. Dendritic spikes amplify the synaptic signal to enhance detection of motion in a simulation of the direction-selective ganglion cell.

    Science.gov (United States)

    Schachter, Michael J; Oesch, Nicholas; Smith, Robert G; Taylor, W Rowland

    2010-08-19

    The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas responds most strongly to a stimulus moving in a specific direction. The DSGC initiates spikes in its dendritic tree, which are thought to propagate to the soma with high probability. Both dendritic and somatic spikes in the DSGC display strong directional tuning, whereas somatic PSPs (postsynaptic potentials) are only weakly directional, indicating that spike generation includes marked enhancement of the directional signal. We used a realistic computational model based on anatomical and physiological measurements to determine the source of the enhancement. Our results indicate that the DSGC dendritic tree is partitioned into separate electrotonic regions, each summing its local excitatory and inhibitory synaptic inputs to initiate spikes. Within each local region the local spike threshold nonlinearly amplifies the preferred response over the null response on the basis of PSP amplitude. Using inhibitory conductances previously measured in DSGCs, the simulation results showed that inhibition is only sufficient to prevent spike initiation and cannot affect spike propagation. Therefore, inhibition will only act locally within the dendritic arbor. We identified the role of three mechanisms that generate directional selectivity (DS) in the local dendritic regions. First, a mechanism for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null side of the cell's dendritic tree and weakens it on the preferred side. Second, spatially offset postsynaptic inhibition generates robust DS in the isolated dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently necessary because it is more robust across the dendritic tree. The pre- and postsynaptic mechanisms together can overcome the local intrinsic DS. These local dendritic mechanisms can perform independent nonlinear computations to make a decision, and there could be analogous mechanisms within cortical circuitry.

  1. Selective Activation of M4 Muscarinic Acetylcholine Receptors Reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents

    Science.gov (United States)

    2015-01-01

    Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders. PMID:25137629

  2. Simultaneously enhanced strength and ductility for 3D-printed stainless steel 316L by selective laser melting

    Science.gov (United States)

    Sun, Zhongji; Tan, Xipeng; Tor, Shu Beng; Chua, Chee Kai

    2018-04-01

    Laser-based powder-bed fusion additive manufacturing or three-dimensional printing technology has gained tremendous attention due to its controllable, digital, and automated manufacturing process, which can afford a refined microstructure and superior strength. However, it is a major challenge to additively manufacture metal parts with satisfactory ductility and toughness. Here we report a novel selective laser melting process to simultaneously enhance the strength and ductility of stainless steel 316L by in-process engineering its microstructure into a crystallographic texture. We find that the tensile strength and ductility of SLM-built stainless steel 316L samples could be enhanced by 16% and 40% respectively, with the engineered textured microstructure compared to the common textured microstructure. This is because the favorable nano-twinning mechanism was significantly more activated in the textured stainless steel 316L samples during plastic deformation. In addition, kinetic simulations were performed to unveil the relationship between the melt pool geometry and crystallographic texture. The new additive manufacturing strategy of engineering the crystallographic texture can be applied to other metals and alloys with twinning-induced plasticity. This work paves the way to additively manufacture metal parts with high strength and high ductility.

  3. Non-Invasive Brain Stimulation to Enhance Upper Limb Motor Practice Poststroke: A Model for Selection of Cortical Site

    Directory of Open Access Journals (Sweden)

    Michelle L. Harris-Love

    2017-05-01

    Full Text Available Motor practice is an essential part of upper limb motor recovery following stroke. To be effective, it must be intensive with a high number of repetitions. Despite the time and effort required, gains made from practice alone are often relatively limited, and substantial residual impairment remains. Using non-invasive brain stimulation to modulate cortical excitability prior to practice could enhance the effects of practice and provide greater returns on the investment of time and effort. However, determining which cortical area to target is not trivial. The implications of relevant conceptual frameworks such as Interhemispheric Competition and Bimodal Balance Recovery are discussed. In addition, we introduce the STAC (Structural reserve, Task Attributes, Connectivity framework, which incorporates patient-, site-, and task-specific factors. An example is provided of how this framework can assist in selecting a cortical region to target for priming prior to reaching practice poststroke. We suggest that this expanded patient-, site-, and task-specific approach provides a useful model for guiding the development of more successful approaches to neuromodulation for enhancing motor recovery after stroke.

  4. Enhancement web proxy cache performance using Wrapper Feature Selection methods with NB and J48

    Science.gov (United States)

    Mahmoud Al-Qudah, Dua'a.; Funke Olanrewaju, Rashidah; Wong Azman, Amelia

    2017-11-01

    Web proxy cache technique reduces response time by storing a copy of pages between client and server sides. If requested pages are cached in the proxy, there is no need to access the server. Due to the limited size and excessive cost of cache compared to the other storages, cache replacement algorithm is used to determine evict page when the cache is full. On the other hand, the conventional algorithms for replacement such as Least Recently Use (LRU), First in First Out (FIFO), Least Frequently Use (LFU), Randomized Policy etc. may discard important pages just before use. Furthermore, using conventional algorithm cannot be well optimized since it requires some decision to intelligently evict a page before replacement. Hence, most researchers propose an integration among intelligent classifiers and replacement algorithm to improves replacement algorithms performance. This research proposes using automated wrapper feature selection methods to choose the best subset of features that are relevant and influence classifiers prediction accuracy. The result present that using wrapper feature selection methods namely: Best First (BFS), Incremental Wrapper subset selection(IWSS)embedded NB and particle swarm optimization(PSO)reduce number of features and have a good impact on reducing computation time. Using PSO enhance NB classifier accuracy by 1.1%, 0.43% and 0.22% over using NB with all features, using BFS and using IWSS embedded NB respectively. PSO rises J48 accuracy by 0.03%, 1.91 and 0.04% over using J48 classifier with all features, using IWSS-embedded NB and using BFS respectively. While using IWSS embedded NB fastest NB and J48 classifiers much more than BFS and PSO. However, it reduces computation time of NB by 0.1383 and reduce computation time of J48 by 2.998.

  5. High carotenoids content can enhance resistance of selected Pinctada fucata families to high temperature stress.

    Science.gov (United States)

    Meng, Zihao; Zhang, Bo; Liu, Baosuo; Li, Haimei; Fan, Sigang; Yu, Dahui

    2017-02-01

    Carotenoids are a class of natural antioxidants widely found in aquatic, and they have significant effects on the growth, survival, and immunity of these organisms. To investigate the mechanisms of carotenoids in high temperature resistance, we observed the immune response of selected pearl oyster Pinctada fucata (Akoya pearl oyster) families with different carotenoids contents to high temperature stress. The results indicated that the survival rate (SR) of P. fucata decreased significantly with increase in temperature from 26 °C to 34 °C and with the decrease of total carotenoids content (TCC); when the TCC was higher, the SR tended to be higher. TCC and total antioxidant capacity (TAC) decreased significantly at 30 °C with increasing stress time. Correlation analysis indicated that TAC was positively and linearly correlated with TCC, and SR was S-type correlated with TCC and TAC. Immune analysis indicated that levels of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) in selected families (with higher TCC) under temperature stress (at 30 °C) were generally significantly lower than in the control group (with lowest TCC) and from 0 to 96 h, the levels of each of these substances varied significantly. Levels of SOD, CAT, and MDA within each family first rose from 0 to 3 h, then decreased to their lowest point after 24 h, and then rose again to their highest levels at 96 h. When TCC was higher, the levels of SOD, CAT, and MDA tended to be lower. These findings indicated that carotenoids play an important role in improving survival rates of P. fucata under high temperature stress by enhancing animals' antioxidant system, and could serve as an index for breeding stress-resistant lines in selective breeding practices. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Advanced display object selection methods for enhancing user-computer productivity

    Science.gov (United States)

    Osga, Glenn A.

    1993-01-01

    The User-Interface Technology Branch at NCCOSC RDT&E Division has been conducting a series of studies to address the suitability of commercial off-the-shelf (COTS) graphic user-interface (GUI) methods for efficiency and performance in critical naval combat systems. This paper presents an advanced selection algorithm and method developed to increase user performance when making selections on tactical displays. The method has also been applied with considerable success to a variety of cursor and pointing tasks. Typical GUI's allow user selection by: (1) moving a cursor with a pointing device such as a mouse, trackball, joystick, touchscreen; and (2) placing the cursor on the object. Examples of GUI objects are the buttons, icons, folders, scroll bars, etc. used in many personal computer and workstation applications. This paper presents an improved method of selection and the theoretical basis for the significant performance gains achieved with various input devices tested. The method is applicable to all GUI styles and display sizes, and is particularly useful for selections on small screens such as notebook computers. Considering the amount of work-hours spent pointing and clicking across all styles of available graphic user-interfaces, the cost/benefit in applying this method to graphic user-interfaces is substantial, with the potential for increasing productivity across thousands of users and applications.

  7. Cellular correlates of enhanced anxiety caused by acute treatment with the selective serotonin reuptake inhibitor fluoxetine in rats

    Directory of Open Access Journals (Sweden)

    Shilpa eRavinder

    2011-12-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are used extensively in the treatment of depression and anxiety disorders. The therapeutic benefits of SSRIs typically require several weeks of continuous treatment. Intriguingly, according to clinical reports, symptoms of anxiety may actually increase during the early stages of treatment although more prolonged treatment alleviates affective symptoms. Consistent with earlier studies that have used animal models to capture this paradoxical effect of SSRIs, we find that rats exhibit enhanced anxiety-like behavior on the elevated plus-maze one hour after a single injection of the SSRI fluoxetine. Next we investigated the potential neural substrates underlying the acute anxiogenic effects by analyzing the morphological and physiological impact of acute fluoxetine treatment on principal neurons of the basolateral amygdala (BLA, a brain area that plays a pivotal role in fear and anxiety. Although earlier studies have shown that behavioral or genetic perturbations that are anxiogenic for rodents also increase dendritic spine-density in the BLA, we find that a single injection of fluoxetine does not cause spinogenesis on proximal apical dendritic segments on BLA principal neurons an hour later. However, at the same time point when a single dose of fluoxetine caused enhanced anxiety, it also enhanced action potential firing in BLA neurons in ex vivo slices. Consistent with this finding, in vitro bath application of fluoxetine caused higher spiking frequency and this increase in excitability was correlated with an increase in the input resistance of these neurons. Our results suggest that enhanced excitability of amygdala neurons may contribute to the increase in anxiety-like behavior observed following acute fluoxetine treatment.

  8. Selection-for-action in visual search

    NARCIS (Netherlands)

    Hannus, A; Cornelissen, FW; Lindemann, O; Bekkering, H

    2005-01-01

    Grasping an object rather than pointing to it enhances processing of its orientation but not its color. Apparently, visual discrimination is selectively enhanced for a behaviorally relevant feature. In two experiments we investigated the limitations and targets of this bias. Specifically, in

  9. Developmental programming of somatic growth, behavior and endocannabinoid metabolism by variation of early postnatal nutrition in a cross-fostering mouse model.

    Science.gov (United States)

    Schreiner, Felix; Ackermann, Merle; Michalik, Michael; Hucklenbruch-Rother, Eva; Bilkei-Gorzo, Andras; Racz, Ildiko; Bindila, Laura; Lutz, Beat; Dötsch, Jörg; Zimmer, Andreas; Woelfle, Joachim

    2017-01-01

    Nutrient deprivation during early development has been associated with the predisposition to metabolic disorders in adulthood. Considering its interaction with metabolism, appetite and behavior, the endocannabinoid (eCB) system represents a promising target of developmental programming. By cross-fostering and variation of litter size, early postnatal nutrition of CB6F1-hybrid mice was controlled during the lactation period (3, 6, or 10 pups/mother). After weaning and redistribution at P21, all pups received standard chow ad libitum. Gene expression analyses (liver, visceral fat, hypothalamus) were performed at P50, eCB concentrations were determined in liver and visceral fat. Locomotor activity and social behavior were analyzed by means of computer-assisted videotracking. Body growth was permanently altered, with differences for length, weight, body mass index and fat mass persisting beyond P100 (all 3>6>10,p6>10 (DAGLα p6>10 (FAAH pOpen-field social behavior testing revealed significant group differences, with formerly underfed mice turning out to be the most sociable animals (p<0.01). Locomotor activity did not differ. Our data indicate a developmental plasticity of somatic growth, behavior and parameters of the eCB system, with long-lasting impact of early postnatal nutrition. Developmental programming of the eCB system in metabolically active tissues, as shown here for liver and fat, may play a role in the formation of the adult cardiometabolic risk profile following perinatal malnutrition in humans.

  10. Selection-for-action in visual search.

    Science.gov (United States)

    Hannus, Aave; Cornelissen, Frans W; Lindemann, Oliver; Bekkering, Harold

    2005-01-01

    Grasping an object rather than pointing to it enhances processing of its orientation but not its color. Apparently, visual discrimination is selectively enhanced for a behaviorally relevant feature. In two experiments we investigated the limitations and targets of this bias. Specifically, in Experiment 1 we were interested to find out whether the effect is capacity demanding, therefore we manipulated the set-size of the display. The results indicated a clear cognitive processing capacity requirement, i.e. the magnitude of the effect decreased for a larger set size. Consequently, in Experiment 2, we investigated if the enhancement effect occurs only at the level of behaviorally relevant feature or at a level common to different features. Therefore we manipulated the discriminability of the behaviorally neutral feature (color). Again, results showed that this manipulation influenced the action enhancement of the behaviorally relevant feature. Particularly, the effect of the color manipulation on the action enhancement suggests that the action effect is more likely to bias the competition between different visual features rather than to enhance the processing of the relevant feature. We offer a theoretical account that integrates the action-intention effect within the biased competition model of visual selective attention.

  11. Food Safety and Sanitary Practices of Selected Hotels in Batangas Province, Philippines: Basis of Proposed Enhancement Measures

    Directory of Open Access Journals (Sweden)

    April M. Perez

    2017-02-01

    Full Text Available This study assessed the extent of food safety and sanitary practices of selected hotels in Batangas province as basis of proposed enhancement measures. The study utilized descriptive method to describe food safety and sanitary practices of selected hotels in Batangas province with a total of 8 hotels (256 respondents. Purposive sampling was used in the study. The questionnaires were designed using the provision of the Sanitation Code of the Philippines, validated and finalized to come up with legitimate results. The study showed that there were eight (8 hotel respondents classified as two, three, four star with considerable years of experience and adequate number of employees. The hotels demonstrated the food safety and sanitary practices always in the areas of restaurant, bar service, catering and banquet and room service. The significant pair-wise comparison for restaurant, bar service, catering and banquet and room service shows that 2 star hotels greatly differs. The researcher recommends that the management should maintain high standard of food safety and sanitary practices among its staff, upgrade the food safety and sanitary practices for food safety accreditation, continuous training of the hotel managers/employees on food safety and sanitary practices.

  12. Production-enhancement partnerships: Successful business arrangements

    International Nuclear Information System (INIS)

    Coble, L.E.; Weitzel, K.R.; Attai, L.F.; Gray, K.A.

    1996-01-01

    Production-enhancement projects are creating changes in business relationships between oil and gas and service companies. The most successful projects are building partnerships. Service companies are being asked to share the risk while supplying services to enhance well performance. Risk sharing creates common project objectives and requires the service company's involvement in initial project planning, job design, and reservoir understanding. Service-work compensation is based on well- or field-performance improvement resulting from the treatment(s). This paper presents an integrated approach to the selection and prioritization of well candidates for production-enhancement jobs or treatments. Processes are illustrated, and data requirements and techniques necessary to select well candidates that provide the highest return on investment are discussed. Field examples demonstrate the techniques, critical factors, and appropriate software used by geoscience and field-operations teams to maximize benefits from production-enhancement projects

  13. The CB1 receptor antagonist AM251 impairs reconsolidation of pavlovian fear memory in the rat basolateral amygdala.

    Science.gov (United States)

    Ratano, Patrizia; Everitt, Barry J; Milton, Amy L

    2014-10-01

    We have investigated the requirement for signaling at CB1 receptors in the reconsolidation of a previously consolidated auditory fear memory, by infusing the CB1 receptor antagonist AM251, or the FAAH inhibitor URB597, directly into the basolateral amygdala (BLA) in conjunction with memory reactivation. AM251 disrupted memory restabilization, but only when administered after reactivation. URB597 produced a small, transient enhancement of memory restabilization when administered after reactivation. The amnestic effect of AM251 was rescued by coadministration of the GABAA receptor antagonist bicuculline at reactivation, indicating that the disruption of reconsolidation was mediated by altered GABAergic transmission in the BLA. These data show that the endocannabinoid system in the BLA is an important modulator of fear memory reconsolidation and that its effects on memory are mediated by an interaction with the GABAergic system. Thus, targeting the endocannabinoid system may have therapeutic potential to reduce the impact of maladaptive memories in neuropsychiatric disorders such as posttraumatic stress disorder.

  14. Pyrene-Phosphonate Conjugate: Aggregation-Induced Enhanced Emission, and Selective Fe3+ Ions Sensing Properties

    Directory of Open Access Journals (Sweden)

    Sachin D. Padghan

    2017-08-01

    Full Text Available A new pyrene-phosphonate colorimetric receptor 1 has been designed and synthesized in a one-step process via amide bond formation between pyrene butyric acid chloride and phosphonate-appended aniline. The pyrene-phosphonate receptor 1 showed aggregation-induced enhanced emission (AIEE properties in water/acetonitrile (ACN solutions. Dynamic light scattering (DLS characterization revealed that the aggregates of receptor 1 at 80% water fraction have an average size of ≈142 nm. Field emission scanning electron microscopy (FE-SEM analysis confirmed the formation of spherical aggregates upon solvent evaporation. The sensing properties of receptor 1 were investigated by UV-vis, fluorescence emission spectroscopy, and other optical methods. Among the tested metal ions, receptor 1 is capable of recognizing the Fe3+ ion selectively. The changes in spectral measurements were explained on the basis of complex formation. The composition of receptor 1 and Fe3+ ions was determined by using Job’s plot and found to be 1:1. The receptor 1–Fe3+ complex showed a reversible UV-vis response in the presence of EDTA.

  15. Biodegradation Resistance and Bioactivity of Hydroxyapatite Enhanced Mg-Zn Composites via Selective Laser Melting

    Directory of Open Access Journals (Sweden)

    Cijun Shuai

    2017-03-01

    Full Text Available Mg-Zn alloys have attracted great attention as implant biomaterials due to their biodegradability and biomechanical compatibility. However, their clinical application was limited due to the too rapid degradation. In the study, hydroxyapatite (HA was incorporated into Mg-Zn alloy via selective laser melting. Results showed that the degradation rate slowed down due to the decrease of grain size and the formation of protective layer of bone-like apatite. Moreover, the grain size continually decreased with increasing HA content, which was attributed to the heterogeneous nucleation and increased number of nucleation particles in the process of solidification. At the same time, the amount of bone-like apatite increased because HA could provide favorable areas for apatite nucleation. Besides, HA also enhanced the hardness due to the fine grain strengthening and second phase strengthening. However, some pores occurred owing to the agglomerate of HA when its content was excessive, which decreased the biodegradation resistance. These results demonstrated that the Mg-Zn/HA composites were potential implant biomaterials.

  16. Comparative evaluation of cerebral aneurysms with selective arterially enhanced CT and DSA

    International Nuclear Information System (INIS)

    Vanderschelden, P.; Flandroy, P.; Dondelinger, R.F.; Martin, D.; Lenelle, J.

    1998-01-01

    The purpose of our study was to compare selective arterially enhanced spiral computed tomographs (ACT) with digital subtraction angiographies (DSA) in the presurgical assessment of cerebral aneurysms. A total of 24 aneurysms in 18 patients were explored in a prospective study by ACT and DSA, using an interactive combined CT-angiography suite. Dimensions of the aneurysm, its relation to the parent vessel, and the aneurysmal index were defined on DSA and on surface-shaded display of 3D reformatted images obtained from ACT. Results were correlated with surgical findings. Three aneurysms suspected on DSA were not confirmed by ACT. One fusiform aneurysm suspected on DSA corresponded to a sacciform aneurysm on ACT. Surgical findings confirmed 20 sacciform aneurysms. The aneurysmal index could be measured in all 20 cases of sacciform aneurysms on ACT and could not be determined with confidence in 55 % of the cases on DSA. DSA and ACT gave identical results in 35 % of cases. In 10 %, the index measured by ACT was superior to that determined by DSA for aneurysms which had a diameter of less than 3 mm. In conclusion, the combination of DSA and ACT improved the results of DSA alone. ACT is a reliable method to measure the aneurysmal index in aneurysms with a diameter superior to 3 mm. (orig.)

  17. Cannabinoids for clinicians: the rise and fall of the cannabinoid antagonists

    OpenAIRE

    Butler, Helen; Korbonits, M?rta

    2009-01-01

    The endocannabinoid system has emerged as a significant player in the control of energy balance and metabolism, through its direct central and peripheral effects, as well as via its interaction with other appetite-regulating pathways. There is mounting evidence that the endocannabinoid system is overactive in obesity and were it possible to safely dampen-down the elevated endocannabinoid tone, lipid and carbohydrate profiles could be improved and weight loss induced. The series of randomised ...

  18. Effect of dietary krill oil supplementation on the endocannabinoidome of metabolically relevant tissues from high-fat-fed mice

    Directory of Open Access Journals (Sweden)

    Cohn Jeffrey S

    2011-07-01

    Full Text Available Abstract Background Omega-3 polyunsaturated fatty acids (ω-3-PUFA are known to ameliorate several metabolic risk factors for cardiovascular disease, and an association between elevated peripheral levels of endogenous ligands of cannabinoid receptors (endocannabinoids and the metabolic syndrome has been reported. We investigated the dose-dependent effects of dietary ω-3-PUFA supplementation, given as krill oil (KO, on metabolic parameters in high fat diet (HFD-fed mice and, in parallel, on the levels, in inguinal and epididymal adipose tissue (AT, liver, gastrocnemius muscle, kidneys and heart, of: 1 the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG, 2 two anandamide congeners which activate PPARα but not cannabinoid receptors, N-oleoylethanolamine and N-palmitoylethanolamine, and 3 the direct biosynthetic precursors of these compounds. Methods Lipids were identified and quantified using liquid chromatography coupled to atmospheric pressure chemical ionization single quadrupole mass spectrometry (LC-APCI-MS or high resolution ion trap-time of flight mass spectrometry (LC-IT-ToF-MS. Results Eight-week HFD increased endocannabinoid levels in all tissues except the liver and epididymal AT, and KO reduced anandamide and/or 2-AG levels in all tissues but not in the liver, usually in a dose-dependent manner. Levels of endocannabinoid precursors were also generally down-regulated, indicating that KO affects levels of endocannabinoids in part by reducing the availability of their biosynthetic precursors. Usually smaller effects were found of KO on OEA and PEA levels. Conclusions Our data suggest that KO may promote therapeutic benefit by reducing endocannabinoid precursor availability and hence endocannabinoid biosynthesis.

  19. Age-related change in renal corticomedullary differentiation: evaluation with noncontrast-enhanced steady-state free precession (SSFP) MRI with spatially selective inversion pulse using variable inversion time.

    Science.gov (United States)

    Noda, Yasufumi; Kanki, Akihiko; Yamamoto, Akira; Higashi, Hiroki; Tanimoto, Daigo; Sato, Tomohiro; Higaki, Atsushi; Tamada, Tsutomu; Ito, Katsuyoshi

    2014-07-01

    To evaluate age-related change in renal corticomedullary differentiation and renal cortical thickness by means of noncontrast-enhanced steady-state free precession (SSFP) magnetic resonance imaging (MRI) with spatially selective inversion recovery (IR) pulse. The Institutional Review Board of our hospital approved this retrospective study and patient informed consent was waived. This study included 48 patients without renal diseases who underwent noncontrast-enhanced SSFP MRI with spatially selective IR pulse using variable inversion times (TIs) (700-1500 msec). The signal intensity of renal cortex and medulla were measured to calculate renal corticomedullary contrast ratio. Additionally, renal cortical thickness was measured. The renal corticomedullary junction was clearly depicted in all patients. The mean cortical thickness was 3.9 ± 0.83 mm. The mean corticomedullary contrast ratio was 4.7 ± 1.4. There was a negative correlation between optimal TI for the best visualization of renal corticomedullary differentiation and age (r = -0.378; P = 0.001). However, there was no significant correlation between renal corticomedullary contrast ratio and age (r = 0.187; P = 0.20). Similarly, no significant correlation was observed between renal cortical thickness and age (r = 0.054; P = 0.712). In the normal kidney, noncontrast-enhanced SSFP MRI with spatially selective IR pulse can be used to assess renal corticomedullary differentiation and cortical thickness without the influence of aging, although optimal TI values for the best visualization of renal corticomedullary junction were shortened with aging. © 2013 Wiley Periodicals, Inc.

  20. (−)1-(Benzofuran-2-yl)-2-propylaminopentane, [(−)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain

    Science.gov (United States)

    Knoll, Joseph; Yoneda, Fumio; Knoll, Berta; Ohde, Hironori; Miklya, Ildikó

    1999-01-01

    The brain constituents β-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain (‘catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (−)Deprenyl (Selegiline) and (−)1-phenyl-2-propylaminopentane [(−)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property.By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (−)1-(benzofuran-2-yl)-2-propylaminopentane [(−)BPAP] was selected as a potential follower of (−)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain.(−)BPAP significantly enhanced in 0.18 μmol 1−1 concentration the impulse propagation mediated release of [3H]-noradrenaline and [3H]-dopamine and in 36 nmol 1−1 concentration the release of [3H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10−12–10−14 M (−)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of β-amyloid in 10−14 M concentration. In rats (−)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 μg kg−1 s.c. In the shuttle box, (−)BPAP in rats was about 130 times more potent than (−)deprenyl in antagonizing tetrabenazine induced inhibition of performance. PMID:10588928

  1. Selective Regulation of Oocyte Meiotic Events Enhances Progress in Fertility Preservation Methods

    Directory of Open Access Journals (Sweden)

    Onder Celik

    2015-01-01

    persistence of the GV oocyte, which reduces the number of good quality eggs. Selective regulation of somatic cell signals and oocyte meiotic events enhance progress in fertility preservation methods, which may give us the opportunity to prevent follicle loss in prematurely aging women and young women with cancer are undergoing chemoradiotherapy.

  2. Highly doped semiconductor plasmonic nanoantenna arrays for polarization selective broadband surface-enhanced infrared absorption spectroscopy of vanillin

    Science.gov (United States)

    Barho, Franziska B.; Gonzalez-Posada, Fernando; Milla, Maria-Jose; Bomers, Mario; Cerutti, Laurent; Tournié, Eric; Taliercio, Thierry

    2017-11-01

    Tailored plasmonic nanoantennas are needed for diverse applications, among those sensing. Surface-enhanced infrared absorption (SEIRA) spectroscopy using adapted nanoantenna substrates is an efficient technique for the selective detection of molecules by their vibrational spectra, even in small quantity. Highly doped semiconductors have been proposed as innovative materials for plasmonics, especially for more flexibility concerning the targeted spectral range. Here, we report on rectangular-shaped, highly Si-doped InAsSb nanoantennas sustaining polarization switchable longitudinal and transverse plasmonic resonances in the mid-infrared. For small array periodicities, the highest reflectance intensity is obtained. Large periodicities can be used to combine localized surface plasmon resonances (SPR) with array resonances, as shown in electromagnetic calculations. The nanoantenna arrays can be efficiently used for broadband SEIRA spectroscopy, exploiting the spectral overlap between the large longitudinal or transverse plasmonic resonances and narrow infrared active absorption features of an analyte molecule. We demonstrate an increase of the vibrational line intensity up to a factor of 5.7 of infrared-active absorption features of vanillin in the fingerprint spectral region, yielding enhancement factors of three to four orders of magnitude. Moreover, an optimized readout for SPR sensing is proposed based on slightly overlapping longitudinal and transverse localized SPR.

  3. Highly doped semiconductor plasmonic nanoantenna arrays for polarization selective broadband surface-enhanced infrared absorption spectroscopy of vanillin

    Directory of Open Access Journals (Sweden)

    Barho Franziska B.

    2017-11-01

    Full Text Available Tailored plasmonic nanoantennas are needed for diverse applications, among those sensing. Surface-enhanced infrared absorption (SEIRA spectroscopy using adapted nanoantenna substrates is an efficient technique for the selective detection of molecules by their vibrational spectra, even in small quantity. Highly doped semiconductors have been proposed as innovative materials for plasmonics, especially for more flexibility concerning the targeted spectral range. Here, we report on rectangular-shaped, highly Si-doped InAsSb nanoantennas sustaining polarization switchable longitudinal and transverse plasmonic resonances in the mid-infrared. For small array periodicities, the highest reflectance intensity is obtained. Large periodicities can be used to combine localized surface plasmon resonances (SPR with array resonances, as shown in electromagnetic calculations. The nanoantenna arrays can be efficiently used for broadband SEIRA spectroscopy, exploiting the spectral overlap between the large longitudinal or transverse plasmonic resonances and narrow infrared active absorption features of an analyte molecule. We demonstrate an increase of the vibrational line intensity up to a factor of 5.7 of infrared-active absorption features of vanillin in the fingerprint spectral region, yielding enhancement factors of three to four orders of magnitude. Moreover, an optimized readout for SPR sensing is proposed based on slightly overlapping longitudinal and transverse localized SPR.

  4. Anthropogenic selection enhances cancer evolution in Tasmanian devil tumours.

    Science.gov (United States)

    Ujvari, Beata; Pearse, Anne-Maree; Swift, Kate; Hodson, Pamela; Hua, Bobby; Pyecroft, Stephen; Taylor, Robyn; Hamede, Rodrigo; Jones, Menna; Belov, Katherine; Madsen, Thomas

    2014-02-01

    The Tasmanian Devil Facial Tumour Disease (DFTD) provides a unique opportunity to elucidate the long-term effects of natural and anthropogenic selection on cancer evolution. Since first observed in 1996, this transmissible cancer has caused local population declines by >90%. So far, four chromosomal DFTD variants (strains) have been described and karyotypic analyses of 253 tumours showed higher levels of tetraploidy in the oldest strain. We propose that increased ploidy in the oldest strain may have evolved in response to effects of genomic decay observed in asexually reproducing organisms. In this study, we focus on the evolutionary response of DFTD to a disease suppression trial. Tumours collected from devils subjected to the removal programme showed accelerated temporal evolution of tetraploidy compared with tumours from other populations where no increase in tetraploid tumours were observed. As ploidy significantly reduces tumour growth rate, we suggest that the disease suppression trial resulted in selection favouring slower growing tumours mediated by an increased level of tetraploidy. Our study reveals that DFTD has the capacity to rapidly respond to novel selective regimes and that disease eradication may result in novel tumour adaptations, which may further imperil the long-term survival of the world's largest carnivorous marsupial.

  5. Enhancement of HHG yield

    International Nuclear Information System (INIS)

    Serrat, C.; Biegert, J.

    2011-01-01

    A static electric field periodically distributed in space controls and enhances the yield in high harmonic generation. The method is relatively simple to implement and allows tuning from the extreme-ultraviolet to soft X-ray. The radiation yield is selectively enhanced due to symmetry breaking induced by a static electric field on the interaction between the driving laser and the medium. The enhanced spectral region is tuned by varying the periodicity of the static electric field. Simulations predict an increase of more than two orders of magnitude for harmonics in the water window spectral range.

  6. Transient and steady-state selection in the striatal microcircuit

    Directory of Open Access Journals (Sweden)

    Adam eTomkins

    2014-01-01

    Full Text Available Although the basal ganglia have been widely studied and implicated in signal processing and action selection, little information is known about the active role the striatal microcircuit plays in action selection in the basal ganglia-thalamo-cortical loops. To address this knowledge gap we use a large scale three dimensional spiking model of the striatum, combined with a rate coded model of the basal ganglia-thalamo-cortical loop, to asses the computational role the striatum plays in action selection. We identify a robust transient phenomena generated by the striatal microcircuit, which temporarily enhances the difference between two competing cortical inputs. We show that this transient is sufficient to modulate decision making in the basal ganglia-thalamo-cortical circuit. We also find that the transient selection originates from a novel adaptation effect in single striatal projection neurons, which is amenable to experimental testing. Finally, we compared transient selection with models implementing classical steady-state selection. We challenged both forms of model to account for recent reports of paradoxically enhanced response selection in Huntington's Disease patients. We found that steady-state selection was uniformly impaired under all simulated Huntington's conditions, but transient selection was enhanced given a sufficient Huntington's-like increase in NMDA receptor sensitivity. Thus our models provide an intriguing hypothesis for the mechanisms underlying the paradoxical cognitive improvements in manifest Huntington's patients.

  7. Dexamethasone rapidly increases GABA release in the dorsal motor nucleus of the vagus via retrograde messenger-mediated enhancement of TRPV1 activity.

    Directory of Open Access Journals (Sweden)

    Andrei V Derbenev

    Full Text Available Glucocorticoids influence vagal parasympathetic output to the viscera via mechanisms that include modulation of neural circuitry in the dorsal vagal complex, a principal autonomic regulatory center. Glucocorticoids can modulate synaptic neurotransmitter release elsewhere in the brain by inducing release of retrograde signalling molecules. We tested the hypothesis that the glucocorticoid agonist dexamethasone (DEX modulates GABA release in the rat dorsal motor nucleus of the vagus (DMV. Whole-cell patch-clamp recordings revealed that DEX (1-10 µM rapidly (i.e. within three minutes increased the frequency of tetrodotoxin-resistant, miniature IPSCs (mIPSCs in 67% of DMV neurons recorded in acutely prepared slices. Glutamate-mediated mEPSCs were also enhanced by DEX (10 µM, and blockade of ionotropic glutamate receptors reduced the DEX effect on mIPSC frequency. Antagonists of type I or II corticosteroid receptors blocked the effect of DEX on mIPSCs. The effect was mimicked by application of the membrane-impermeant BSA-conjugated DEX, and intracellular blockade of G protein function with GDP βS in the recorded cell prevented the effect of DEX. The enhancement of GABA release was blocked by the TRPV1 antagonists, 5'-iodoresiniferatoxin or capsazepine, but was not altered by the cannabinoid type 1 receptor antagonist AM251. The DEX effect was prevented by blocking fatty acid amide hydrolysis or by inhibiting anandamide transport, implicating involvement of the endocannabinoid system in the response. These findings indicate that DEX induces an enhancement of GABA release in the DMV, which is mediated by activation of TRPV1 receptors on afferent terminals. The effect is likely induced by anandamide or other 'endovanilloid', suggesting activation of a local retrograde signal originating from DMV neurons to enhance synaptic inhibition locally in response to glucocorticoids.

  8. p-p Heterojunction of Nickel Oxide-Decorated Cobalt Oxide Nanorods for Enhanced Sensitivity and Selectivity toward Volatile Organic Compounds.

    Science.gov (United States)

    Suh, Jun Min; Sohn, Woonbae; Shim, Young-Seok; Choi, Jang-Sik; Song, Young Geun; Kim, Taemin L; Jeon, Jong-Myeong; Kwon, Ki Chang; Choi, Kyung Soon; Kang, Chong-Yun; Byun, Hyung-Gi; Jang, Ho Won

    2018-01-10

    The utilization of p-p isotype heterojunctions is an effective strategy to enhance the gas sensing properties of metal-oxide semiconductors, but most previous studies focused on p-n heterojunctions owing to their simple mechanism of formation of depletion layers. However, a proper choice of isotype semiconductors with appropriate energy bands can also contribute to the enhancement of the gas sensing performance. Herein, we report nickel oxide (NiO)-decorated cobalt oxide (Co 3 O 4 ) nanorods (NRs) fabricated using the multiple-step glancing angle deposition method. The effective decoration of NiO on the entire surface of Co 3 O 4 NRs enabled the formation of numerous p-p heterojunctions, and they exhibited a 16.78 times higher gas response to 50 ppm of C 6 H 6 at 350 °C compared to that of bare Co 3 O 4 NRs with the calculated detection limit of approximately 13.91 ppb. Apart from the p-p heterojunctions, increased active sites owing to the changes in the orientation of the exposed lattice surface and the catalytic effects of NiO also contributed to the enhanced gas sensing properties. The advantages of p-p heterojunctions for gas sensing applications demonstrated in this work will provide a new perspective of heterostructured metal-oxide nanostructures for sensitive and selective gas sensing.

  9. Methylphenidate produces selective enhancement of declarative memory consolidation in healthy volunteers.

    Science.gov (United States)

    Linssen, A M W; Vuurman, E F P M; Sambeth, A; Riedel, W J

    2012-06-01

    Methylphenidate inhibits the reuptake of dopamine and noradrenaline and is used to treat children with attention deficit hyperactivity disorder (ADHD). Besides reducing behavioral symptoms, it improves their cognitive function. There are also observations of methylphenidate-induced cognition enhancement in healthy adults, although studies in this area are relatively sparse. We assessed the possible memory-enhancing properties of methylphenidate. In the current study, the possible enhancing effects of three doses of methylphenidate on declarative and working memory, attention, response inhibition and planning were investigated in healthy volunteers. In a double blind placebo-controlled crossover study, 19 healthy young male volunteers were tested after a single dose of placebo or 10, 20 or 40 mg of methylphenidate. Cognitive performance testing included a word learning test as a measure of declarative memory, a spatial working memory test, a set-shifting test, a stop signal test and a computerized version of the Tower of London planning test. Declarative memory consolidation was significantly improved relative to placebo after 20 and 40 mg of methylphenidate. Methylphenidate also improved set shifting and stopped signal task performance but did not affect spatial working memory or planning. To the best of our knowledge, this is the first study reporting enhanced declarative memory consolidation after methylphenidate in a dose-related fashion over a dose range that is presumed to reflect a wide range of dopamine reuptake inhibition.

  10. Enhanced binding affinity, remarkable selectivity, and high capacity of CO 2 by dual functionalization of a rht-type metal-organic framework

    KAUST Repository

    Li, Baiyan

    2011-12-23

    Open and friendly: The smallest member of the rht-type metal-organic frameworks (MOFs, see picture) constructed by a hexacarboxylate ligand with a nitrogen-rich imino triazine backbone shows a significantly enhanced gas binding affinity relative to all other isoreticular rht-type MOFs. The high adsorption capacity and remarkable selectivity of CO 2 are attributed to the high density of open metal and Lewis basic sites in the framework. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Emotional Memories Are Not All Created Equal: Evidence for Selective Memory Enhancement

    Science.gov (United States)

    Anderson, Adam K.; Grabski, Wojtek; Lacka, Dominika; Yamaguchi, Yuki

    2006-01-01

    Human brain imaging studies have shown that greater amygdala activation to emotional relative to neutral events leads to enhanced episodic memory. Other studies have shown that fearful faces also elicit greater amygdala activation relative to neutral faces. To the extent that amygdala recruitment is sufficient to enhance recollection, these…

  12. Selective enhancement of surface-state emission and simultaneous quenching of interband transition in white-luminophor CdS nanocrystals using localized plasmon coupling

    Energy Technology Data Exchange (ETDEWEB)

    Ozel, Tuncay; Soganci, Ibrahim Murat; Nizamoglu, Sedat; Huyal, Ilkem Ozge; Mutlugun, Evren; Demir, Hilmi Volkan [Department of Physics, Department of Electrical and Electronics Engineering, Nanotechnology Research Center and Institute of Materials Science and Nanotechnology, Bilkent University, Ankara 06800 (Turkey); Sapra, Sameer; Gaponik, Nikolai; Eychmueller, Alexander [Physical Chemistry/Electrochemistry Group, Technische Universitaet Dresden, Bergstr. 66b, Dresden 01062 (Germany)], E-mail: volkan@bilkent.edu.tr

    2008-08-15

    We propose and demonstrate the controlled modification and selective enhancement of surface-state emission in white-luminophor CdS nanocrystals (NCs) by plasmon-coupling them with proximal metal nanostructures. By carefully designing nano-Ag films to match their localized plasmon resonance spectrally with the surface-state emission peak of CdS NCs, we experimentally show that the surface-state emission is substantially enhanced in the visible wavelength, while the interband (band-edge) transition at the shorter wavelength far away from the plasmon resonance is simultaneously significantly suppressed. With such plasmon tuning and consequent strong plasmon coupling specifically for the surface-state transitions, the surface-state emission is made stronger than the band-edge emission. This corresponds to an enhancement factor of 12.7-fold in the ratio of the surface-state peak emission to the band-edge peak emission of the plasmon-coupled film sample compared with that in solution. Such a plasmonic engineering of surface-state emission in trap-rich CdS white nanoluminophors holds great promise for future solid-state lighting.

  13. Selective enhancement of surface-state emission and simultaneous quenching of interband transition in white-luminophor CdS nanocrystals using localized plasmon coupling

    International Nuclear Information System (INIS)

    Ozel, Tuncay; Soganci, Ibrahim Murat; Nizamoglu, Sedat; Huyal, Ilkem Ozge; Mutlugun, Evren; Demir, Hilmi Volkan; Sapra, Sameer; Gaponik, Nikolai; Eychmueller, Alexander

    2008-01-01

    We propose and demonstrate the controlled modification and selective enhancement of surface-state emission in white-luminophor CdS nanocrystals (NCs) by plasmon-coupling them with proximal metal nanostructures. By carefully designing nano-Ag films to match their localized plasmon resonance spectrally with the surface-state emission peak of CdS NCs, we experimentally show that the surface-state emission is substantially enhanced in the visible wavelength, while the interband (band-edge) transition at the shorter wavelength far away from the plasmon resonance is simultaneously significantly suppressed. With such plasmon tuning and consequent strong plasmon coupling specifically for the surface-state transitions, the surface-state emission is made stronger than the band-edge emission. This corresponds to an enhancement factor of 12.7-fold in the ratio of the surface-state peak emission to the band-edge peak emission of the plasmon-coupled film sample compared with that in solution. Such a plasmonic engineering of surface-state emission in trap-rich CdS white nanoluminophors holds great promise for future solid-state lighting

  14. The endocannabinoid system and its role in schizophrenia: a systematic review of the literature O sistema endocanabinoide e seu papel na esquizofrenia: uma revisão sistemática da literatura

    Directory of Open Access Journals (Sweden)

    Rodrigo Ferretjans

    2012-10-01

    Full Text Available OBJECTIVE: Schizophrenia is a psychiatric disorder whose mechanisms have remained only partially elucidated. The current proposals regarding its biological basis, such as the dopaminergic hypothesis, do not fully explain the diversity of its symptoms, indicating that other processes may be involved. This paper aims to review evidence supporting the involvement of the endocannabinoid system (ECS, a neurotransmitter group that is the target of Cannabis sativa compounds, in this disorder. METHODS: A systematic review of original papers, published in English, indexed in PubMed up to April, 2012. RESULTS: Most studies employed genetics and histological, neuroimaging or neurochemical methods - either in vivo or post-mortem - to investigate whether components of the ECS are compromised in patients. Overall, the data show changes in cannabinoid receptors in certain brain regions as well as altered levels in endocannabinoid levels in cerebrospinal fluid and/or blood. CONCLUSIONS: Although a dysfunction of the ECS has been described, results are not entirely consistent across studies. Further data are warrant to better define a role of this system in schizophrenia.OBJETIVO: A esquizofrenia é um transtorno psiquiátrico cujos mecanismos permanecem apenas parcialmente elucidados. As atuais propostas relativas à base biológica, tais como a hipótese dopaminérgica, não explicam por completo a diversidade de seus sintomas, o que indica que outros processos podem estar envolvidos. Este artigo tem como objetivo revisar indícios que sustentem o envolvimento do sistema endocanabinoide (SECB, um grupo de neurotransmissoresalvo dos compostos da Cannabis sativa, nesse transtorno. MÉTODOS: Revisão sistemática dos artigos originais, publicados em inglês e indexados no PubMed até abril de 2012. RESULTADOS: A maioria dos estudos empregou métodos neuroquímicos ou de neuroimagem genéticos e histológicos - tanto in vivo quanto post-mortem - para investigar se

  15. Selective Audiovisual Semantic Integration Enabled by Feature-Selective Attention.

    Science.gov (United States)

    Li, Yuanqing; Long, Jinyi; Huang, Biao; Yu, Tianyou; Wu, Wei; Li, Peijun; Fang, Fang; Sun, Pei

    2016-01-13

    An audiovisual object may contain multiple semantic features, such as the gender and emotional features of the speaker. Feature-selective attention and audiovisual semantic integration are two brain functions involved in the recognition of audiovisual objects. Humans often selectively attend to one or several features while ignoring the other features of an audiovisual object. Meanwhile, the human brain integrates semantic information from the visual and auditory modalities. However, how these two brain functions correlate with each other remains to be elucidated. In this functional magnetic resonance imaging (fMRI) study, we explored the neural mechanism by which feature-selective attention modulates audiovisual semantic integration. During the fMRI experiment, the subjects were presented with visual-only, auditory-only, or audiovisual dynamical facial stimuli and performed several feature-selective attention tasks. Our results revealed that a distribution of areas, including heteromodal areas and brain areas encoding attended features, may be involved in audiovisual semantic integration. Through feature-selective attention, the human brain may selectively integrate audiovisual semantic information from attended features by enhancing functional connectivity and thus regulating information flows from heteromodal areas to brain areas encoding the attended features.

  16. The influence of cannabinoids on learning and memory processes of the dorsal striatum.

    Science.gov (United States)

    Goodman, Jarid; Packard, Mark G

    2015-11-01

    Extensive evidence indicates that the mammalian endocannabinoid system plays an integral role in learning and memory. Our understanding of how cannabinoids influence memory comes predominantly from studies examining cognitive and emotional memory systems mediated by the hippocampus and amygdala, respectively. However, recent evidence suggests that cannabinoids also affect habit or stimulus-response (S-R) memory mediated by the dorsal striatum. Studies implementing a variety of maze tasks in rats indicate that systemic or intra-dorsolateral striatum infusions of cannabinoid receptor agonists or antagonists impair habit memory. In mice, cannabinoid 1 (CB1) receptor knockdown can enhance or impair habit formation, whereas Δ(9)THC tolerance enhances habit formation. Studies in human cannabis users also suggest an enhancement of S-R/habit memory. A tentative conclusion based on the available data is that acute disruption of the endocannabinoid system with either agonists or antagonists impairs, whereas chronic cannabinoid exposure enhances, dorsal striatum-dependent S-R/habit memory. CB1 receptors are required for multiple forms of striatal synaptic plasticity implicated in memory, including short-term and long-term depression. Interactions with the hippocampus-dependent memory system may also have a role in some of the observed effects of cannabinoids on habit memory. The impairing effect often observed with acute cannabinoid administration argues for cannabinoid-based treatments for human psychopathologies associated with a dysfunctional habit memory system (e.g. post-traumatic stress disorder and drug addiction/relapse). In addition, the enhancing effect of repeated cannabinoid exposure on habit memory suggests a novel neurobehavioral mechanism for marijuana addiction involving the dorsal striatum-dependent memory system. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Enhanced selective photocatalytic CO{sub 2} reduction into CO over Ag/CdS nanocomposites under visible light

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Zezhou; Qin, Jiani; Jiang, Min; Ding, Zhengxin; Hou, Yidong, E-mail: ydhou@fzu.edu.cn

    2017-01-01

    Highlights: • Ag/CdS nanocomposites were prepared by a facile photodeposition method. • Ag/CdS was more effective as a photocatalyst for CO{sub 2} reduction than CdS. • Ag as cocatalyst served as electron trap as well as active site for CO{sub 2} reduction reaction. - Abstract: Photocatalytic reduction of carbon dioxide can convert chemically inert carbon dioxide into useful chemical fuel in a mild manner. Herein, Ag-CdS nanocomposites were prepared by photodeposition method and examined for photocatalytic CO{sub 2} reduction under visible light. Meanwhile, the nanocomposites were characterized by XRD, SEM, TEM, XPS, DRS and PL in detail. The results show that, the deposition of Ag improves the photocatalytic performance of CdS, especially in the selectivity of CO{sub 2}-to-CO. The highest photocatalytic activity is achieved over 1.0 wt.% Ag/CdS, with an increase by 3 times in comparison to CdS. In this reaction system, Ag can serve as electron trap as well as active site for CO{sub 2} reduction, which is probably responsible for the enhanced activity and selectivity of CO{sub 2} to CO over Ag/CdS. The possible mechanism of CO{sub 2} photoreduction over Ag/CdS was proposed in view of the abovementioned analysis.

  18. Enhanced Cooperation under the Lisbon Treaty

    NARCIS (Netherlands)

    Groenendijk, Nico

    2011-01-01

    Enhanced cooperation is often regarded as being a way out of EU decision-making deadlock and as a major possibility of proceeding with European integration in selected areas. Although the mechanism has been in place since the Treaty of Amsterdam, enhanced cooperation has only recently become a

  19. Comparative effects of parathion and chlorpyrifos on extracellular endocannabinoid levels in rat hippocampus: Influence on cholinergic toxicity

    International Nuclear Information System (INIS)

    Liu, Jing; Parsons, Loren; Pope, Carey

    2013-01-01

    Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). Endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) can modulate neurotransmission by inhibiting neurotransmitter release. We proposed that differential inhibition of eCB-degrading enzymes (fatty acid amide hydrolase, FAAH, and monoacylglycerol lipase, MAGL) by PS and CPF leads to differences in extracellular eCB levels and toxicity. Microdialysis cannulae were implanted into hippocampus of adult male rats followed by treatment with vehicle (peanut oil, 2 ml/kg, sc), PS (27 mg/kg) or CPF (280 mg/kg) 6–7 days later. Signs of toxicity, AChE, FAAH and MAGL inhibition, and extracellular levels of AEA and 2AG were measured 2 and 4 days later. Signs were noted in PS-treated rats but not in controls or CPF-treated rats. Cholinesterase inhibition was extensive in hippocampus with PS (89–90%) and CPF (78–83%) exposure. FAAH activity was also markedly reduced (88–91%) by both OPs at both time-points. MAGL was inhibited by both OPs but to a lesser degree (35–50%). Increases in extracellular AEA levels were noted after either PS (about 2-fold) or CPF (about 3-fold) while lesser treatment-related 2-AG changes were noted. The cannabinoid CB1 receptor antagonist/inverse agonist AM251 (3 mg/kg, ip) had no influence on functional signs after CPF but markedly decreased toxicity in PS-treated rats. The results suggest that extracellular eCBs levels can be markedly elevated by both PS and CPF. CB1-mediated signaling appears to play a role in the acute toxicity of PS but the role of eCBs in CPF toxicity remains unclear. - Highlights: • Chlorpyrifos and parathion both extensively inhibited hippocampal cholinesterase. • Functional signs were only noted with parathion. • Chlorpyrifos and parathion increased hippocampal extracellular anandamide levels. • 2-Arachidonoylglycerol levels were

  20. Comparative effects of parathion and chlorpyrifos on extracellular endocannabinoid levels in rat hippocampus: Influence on cholinergic toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jing [Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK (United States); Parsons, Loren [Committee on Neurobiology of Affective Disorders, The Scripps Research Institute, La Jolla, CA (United States); Pope, Carey, E-mail: carey.pope@okstate.edu [Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK (United States)

    2013-11-01

    Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). Endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) can modulate neurotransmission by inhibiting neurotransmitter release. We proposed that differential inhibition of eCB-degrading enzymes (fatty acid amide hydrolase, FAAH, and monoacylglycerol lipase, MAGL) by PS and CPF leads to differences in extracellular eCB levels and toxicity. Microdialysis cannulae were implanted into hippocampus of adult male rats followed by treatment with vehicle (peanut oil, 2 ml/kg, sc), PS (27 mg/kg) or CPF (280 mg/kg) 6–7 days later. Signs of toxicity, AChE, FAAH and MAGL inhibition, and extracellular levels of AEA and 2AG were measured 2 and 4 days later. Signs were noted in PS-treated rats but not in controls or CPF-treated rats. Cholinesterase inhibition was extensive in hippocampus with PS (89–90%) and CPF (78–83%) exposure. FAAH activity was also markedly reduced (88–91%) by both OPs at both time-points. MAGL was inhibited by both OPs but to a lesser degree (35–50%). Increases in extracellular AEA levels were noted after either PS (about 2-fold) or CPF (about 3-fold) while lesser treatment-related 2-AG changes were noted. The cannabinoid CB1 receptor antagonist/inverse agonist AM251 (3 mg/kg, ip) had no influence on functional signs after CPF but markedly decreased toxicity in PS-treated rats. The results suggest that extracellular eCBs levels can be markedly elevated by both PS and CPF. CB1-mediated signaling appears to play a role in the acute toxicity of PS but the role of eCBs in CPF toxicity remains unclear. - Highlights: • Chlorpyrifos and parathion both extensively inhibited hippocampal cholinesterase. • Functional signs were only noted with parathion. • Chlorpyrifos and parathion increased hippocampal extracellular anandamide levels. • 2-Arachidonoylglycerol levels were

  1. Advanced olive selections with enhanced quality for minor constituents

    Directory of Open Access Journals (Sweden)

    Velasco, L.

    2015-12-01

    Full Text Available Squalene, phytosterols and tocopherols are minor constituents of paramount importance for the olive fruit and oil quality. The objective of this research was to conduct a two-year evaluation of these compounds in the fruits of seven advanced breeding selections. They were mainly selected for early bearing and high oil content from progenies of crosses between the cultivars ‘Arbequina’ and ‘Picual’. An analysis of variance showed high genotypic effects, non-significant year effects, and genotype x year interactions of low magnitude. The selections showed great variability for the traits, surpassing in some cases the parental values. One selection with total tocopherol content of 263 mg·kg−1 fruit flesh, compared to a maximum of 148 mg·kg −1 in the parents, and another one with Δ5-avenasterol concentration of 30.7% of total sterols, compared to a maximum of 22.1% in the parents, were the most relevant phenotypes. These selections may play an important role for improving olive fruit and oil quality for specific market niches.Compuestos como el escualeno, los fitoesteroles y los tocoferoles tienen una enorme importancia para la calidad del fruto y del aceite de oliva. El objetivo de este trabajo fue la evaluación durante dos años de estos compuestos en los frutos de siete selecciones avanzadas de olivo, seleccionadas principalmente para entrada temprana en producción y alto contenido en aceite a partir de las descendencias de cruzamientos entre los cultivares ‘Arbequina’ y ‘Picual’. El análisis de la varianza mostró, para la mayoría de los caracteres, un elevado efecto del genotipo, ausencia de efecto del factor año, e interacciones entre año y genotipo de baja magnitud. Las selecciones mostraron gran variabilidad para todos los caracteres, sobrepasando en algunos casos los valores de los parentales. Entre las selecciones con valores superiores a los parentales, destacaron una selección con un contenido en tocoferoles

  2. Selective Induction of Optical Magnetism.

    Science.gov (United States)

    Manna, Uttam; Lee, Jung-Hoon; Deng, Tian-Song; Parker, John; Shepherd, Nolan; Weizmann, Yossi; Scherer, Norbert F

    2017-12-13

    An extension of the Maxwell-Faraday law of electromagnetic induction to optical frequencies requires spatially appropriate materials and optical beams to create resonances and excitations with curl. Here we employ cylindrical vector beams with azimuthal polarization to create electric fields that selectively drive magnetic responses in dielectric core-metal nanoparticle "satellite" nanostructures. These optical frequency magnetic resonances are induced in materials that do not possess spin or orbital angular momentum. Multipole expansion analysis of the scattered fields obtained from electrodynamics simulations show that the excitation with azimuthally polarized beams selectively enhances magnetic vs electric dipole resonances by nearly 100-fold in experiments. Multipolar resonances (e.g., quadrupole and octupole) are enhanced 5-fold by focused azimuthally versus linearly polarized beams. We also selectively excite electric multipolar resonances in the same identical nanostructures with radially polarized light. This work opens new opportunities for spectroscopic investigation and control of "dark modes", Fano resonances, and magnetic modes in nanomaterials and engineered metamaterials.

  3. Selective inhibition of phosphodiesterase 5 enhances glutamatergic synaptic plasticity and memory in mice.

    Science.gov (United States)

    Uthayathas, Subramaniam; Parameshwaran, Kodeeswaran; Karuppagounder, Senthilkumar S; Ahuja, Manuj; Dhanasekaran, Muralikrishnan; Suppiramaniam, Vishnu

    2013-11-01

    Phosphodiesterases (PDEs) belong to a family of proteins that control metabolism of cyclic nucleotides. Targeting PDE5, for enhancing cellular function, is one of the therapeutic strategies for male erectile dysfunction. We have investigated whether in vivo inhibition of PDE5, which is expressed in several brain regions, will enhance memory and synaptic transmission in the hippocampus of healthy mice. We have found that acute administration of sildenafil, a specific PDE5 inhibitor, enhanced hippocampus-dependent memory tasks. To elucidate the underlying mechanism in the memory enhancement, effects of sildenafil on long-term potentiation (LTP) were measured. The level of LTP was significantly elevated, with concomitant increases in basal synaptic transmission, in mice treated with sildenafil (1 mg/kg/day) for 15 days compared to control mice. These results suggest that moderate PDE5 inhibition enhances memory by increasing synaptic plasticity and transmission in the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

  4. Selective spatial enhancement: Attentional spotlight size impacts spatial but not temporal perception.

    Science.gov (United States)

    Goodhew, Stephanie C; Shen, Elizabeth; Edwards, Mark

    2016-08-01

    An important but often neglected aspect of attention is how changes in the attentional spotlight size impact perception. The zoom-lens model predicts that a small ("focal") attentional spotlight enhances all aspects of perception relative to a larger ("diffuse" spotlight). However, based on the physiological properties of the two major classes of visual cells (magnocellular and parvocellular neurons) we predicted trade-offs in spatial and temporal acuity as a function of spotlight size. Contrary to both of these accounts, however, across two experiments we found that attentional spotlight size affected spatial acuity, such that spatial acuity was enhanced for a focal relative to a diffuse spotlight, whereas the same modulations in spotlight size had no impact on temporal acuity. This likely reflects the function of attention: to induce the high spatial resolution of the fovea in periphery, where spatial resolution is poor but temporal resolution is good. It is adaptive, therefore, for the attentional spotlight to enhance spatial acuity, whereas enhancing temporal acuity does not confer the same benefit.

  5. CA1 Pyramidal Cell Theta-Burst Firing Triggers Endocannabinoid-Mediated Long-Term Depression at Both Somatic and Dendritic Inhibitory Synapses

    Science.gov (United States)

    Younts, Thomas J.; Chevaleyre, Vivien

    2013-01-01

    Endocannabinoids (eCBs) are retrograde lipid messengers that, by targeting presynaptic type 1 cannabinoid receptors (CB1Rs), mediate short- and long-term synaptic depression of neurotransmitter release throughout the brain. Short-term depression is typically triggered by postsynaptic, depolarization-induced calcium rises, whereas long-term depression is induced by synaptic activation of Gq/11 protein-coupled receptors. Here we report that a physiologically relevant pattern of postsynaptic activity, in the form of theta-burst firing (TBF) of hippocampal CA1 pyramidal neurons, can trigger long-term depression of inhibitory transmission (iLTD) in rat hippocampal slices. Paired recordings between CA1 interneurons and pyramidal cells, followed by post hoc morphological reconstructions of the interneurons' axon, revealed that somatic and dendritic inhibitory synaptic inputs equally expressed TBF-induced iLTD. Simultaneous recordings from neighboring pyramidal cells demonstrated that eCB signaling triggered by TBF was highly restricted to only a single, active cell. Furthermore, pairing submaximal endogenous activation of metabotropic glutamate or muscarinic acetylcholine receptors with submaximal TBF unmasked associative iLTD. Although CB1Rs are also expressed at Schaffer-collateral excitatory terminals, long-term plasticity under various recording conditions was spared at these synapses. Consistent with this observation, TBF also shifted the balance of excitation and inhibition in favor of excitatory throughput, thereby altering information flow through the CA1 circuit. Given the near ubiquity of burst-firing activity patterns and CB1R expression in the brain, the properties described here may be a general means by which neurons fine tune the strength of their inputs in a cell-wide and cell-specific manner. PMID:23966696

  6. Simulation of selected genealogies.

    Science.gov (United States)

    Slade, P F

    2000-02-01

    Algorithms for generating genealogies with selection conditional on the sample configuration of n genes in one-locus, two-allele haploid and diploid models are presented. Enhanced integro-recursions using the ancestral selection graph, introduced by S. M. Krone and C. Neuhauser (1997, Theor. Popul. Biol. 51, 210-237), which is the non-neutral analogue of the coalescent, enables accessible simulation of the embedded genealogy. A Monte Carlo simulation scheme based on that of R. C. Griffiths and S. Tavaré (1996, Math. Comput. Modelling 23, 141-158), is adopted to consider the estimation of ancestral times under selection. Simulations show that selection alters the expected depth of the conditional ancestral trees, depending on a mutation-selection balance. As a consequence, branch lengths are shown to be an ineffective criterion for detecting the presence of selection. Several examples are given which quantify the effects of selection on the conditional expected time to the most recent common ancestor. Copyright 2000 Academic Press.

  7. An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells.

    Science.gov (United States)

    Gonsky, R; Deem, R L; Bream, J H; Young, H A; Targan, S R

    2006-07-01

    This study examines mucosa-specific regulatory pathways involved in modulation of interferon-gamma (IFN-gamma) in lamina propria T cells. Previous studies identified mucosa-specific CD2 cis-elements within the -204 to -108 bp IFNG promoter. Within this region, a single-site nucleotide polymorphism, -179G/T, imparts tumor necrosis factor-alpha stimulation of IFNG in peripheral blood lymphocytes, and is linked with accelerated AIDS progression. We discovered a putative estrogen response element (ERE) introduced by the -179T, which displays selective activation in peripheral blood mononuclear cells (PBMC) vs lamina propria mononuclear cells (LPMC). Transfection of PBMC with constructs containing the -179G or -179T site revealed CD2-mediated enhancement of the -179T compared to -179G allele, although, in LPMC, a similar level of expression was detected. Electrophoretic mobility shift assay (EMSA) analysis demonstrated CD2-mediated nucleoprotein binding to the -179T but not the -179G in PBMC. In LPMC, binding is constitutive to both -179G and -179T regions. Sequence and EMSA analysis suggests that the -179T allele creates an ERE-like binding site capable of binding recombinant estrogen receptor. Estrogen response element transactivation is enhanced by CD2 signaling, but inhibited by estrogen in PBMC but not in LPMC, although expression of estrogen receptor was similar. This is the first report to describe a potential molecular mechanism responsible for selectively controlling IFN-gamma production in LPMC.

  8. Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke.

    Science.gov (United States)

    Zhang, Ming; Martin, Billy R; Adler, Martin W; Razdan, Raj J; Kong, Weimin; Ganea, Doina; Tuma, Ronald F

    2009-06-01

    Recognition of the importance of the endocannabinoid system in both homeostasis and pathologic responses raised interest recently in the development of therapeutic agents based on this system. The CB(2) receptor, a component of the endocannabinoid system, has significant influence on immune function and inflammatory responses. Inflammatory responses are major contributors to central nervous system (CNS) injury in a variety of diseases. In this report, we present evidence that activation of CB(2) receptors, by selective CB(2) agonists, reduces inflammatory responses that contribute to CNS injury. The studies demonstrate neuroprotective effects in experimental autoimmune encephalomyelitis, a model of multiple sclerosis, and in a murine model of cerebral ischemia/reperfusion injury. In both cases, CB(2) receptor activation results in reduced white cell rolling and adhesion to cerebral microvessels, a reduction in immune cell invasion, and improved neurologic function after insult. In addition, administration of the CB(1) antagonist SR141716A reduces infarct size following ischemia/reperfusion injury. Administration of both a selective CB(2) agonist and a CB(1) antagonist has the unique property of increasing blood flow to the brain during the occlusion period, suggesting an effect on collateral blood flow. In summary, selective CB(2) receptor agonists and CB(1) receptor antagonists have significant potential for neuroprotection in animal models of two devastating diseases that currently lack effective treatment options.

  9. Innovation During the Supplier Selection Process

    DEFF Research Database (Denmark)

    Pilkington, Alan; Pedraza, Isabel

    2014-01-01

    Established ideas on supplier selection have not moved much from the original premise of how to choose between bidders. Whilst we have added many different tools and refinements to choose between alternative suppliers, its nature has not evolved. We move the original selection process approach...... observed through an ethnographic embedded researcher study has refined the selection process and has two selection stages one for first supply covering tool/process developed and another later for resupply of mature parts. We report the details of the process, those involved, the criteria employed...... and identify benefits and weaknesses of this enhanced selection process....

  10. Selective phosphodiesterase inhibitors: a promising target for cognition enhancement

    OpenAIRE

    Reneerkens, Olga A. H.; Rutten, Kris; Steinbusch, Harry W. M.; Blokland, Arjan; Prickaerts, Jos

    2008-01-01

    Rationale One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer?s disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increa...

  11. Modulation of subventricular zone oligodendrogenesis: a role for hemopressin?

    Directory of Open Access Journals (Sweden)

    Sara eXapelli

    2014-02-01

    Full Text Available Neural stem cells (NSCs from the subventricular zone (SVZ have been indicated as a source of new oligodendrocytes to use in regenerative medicine for myelin pathologies. Indeed, NSCs are multipotent cells that can self-renew and differentiate into all neural cell types of the central nervous system (CNS. In normal conditions, SVZ cells are poorly oligodendrogenic, nevertheless their oligodendrogenic potential is boosted following demyelination. Importantly, progressive restriction into the oligodendrocyte fate is specified by extrinsic and intrinsic factors, endocannabinoids being one of these factors. Although a role for endocannabinoids in oligodendrogenesis has already been foreseen, selective agonists and antagonists of cannabinoids receptors produce severe adverse side effects. Herein, we show that hemopressin, a modulator of CB1 receptors, increased oligodendroglial differentiation in SVZ neural stem/progenitor cell cultures derived from neonatal mice. The original results presented in this work suggest that hemopressin and derivatives may be of potential interest for the development of future strategies to treat demyelinating diseases.

  12. Laser enhanced radioactive decay and selective transmutation of nuclear waste

    International Nuclear Information System (INIS)

    Saloman, R.; Aarnio, P.; Ala-Heikkila, J.; Hakola, A.; Santala, M.

    2007-01-01

    We have investigated narrow-band coherent laser radiation - ranging from visible to X- and to gamma-ray wave length region - and their interactions both directly with photon-nuclear couplings and indirectly through the photon-electron and electron-nucleus interactions. In particular we discuss various means of selective excitation of nuclear resonance states by narrowband lasers. During the relaxation process the active nucleus may return to its initial ground-state or find another final state. In the latter case the nucleus is transmuted into a state which may have beneficial properties for instance concerning radioactivity. One ideal case would be the destruction of long-lived nuclear waste isotopes into faster decaying ones. The essential presumption is that the excitation process is selective and efficient as regards background processes due to unwanted excitation channels of the primary isotope and due to other surrounding nuclides. The paper consists of 1) a short review of generating short-wave length coherent light sources, 2) a survey of potential photon-induced nuclear states and their decay channels, and 3) a determination of the selectivity of the transmutation process

  13. Rimonabant, a selective cannabinoid1 receptor antagonist, protects against light-induced retinal degeneration in vitro and in vivo.

    Science.gov (United States)

    Imamura, Tomoyo; Tsuruma, Kazuhiro; Inoue, Yuki; Otsuka, Tomohiro; Ohno, Yuta; Ogami, Shiho; Yamane, Shinsaku; Shimazawa, Masamitsu; Hara, Hideaki

    2017-05-15

    The endocannabinoid system is involved in some neurodegenerative diseases such as Alzheimer's disease. An endogenous constellation of proteins related to cannabinoid 1 receptor signaling, including free fatty acids, diacylglycerol lipase, and N-acylethanolamine-hydrolyzing acid amidase, are localized in the murine retina. Moreover, the expression levels of endogenous agonists of cannabinoid receptors are changed in the vitreous fluid. However, the role of the endocannabinoid system in the retina, particularly in the light-induced photoreceptor degeneration, remains unknown. Therefore, we investigated involvement of the cannabinoid 1 receptor in light-induced retinal degeneration using in vitro and in vivo models. To evaluate the effect of cannabinoid 1 receptors in light irradiation-induced cell death, the mouse retinal cone-cell line (661W) was treated with a cannabinoid 1 receptor antagonist, rimonabant. Time-dependent changes of expression and localization of retinal cannabinoid 1 receptors were measured using Western blot and immunostaining. Retinal damage was induced in mice by exposure to light, followed by intravitreal injection of rimonabant. Electroretinograms and histologic analyses were performed. Rimonabant suppressed light-induced photoreceptor cell death. Cannabinoid 1 receptor expression was upregulated by light exposure. Treatment with rimonabant improved both a- and b-wave amplitudes and the thickness of the outer nuclear layer. These results suggest that the cannabinoid 1 receptor is involved in light-induced retinal degeneration and it may represent a therapeutic target in the light-induced photoreceptor degeneration related diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Enhanced and Selective Antiproliferative Activity of Methotrexate-Functionalized-Nanocapsules to Human Breast Cancer Cells (MCF-7

    Directory of Open Access Journals (Sweden)

    Catiúscia P. de Oliveira

    2018-01-01

    Full Text Available Methotrexate is a folic acid antagonist and its incorporation into nanoformulations is a promising strategy to increase the drug antiproliferative effect on human breast cancer cells by overexpressing folate receptors. To evaluate the efficiency and selectivity of nanoformulations containing methotrexate and its diethyl ester derivative, using two mechanisms of drug incorporation (encapsulation and surface functionalization in the in vitro cellular uptake and antiproliferative activity in non-tumoral immortalized human keratinocytes (HaCaT and in human breast carcinoma cells (MCF-7. Methotrexate and its diethyl ester derivative were incorporated into multiwall lipid-core nanocapsules with hydrodynamic diameters lower than 160 nm and higher drug incorporation efficiency. The nanoformulations were applied to semiconfluent HaCaT or MCF-7 cells. After 24 h, the nanocapsules were internalized into HaCaT and MCF-7 cells; however, no significant difference was observed between the nanoformulations in HaCaT (low expression of folate receptors, while they showed significantly higher cellular uptakes than the blank-nanoformulation in MCF-7, which was the highest uptakes observed for the drug functionalized-nanocapsules. No antiproliferative activity was observed in HaCaT culture, whereas drug-containing nanoformulations showed antiproliferative activity against MCF-7 cells. The effect was higher for drug-surface functionalized nanocapsules. In conclusion, methotrexate-functionalized-nanocapsules showed enhanced and selective antiproliferative activity to human breast cancer cells (MCF-7 being promising products for further in vivo pre-clinical evaluations.

  15. Selective tuning of enhancement in near band edge emission in hydrothermally grown ZnO nanorods coated with gold

    Energy Technology Data Exchange (ETDEWEB)

    Dixit, Tejendra, E-mail: phd12110211@iiti.ac.in [Molecular and Nanoelectronics Research Group (MNRG), Department of Electrical Engineering, IIT Indore, Indore, Madhya Pradesh (India); Palani, I.A., E-mail: palaniia@iiti.ac.in [Mechatronics and Instrumentation Lab, Department of Mechanical Engineering, IIT Indore, Indore, Madhya Pradesh (India); Centre of Material Science and Engineering, IIT Indore, Indore, Madhya Pradesh (India); Singh, Vipul, E-mail: vipul@iiti.ac.in [Molecular and Nanoelectronics Research Group (MNRG), Department of Electrical Engineering, IIT Indore, Indore, Madhya Pradesh (India); Centre of Material Science and Engineering, IIT Indore, Indore, Madhya Pradesh (India)

    2016-02-15

    The room-temperature photoluminescence (PL) spectra of hydrothermally grown ZnO nanorods (NRs) coated with Au using dc sputtering and thermal evaporation were systematically investigated. Au coated (via dc sputtering) ZnO NRs were found to exhibit very large near band edge emission enhancement, on the contrary Au coated (via thermal evaporation) ZnO NRs showed suppression in the near band edge emission peak. These observed results were further confirmed by excitation intensity (EI) dependent PL spectra of different samples. Further using Raman spectra it has been observed that the longitudinal optical (LO) phonons exhibit an enhancement and a weakening by the Au coatings, using dc sputtering and thermal evaporation respectively. Finally by controlling the concentration of KMnO{sub 4} as an additive during the hydrothermal growth, selective tuning in the defect density was carried out, which was later utilized to probe the effect of defect density of the Au–ZnO plasmonic coupling. Moreover, our results strongly suggest that the EI dependent PL has a strong dependence on the metal coating technique. The findings presented in this article clearly indicate the dependence of Au–ZnO plasmonic coupling on the overall defect density and the process of Au deposition.

  16. Selectively enhanced expression of prophenoloxidase activating enzyme 1 (PPAE1 at a bacteria clearance site in the white shrimp, Litopenaeus vannamei

    Directory of Open Access Journals (Sweden)

    Jang In-Kwon

    2011-12-01

    Full Text Available Abstract Background The prophenoloxidase-activating (PO activating system plays an important role in the crustacean innate immunity, particularly in wound healing and pathogen defense. A key member of this system is prophenoloxidase-activating enzyme (PPAE, which is the direct activator of prophenoloxidase (proPO. Despite their importance in crustacean PO activating system, the studies on them remain limited. Results Here we report on a PPAE of white shrimp, Litopenaeus vannamei (lvPPAE1, which showed 94% similarity to PPAE1 of Penaeus monodon. We found that lvPPAE1 in fluid hemocytes was down regulated after challenge by Vibrio harveyi but was enhanced when shrimps were exposed to a bacteria-rich environment for long-term. In vivo gene silence of lvPPAE1 by RNAi can significantly reduce the phenoloxidase activity (PO and increase the susceptibility of shrimps to V. harveyi. Although lvPPAE1 was down-regulated in fluid hemocytes by Vibrio challenge, its expression increased significantly in gill after bacteria injection, which is the primary bacteria-clearance tissue. Conclusion Suppressed expression in fluid hemocytes and enhanced expression in gill indicates selectively enhanced expression at the bacterial clearance site. This is a novel feature for PPAE expression. The results will contribute to our understanding of the PO activating system in crustaceans.

  17. Study on Sensory Quality, Antioxidant Properties, and Maillard Reaction Products Formation in Rye-Buckwheat Cakes Enhanced with Selected Spices

    Directory of Open Access Journals (Sweden)

    Małgorzata Przygodzka

    2015-01-01

    Full Text Available The effect of selected spices included in the recipe of rye-buckwheat cakes on sensory quality, nutritional value, and Maillard reaction (MR products formation was addressed in this study. The cakes with cloves, nutmeg, allspice, cinnamon, vanilla, and spice mix addition revealed the highest overall quality values. Cakes enriched with cloves, allspice, and spice mix showed the highest rutin content and almost threefold higher available lysine contents whereas cakes enhanced with mix, cloves, and cinnamon were the richest source of phenolic compounds. The highest antioxidant capacity showed cakes with cloves and spice mix. The furosine, a marker of early stage of MR, was decreased in cakes with cloves, allspice, spice mix, and vanilla whereas fluorescent intermediatory compounds were reduced in cakes enhanced with cloves, allspice, and cinnamon. In contrast, browning index was increased as compared to cakes without spices. The FAST index was significantly lowered in all cakes enriched with spices, especially with cloves, allspice, and mix addition. The presence of cloves, allspice, and vanilla in cake formula was the most efficient in acrylamide strategy. It can be suggested that cloves, allspice, and vanilla might be used for production of safety and good quality cakes.

  18. Spatial light modulator array with heat minimization and image enhancement features

    Science.gov (United States)

    Jain, Kanti [Briarcliff Manor, NY; Sweatt, William C [Albuquerque, NM; Zemel, Marc [New Rochelle, NY

    2007-01-30

    An enhanced spatial light modulator (ESLM) array, a microelectronics patterning system and a projection display system using such an ESLM for heat-minimization and resolution enhancement during imaging, and the method for fabricating such an ESLM array. The ESLM array includes, in each individual pixel element, a small pixel mirror (reflective region) and a much larger pixel surround. Each pixel surround includes diffraction-grating regions and resolution-enhancement regions. During imaging, a selected pixel mirror reflects a selected-pixel beamlet into the capture angle of a projection lens, while the diffraction grating of the pixel surround redirects heat-producing unused radiation away from the projection lens. The resolution-enhancement regions of selected pixels provide phase shifts that increase effective modulation-transfer function in imaging. All of the non-selected pixel surrounds redirect all radiation energy away from the projection lens. All elements of the ESLM are fabricated by deposition, patterning, etching and other microelectronic process technologies.

  19. Cross-validated stable-isotope dilution GC-MS and LC-MS/MS assays for monoacylglycerol lipase (MAGL) activity by measuring arachidonic acid released from the endocannabinoid 2-arachidonoyl glycerol.

    Science.gov (United States)

    Kayacelebi, Arslan Arinc; Schauerte, Celina; Kling, Katharina; Herbers, Jan; Beckmann, Bibiana; Engeli, Stefan; Jordan, Jens; Zoerner, Alexander A; Tsikas, Dimitrios

    2017-03-15

    2-Arachidonoyl glycerol (2AG) is an endocannabinoid that activates cannabinoid (CB) receptors CB1 and CB2. Monoacylglycerol lipase (MAGL) inactivates 2AG through hydrolysis to arachidonic acid (AA) and glycerol, thus modulating the activity at CB receptors. In the brain, AA released from 2AG by the action of MAGL serves as a substrate for cyclooxygenases which produce pro-inflammatory prostaglandins. Here we report stable-isotope GC-MS and LC-MS/MS assays for the reliable measurement of MAGL activity. The assays utilize deuterium-labeled 2AG (d 8 -2AG; 10μM) as the MAGL substrate and measure deuterium-labeled AA (d 8 -AA; range 0-1μM) as the MAGL product. Unlabelled AA (d 0 -AA, 1μM) serves as the internal standard. d 8 -AA and d 0 -AA are extracted from the aqueous buffered incubation mixtures by ethyl acetate. Upon solvent evaporation the residue is reconstituted in the mobile phase prior to LC-MS/MS analysis or in anhydrous acetonitrile for GC-MS analysis. LC-MS/MS analysis is performed in the negative electrospray ionization mode by selected-reaction monitoring the mass transitions [M-H] - →[M-H - CO 2 ] - , i.e., m/z 311→m/z 267 for d 8 -AA and m/z 303→m/z 259 for d 0 -AA. Prior to GC-MS analysis d 8 -AA and d 0 -AA were converted to their pentafluorobenzyl (PFB) esters by means of PFB-Br. GC-MS analysis is performed in the electron-capture negative-ion chemical ionization mode by selected-ion monitoring the ions [M-PFB] - , i.e., m/z 311 for d 8 -AA and m/z 303 for d 0 -AA. The GC-MS and LC-MS/MS assays were cross-validated. Linear regression analysis between the concentration (range, 0-1μM) of d 8 -AA measured by LC-MS/MS (y) and that by GC-MS (x) revealed a straight line (r 2 =0.9848) with the regression equation y=0.003+0.898x, indicating a good agreement. In dog liver, we detected MAGL activity that was inhibitable by the MAGL inhibitor JZL-184. Exogenous eicosatetraynoic acid is suitable as internal standard for the quantitative determination

  20. The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties.

    Directory of Open Access Journals (Sweden)

    Francesca Rossi

    Full Text Available Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses. The immunosuppressive properties of human mesenchymal stromal cells have attracted much attention from immunologists, stem cell biologists and clinicians. Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated. Endocannabinoids, mainly acting through the cannabinoid receptor subtype 2, are able to modulate cytokine release and to act as immunosuppressant when added to activated T lymphocytes. In the present study, we have investigated, through a multidisciplinary approach, the involvement of the endocannabinoids in migration, viability and cytokine release of human mesenchymal stromal cells. We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

  1. Selectivity Enhancement in Molecularly Imprinted Polymers for Binding of Bisphenol A

    Directory of Open Access Journals (Sweden)

    Noof A. Alenazi

    2016-10-01

    Full Text Available Bisphenol A (BPA is an estrogen-mimicking chemical that can be selectively detected in water using a chemical sensor based on molecularly imprinted polymers (MIPs. However, the utility of BPA-MIPs in sensor applications is limited by the presence of non-specific binding sites. This study explored a dual approach to eliminating these sites: optimizing the molar ratio of the template (bisphenol A to functional monomer (methacrylic acid to cross-linker (ethylene glycol dimethacrylate, and esterifying the carboxylic acid residues outside of specific binding sites by treatment with diazomethane. The binding selectivity of treated MIPs and non-treated MIPs for BPA and several potential interferents was compared by capillary electrophoresis with ultraviolet detection. Baclofen, diclofenac and metformin were demonstrated to be good model interferents to test all MIPs for selective binding of BPA. Treated MIPs demonstrated a significant decrease in binding of the interferents while offering high selectivity toward BPA. These results demonstrate that conventional optimization of the molar ratio, together with advanced esterification of non-specific binding sites, effectively minimizes the residual binding of interferents with MIPs to facilitate BPA sensing.

  2. Enhanced individual selection for selecting fast growing fish: the "PROSPER" method, with application on brown trout (Salmo trutta fario

    Directory of Open Access Journals (Sweden)

    Vandeputte Marc

    2004-11-01

    Full Text Available Abstract Growth rate is the main breeding goal of fish breeders, but individual selection has often shown poor responses in fish species. The PROSPER method was developed to overcome possible factors that may contribute to this low success, using (1 a variable base population and high number of breeders (Ne > 100, (2 selection within groups with low non-genetic effects and (3 repeated growth challenges. Using calculations, we show that individual selection within groups, with appropriate management of maternal effects, can be superior to mass selection as soon as the maternal effect ratio exceeds 0.15, when heritability is 0.25. Practically, brown trout were selected on length at the age of one year with the PROSPER method. The genetic gain was evaluated against an unselected control line. After four generations, the mean response per generation in length at one year was 6.2% of the control mean, while the mean correlated response in weight was 21.5% of the control mean per generation. At the 4th generation, selected fish also appeared to be leaner than control fish when compared at the same size, and the response on weight was maximal (≈130% of the control mean between 386 and 470 days post fertilisation. This high response is promising, however, the key points of the method have to be investigated in more detail.

  3. Laser nanostructured Co nanocylinders-Al{sub 2}O{sub 3} cermets for enhanced & flexible solar selective absorbers applications

    Energy Technology Data Exchange (ETDEWEB)

    Karoro, A., E-mail: angela@tlabs.ac.za [UNESCO-UNISA Africa Chair in Nanosciences-Nanotechnology, College of Graduate Studies, University of South Africa, Muckleneuk ridge, PO Box 392, Pretoria (South Africa); Nanosciences African Network (NANOAFNET), iThemba LABS-National Research Foundation, 1 Old Faure road, Somerset West 7129, PO Box 722, Western Cape (South Africa); Nuru, Z.Y.; Kotsedi, L.; Bouziane, Kh. [UNESCO-UNISA Africa Chair in Nanosciences-Nanotechnology, College of Graduate Studies, University of South Africa, Muckleneuk ridge, PO Box 392, Pretoria (South Africa); Nanosciences African Network (NANOAFNET), iThemba LABS-National Research Foundation, 1 Old Faure road, Somerset West 7129, PO Box 722, Western Cape (South Africa); Mothudi, B.M. [UNESCO-UNISA Africa Chair in Nanosciences-Nanotechnology, College of Graduate Studies, University of South Africa, Muckleneuk ridge, PO Box 392, Pretoria (South Africa); Physics Dept., University of South Africa, Muckleneuk ridge, PO Box 392, Pretoria (South Africa); Maaza, M. [UNESCO-UNISA Africa Chair in Nanosciences-Nanotechnology, College of Graduate Studies, University of South Africa, Muckleneuk ridge, PO Box 392, Pretoria (South Africa); Nanosciences African Network (NANOAFNET), iThemba LABS-National Research Foundation, 1 Old Faure road, Somerset West 7129, PO Box 722, Western Cape (South Africa)

    2015-08-30

    Highlights: • Co-Al{sub 2}O{sub 3} was synthesized by electrodeposition & femtosecond laser structuring. • The ultrafast laser structuring significantly increases the solar absorption. • Co-Al{sub 2}O{sub 3} exhibited 0.98 solar absorptance and 0.03 thermal emittance. - Abstract: We report on the structural and optical properties of laser surface structured Co nanocylinders-Al{sub 2}O{sub 3} cermets on flexible Aluminium substrate for enhanced solar selective absorbers applications. This new family of solar selective absorbers coating consisting of Co nanocylinders embedded into nanoporous alumina template which were produced by standard electrodeposition and thereafter submitted to femtosecond laser surface structuring. While their structural and chemical properties were investigated by X-ray diffraction, scanning electron microscopy, energy dispersive spectrometry and atomic force microscopy, their optical characteristics were investigated by specular & diffuse reflectance. The optimized samples exhibit an elevated optical absorptance α(λ) above 98% and an emittance ε(λ) ∼0.03 in the spectral range of 200–1100 nm. This set of values was suggested to be related to several surface and volume phenomena such as light trapping, plasmon surface effect as well as angular dependence of light reflection induced by the ultrafast laser multi-scale structuring.

  4. CANNABIS USE BY INDIVIDUALS WITH MULTIPLE SCLEROSIS: EFFECTS ON SPECIFIC IMMUNE PARAMETERS

    Science.gov (United States)

    Sexton, Michelle; Cudaback, Eiron; Abdullah, Rehab A.; Finnell, John; Mischley, Laurie K; Rozga, Mary; Lichtman, Aron H.; Stella, Nephi

    2014-01-01

    Cannabinoids affect immune responses in ways that may be beneficial for autoimmune diseases. We sought to determine whether chronic Cannabis use differentially modulates a select number of immune parameters in healthy controls and individuals with multiple sclerosis (MS cases). Subjects were enrolled and consented to a single blood draw, matched for age and BMI. We measured monocyte migration isolated from each subject, as well as plasma levels of endocannabinoids and cytokines. Cases met definition of MS by international diagnostic criteria. Monocyte cell migration measured in control subjects and individuals with MS were similarly inhibited by a set ratio of phytocannabinoids. The plasma levels of CCL2 and IL17 were reduced in non-naïve cannabis users irrespective of the cohorts. We detected a significant increase in the endocannabinoid arachidonoylethanolamine (AEA) in serum from individuals with MS compared to control subjects, and no significant difference in levels of other endocannabinoids and signaling lipids irrespective of Cannabis use. Chronic Cannabis use may affect the immune response to similar extent in individuals with MS and control subjects through the ability of phytocannabinoids to reduce both monocyte migration and cytokine levels in serum. From a panel of signaling lipids, only the levels of AEA are increased in individuals with MS, irrespective from Cannabis use or not. Our results suggest that both MS cases and controls respond similarly to chronic Cannabis use with respect to the immune parameters measured in this study. PMID:25135301

  5. ENHANCEMENT OF THE SENSITIVITY AND SELECTIVITY OF THE VOLTAMMETRIC SENSOR FOR URIC ACID USING MOLECULARLY IMPRINTED POLYMER

    Directory of Open Access Journals (Sweden)

    Miratul Khasanah

    2010-12-01

    Full Text Available The sensitivity and selectivity of voltammetric sensor for uric acid can be improved by modifying the working electrode using a polymer with a molecular template (molecularly imprinted polymer, MIP. Polymer and MIP was synthesized from methacrylic acid (MAA as monomer, ethylene glycol dimethacrylic acid (EGDMA as cross-linker, uric acid (UA as template and the results were characterized by various methods. The poly-MAA formation was identified by a decrease in the intensity of infrared (IR spectra at ~1540 cm-1 (C=C and an increase at ~1700 cm-1 (C=O compared to the IR spectra of the MAA and EGDMA. The SEM analysis showed that the cavity of polymer is small enough (~ 0.1 µm and homogeneous. Establishment of MIP was carried out by extracting of the uric acid from the polymer network. The IR spectra of MIP exhibited the decrease in intensity at ~1700 cm-1 (C=O compared to the non imprinted polymer (NIP. The data of BET analysis showed that polymer pore size increase slightly from 37.71 Å to 38.02 Å after the extraction process of uric acid from the polymer network. Its may be due to incomplete extraction of uric acid from the polymer network. Modifications of hanging mercury drop electrode using MIP made from MAA, EGDMA, and UA with a mole ratio of 1:3:1 produced a sensitive and selective voltammetric sensor for uric acid. The sensitivity obtained was 16.405 nA L/µg. The presence of ascorbic acid in equal concentration with uric acid decreased the current response of only 0.08%. Compared to HMDE electrode, the sensitivity and selectivity of the HMDE-MIP sensor enhanced about 100 and 700 times, respectively. The detection limit was found to be 5.94 x10-10 M.

  6. Enhanced selectivity of boron doped diamond electrodes for the detection of dopamine and ascorbic acid by increasing the film thickness

    Energy Technology Data Exchange (ETDEWEB)

    Qi, Yao; Long, Hangyu [School of Material Science and Engineering, Central South University, Changsha 410083 (China); Ma, Li, E-mail: marycsupm@csu.edu.cn [State Key Laboratory of Powder Metallurgy, Central South University, Changsha 410083 (China); Wei, Quiping, E-mail: qiupwei@csu.edu.cn [School of Material Science and Engineering, Central South University, Changsha 410083 (China); State Key Laboratory of Powder Metallurgy, Central South University, Changsha 410083 (China); Li, Site [School of Material Science and Engineering, Central South University, Changsha 410083 (China); Yu, Zhiming [School of Material Science and Engineering, Central South University, Changsha 410083 (China); State Key Laboratory of Powder Metallurgy, Central South University, Changsha 410083 (China); Hu, Jingyuan [School of Material Science and Engineering, Central South University, Changsha 410083 (China); Liu, Peizhi [Key laboratory of interface science and engineering in advanced materials, Ministry of Education, Taiyuan University of Technology, Taiyuan 030024,PR China (China); Wang, Yijia [School of Material Science and Engineering, Central South University, Changsha 410083 (China); Meng, Lingcong [Department of Chemistry, University of Warwick, Coventry, West Midlands CV4 7AL (United Kingdom)

    2016-12-30

    Highlights: • BDD electrodes with different thickness have been fabricated. • BDD electrodes are used for simultaneous detection of DA and AA. • Anodic pretreatment enhance the separation of DA and AA oxidation peak potential. • Thicker BDD electrode show better performance for DA detection coexisting with AA. - Abstract: In this paper, boron doped diamond (BDD) with different thickness were prepared by hot filament chemical vapor deposition. The performance of BDD electrodes for detecting dopamine (DA) and ascorbic acid (AA) were investigated. Scanning electron microscopy and Raman spectra reveal the grain size increases and the film quality improves with the increase of film thickness. Electrochemical test show that the transfer coefficient in [Fe{sub 3} (CN) {sub 6}]{sup 3−/4−} redox system increases with the increase of the film thickness. The results of selectivity and sensitivity for DA mixed with AA detection show that 8h-BDD and 12h-BDD electrodes possess well selective separated oxidation peaks of DA and AA, and the 12h-BDD electrode exhibits optimal sensitivity until the DA concentration drops to 1 μ M.

  7. Artificial neural network models: A decision support tool for enhancing seedling selection in sugarcane

    Science.gov (United States)

    Currently, sugarcane selection begins at the seedling stage with visual selection for cane yield and other yield-related traits. Although subjective and inefficient, visual selection remains the primary method for selection. Visual selection is inefficient because of the confounding effect of genoty...

  8. Ultraviolet Resonant Raman Enhancements in the Detection of Explosives

    Energy Technology Data Exchange (ETDEWEB)

    Short Jr., Billy Joe [Naval Postgraduate School, Monterey, CA (United States)

    2009-06-01

    Raman-based spectroscopy is potentially militarily useful for standoff detection of high explosives. Normal (non-resonance) and resonance Raman spectroscopies are both light scattering techniques that use a laser to measure the vibrational spectrum of a sample. In resonance Raman, the laser is tuned to match the wavelength of a strong electronic absorbance in the molecule of interest, whereas, in normal Raman the laser is not tuned to any strong electronic absorbance bands. The selection of appropriate excitation wavelengths in resonance Raman can result in a dramatic increase in the Raman scattering efficiency of select band(s) associated with the electronic transition. Other than the excitation wavelength, however, resonance Raman is performed experimentally the same as normal Raman. In these studies, normal and resonance Raman spectral signatures of select solid high explosive (HE) samples and explosive precursors were collected at 785 nm, 244 nm and 229 nm. Solutions of PETN, TNT, and explosive precursors (DNT & PNT) in acetonitrile solvent as an internal Raman standard were quantitatively evaluated using ultraviolet resonance Raman (UVRR) microscopy and normal Raman spectroscopy as a function of power and select excitation wavelengths. Use of an internal standard allowed resonance enhancements to be estimated at 229 nm and 244 nm. Investigations demonstrated that UVRR provided ~2000-fold enhancement at 244 nm and ~800-fold improvement at 229 nm while PETN showed a maximum of ~25-fold at 244 nm and ~190-fold enhancement at 229 nm solely from resonance effects when compared to normal Raman measurements. In addition to the observed resonance enhancements, additional Raman signal enhancements are obtained with ultraviolet excitation (i.e., Raman scattering scales as !4 for measurements based on scattered photons). A model, based partly on the resonance Raman enhancement results for HE solutions, is presented for estimating Raman enhancements for solid HE samples.

  9. Nonsteroidal selective androgen receptor modulators enhance female sexual motivation.

    Science.gov (United States)

    Jones, Amanda; Hwang, Dong Jin; Duke, Charles B; He, Yali; Siddam, Anjaiah; Miller, Duane D; Dalton, James T

    2010-08-01

    Women experience a decline in estrogen and androgen levels after natural or surgically induced menopause, effects that are associated with a loss of sexual desire and bone mineral density. Studies in our laboratories have shown the beneficial effects of selective androgen receptor modulators (SARMs) in the treatment of osteoporosis and muscle wasting in animal models. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-propionamide analogs was synthesized to evaluate the effects of B-ring substitutions on in vitro and in vivo pharmacologic activity, especially female sexual motivation. The androgen receptor (AR) relative binding affinities ranged from 0.1 to 26.5% (relative to dihydrotestosterone) and demonstrated a range of agonist activity at 100 nM. In vivo pharmacologic activity was first assessed by using male rats. Structural modifications to the B-ring significantly affected the selectivity of the SARMs, demonstrating that single-atom substitutions can dramatically and unexpectedly influence activity in androgenic (i.e., prostate) and anabolic (i.e., muscle) tissues. (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro,4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) displayed full agonist activity in androgenic and anabolic tissues; however, the remaining SARMs were more prostate-sparing, selectively maintaining the size of the levator ani muscle in castrated rats. The partner-preference paradigm was used to evaluate the effects of SARMs on female sexual motivation. With the exception of two four-halo substituted analogs, the SARMs increased sexual motivation in ovariectomized rats, with potency and efficacy comparable with testosterone propionate. These results indicate that the AR is important in regulating female libido given the nonaromatizable nature of SARMs and it could be a superior alternative to steroidal testosterone preparations in the treatment of hypoactive sexual desire disorder.

  10. Enhancing the selection of backoff interval using fuzzy logic over wireless Ad Hoc networks.

    Science.gov (United States)

    Ranganathan, Radha; Kannan, Kathiravan

    2015-01-01

    IEEE 802.11 is the de facto standard for medium access over wireless ad hoc network. The collision avoidance mechanism (i.e., random binary exponential backoff-BEB) of IEEE 802.11 DCF (distributed coordination function) is inefficient and unfair especially under heavy load. In the literature, many algorithms have been proposed to tune the contention window (CW) size. However, these algorithms make every node select its backoff interval between [0, CW] in a random and uniform manner. This randomness is incorporated to avoid collisions among the nodes. But this random backoff interval can change the optimal order and frequency of channel access among competing nodes which results in unfairness and increased delay. In this paper, we propose an algorithm that schedules the medium access in a fair and effective manner. This algorithm enhances IEEE 802.11 DCF with additional level of contention resolution that prioritizes the contending nodes according to its queue length and waiting time. Each node computes its unique backoff interval using fuzzy logic based on the input parameters collected from contending nodes through overhearing. We evaluate our algorithm against IEEE 802.11, GDCF (gentle distributed coordination function) protocols using ns-2.35 simulator and show that our algorithm achieves good performance.

  11. Effects of caffeine on striatal neurotransmission: focus on cannabinoid CB1 receptors.

    Science.gov (United States)

    Rossi, Silvia; De Chiara, Valentina; Musella, Alessandra; Mataluni, Giorgia; Sacchetti, Lucia; Siracusano, Alberto; Bernardi, Giorgio; Usiello, Alessandro; Centonze, Diego

    2010-04-01

    Caffeine is the most commonly self-administered psychoactive substance worldwide. At usual doses, the effects of caffeine on vigilance, attention, mood and arousal largely depend on the modulation of central adenosine receptors. The present review article describes the action of caffeine within the striatum, to provide a possible molecular mechanism at the basis of the psychomotor and reinforcing properties of this pharmacological agent. The striatum is in fact a subcortical area involved in sensorimotor, cognitive, and emotional processes, and recent experimental findings showed that chronic caffeine consumption enhances the sensitivity of striatal GABAergic synapses to the stimulation of cannabinoid CB1 receptors. The endocannabinoid system is involved in the psychoactive effects of many compounds, and adenosine A2A receptors (the main receptor target of caffeine) elicit a permissive effect towards CB1 receptors, thus suggesting that A2A-CB1 receptor interaction plays a major role in the generation and maintenance of caffeine reinforcing behavior. Aim of this review is to describe the effects of caffeine on striatal neurotransmission with special reference to the modulation of the endocannabinoid system.

  12. Visual attention spreads broadly but selects information locally.

    Science.gov (United States)

    Shioiri, Satoshi; Honjyo, Hajime; Kashiwase, Yoshiyuki; Matsumiya, Kazumichi; Kuriki, Ichiro

    2016-10-19

    Visual attention spreads over a range around the focus as the spotlight metaphor describes. Spatial spread of attentional enhancement and local selection/inhibition are crucial factors determining the profile of the spatial attention. Enhancement and ignorance/suppression are opposite effects of attention, and appeared to be mutually exclusive. Yet, no unified view of the factors has been provided despite their necessity for understanding the functions of spatial attention. This report provides electroencephalographic and behavioral evidence for the attentional spread at an early stage and selection/inhibition at a later stage of visual processing. Steady state visual evoked potential showed broad spatial tuning whereas the P3 component of the event related potential showed local selection or inhibition of the adjacent areas. Based on these results, we propose a two-stage model of spatial attention with broad spread at an early stage and local selection at a later stage.

  13. Preventive Effects of Resveratrol on Endocannabinoid System and Synaptic Protein Modifications in Rat Cerebral Cortex Challenged by Bilateral Common Carotid Artery Occlusion and Reperfusion

    Directory of Open Access Journals (Sweden)

    Gianfranca Carta

    2018-01-01

    Full Text Available This study aims to evaluate the putative roles of a single acute dose of resveratrol (RVT in preventing cerebral oxidative stress induced by bilateral common carotid artery occlusion, followed by reperfusion (BCCAO/R and to investigate RVT’s ability to preserve the neuronal structural integrity. Frontal and temporal-occipital cortices were examined in two groups of adult Wistar rats, sham-operated and submitted to BCCAO/R. In both groups, 6 h before surgery, half the rats were gavage-fed with a single dose of RVT (40 mg/per rat in 300 µL of sunflower oil as the vehicle, while the second half received the vehicle alone. In the frontal cortex, RVT pre-treatment prevented the BCCAO/R-induced increase of lipoperoxides, augmented concentrations of palmitoylethanolamide and docosahexaenoic acid, increased relative levels of the cannabinoid receptors type 1 (CB1 and 2 (CB2, and peroxisome-proliferator-activated-receptor (PPAR-α proteins. Increased expression of CB1/CB2 receptors mirrored that of synaptophysin and post-synaptic density-95 protein. No BCCAO/R-induced changes occurred in the temporal-occipital cortex. Collectively, our results demonstrate that, in the frontal cortex, RVT pre-treatment prevents the BCCAO/R-induced oxidative stress and modulates the endocannabinoid and PPAR-α systems. The increased expression of synaptic structural proteins further suggests the possible efficacy of RVT as a dietary supplement to preserve the nervous tissue metabolism and control the physiological response to the hypoperfusion/reperfusion challenge.

  14. Attentional Selection of Feature Conjunctions Is Accomplished by Parallel and Independent Selection of Single Features.

    Science.gov (United States)

    Andersen, Søren K; Müller, Matthias M; Hillyard, Steven A

    2015-07-08

    Experiments that study feature-based attention have often examined situations in which selection is based on a single feature (e.g., the color red). However, in more complex situations relevant stimuli may not be set apart from other stimuli by a single defining property but by a specific combination of features. Here, we examined sustained attentional selection of stimuli defined by conjunctions of color and orientation. Human observers attended to one out of four concurrently presented superimposed fields of randomly moving horizontal or vertical bars of red or blue color to detect brief intervals of coherent motion. Selective stimulus processing in early visual cortex was assessed by recordings of steady-state visual evoked potentials (SSVEPs) elicited by each of the flickering fields of stimuli. We directly contrasted attentional selection of single features and feature conjunctions and found that SSVEP amplitudes on conditions in which selection was based on a single feature only (color or orientation) exactly predicted the magnitude of attentional enhancement of SSVEPs when attending to a conjunction of both features. Furthermore, enhanced SSVEP amplitudes elicited by attended stimuli were accompanied by equivalent reductions of SSVEP amplitudes elicited by unattended stimuli in all cases. We conclude that attentional selection of a feature-conjunction stimulus is accomplished by the parallel and independent facilitation of its constituent feature dimensions in early visual cortex. The ability to perceive the world is limited by the brain's processing capacity. Attention affords adaptive behavior by selectively prioritizing processing of relevant stimuli based on their features (location, color, orientation, etc.). We found that attentional mechanisms for selection of different features belonging to the same object operate independently and in parallel: concurrent attentional selection of two stimulus features is simply the sum of attending to each of those

  15. Surface-imprinted core–shell Au nanoparticles for selective detection of bisphenol A based on surface-enhanced Raman scattering

    International Nuclear Information System (INIS)

    Xue, Jin-Qun; Li, Da-Wei; Qu, Lu-Lu; Long, Yi-Tao

    2013-01-01

    Graphical abstract: -- Highlights: •The molecularly imprinted polymer capped core–shell AuNPs (MIP-ir-AuNPs) were fabricated as a specific functional SERS substrate. •MIP-ir-AuNPs could be utilized in rapid and selective detection of BPA. •MIP-ir-AuNPs displayed good capability for determination of BPA in real samples. -- Abstract: Surface-imprinted core–shell Au nanoparticles (AuNPs) were explored for the highly selective detection of bisphenol A (BPA) by surface-enhanced Raman scattering (SERS). A triethoxysilane-template complex (BPA-Si) was synthesized and then utilized to fabricate a molecularly imprinted polymer (MIP) layer on the AuNPs via a sol–gel process. The imprinted BPA molecules were removed by a simple thermal treatment to generated the imprint-removed material, MIP-ir-AuNPs, with the desired recognition sites that could selectively rebind the BPA molecules. The morphological and polymeric characteristics of MIP-ir-AuNPs were investigated by transmission electron microscopy and Fourier-transform infrared spectroscopy. The results demonstrated that the MIP-ir-AuNPs were fabricated with a 2 nm MIP shell layer within which abundant amine groups were generated. The rebinding kinetics study showed that the MIP-ir-AuNPs could reach the equilibrium adsorption for BPA within 10 min owning to the advantage of ultrathin core–shell nanostructure. Moreover, a linear relationship between SERS intensity and the concentration of BPA on the MIP-ir-AuNPs was observed in the range of 0.5–22.8 mg L −1 , with a detection limit of 0.12 mg L −1 (blank ± 3 × s.d.). When applied to SERS detection, the developed surface-imprinted core–shell MIP-ir-AuNPs could recognize BPA and prevent interference from the structural analogues such as hexafluorobisphenol A (BPAF) and diethylstilbestrol (DES). These results revealed that the proposed method displayed significant potential utility in rapid and selective detection of BPA in real samples

  16. Spacer for enhancing selectivity of functionalized polymer towards Pu(IV)

    International Nuclear Information System (INIS)

    Chavan, Vivek; Pandey, A.K.; Goswami, A.

    2012-01-01

    To address problems in selective and fast preconcentration of Pu(IV) at ultratrace concentration from the multicomponents aqueous media and low level nuclear waste, a new functionalized polymer sorbent was developed

  17. Optical wireless links with enhanced linearity and selectivity [Invited

    Science.gov (United States)

    Green, Roger J.; Sweet, C.; Idrus, S.

    2005-10-01

    Optical wireless is an attractive medium as an alternative to optical fiber communications, and also to RF, because of its high bandwidth and relative ease of use, especially when it comes to deployment in new physical situations. We describe an optical wireless link approach that offers a performance that gives analog transmission with significantly reduced distortion levels and enhanced reception sensitivity by combining a novel hybrid detector-amplifier technique. Reduction of distortion by 40 dB and improvement in sensitivity of 20-30 dB is possible, using the techniques described.

  18. Selection and breeding of grain legumes in Australia for enhanced nodulation and N2 fixation

    International Nuclear Information System (INIS)

    Herridge, D.F.; Holland, J.F.; Rose, I.A.; Redden, R.J.

    1998-01-01

    During the period 1980-87, the areas sown to grain legumes in Australia increased dramatically, from 0.25 Mha to 1.65 Mha. These increases occurred in the western and southern cereal belts, but not in the north which N continued to be supplied by the mineralization of soil organic matter. Therefore, there was a need to promote the use of N 2 -fixing legumes in the cereal-dominated northern cropping belt. Certain problems had to be addressed before farmers would accept legumes and change established patterns of cropping. Here we describe our efforts to improve N 2 fixation by soybean, common bean and pigeon pea. Selection and breeding for enhanced N 2 fixation of soybean commenced at Tamworth in 1980 after surveys of commercial crops indicated that nodulation was sometimes inadequate, particularly on new land, and that the levels of fixed-N inputs were variable and often low. Similar programmes were established in 1985 (common bean) and 1988 (pigeon bean). Progress was made in increasing N 2 fixation by these legumes towards obtaining economic yields without fertilizer N and contributing organic N for the benefit of subsequent cereal crops

  19. 5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Pelrine, Eliza; Pasik, Sara Diana; Bayat, Leyla; Goldschmiedt, Debora; Bauer, Elizabeth P

    2016-12-01

    Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat anxiety and depression, yet they paradoxically increase anxiety during initial treatment. Acute administration of these drugs prior to learning can also enhance Pavlovian cued fear conditioning. This potentiation has been previously reported to depend upon the bed nucleus of the stria terminalis (BNST). Here, using temporary inactivation, we confirmed that the BNST is not necessary for the acquisition of cued or contextual fear memory. Systemic administration of the SSRI citalopram prior to fear conditioning led to an upregulation of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the oval nucleus of the BNST, and a majority of these neurons expressed the 5-HT2C receptor. Finally, local infusions of a 5-HT2C receptor antagonist directly into the oval nucleus of the BNST prevented the fear memory-enhancing effects of citalopram. These findings highlight the ability of the BNST circuitry to be recruited into gating fear and anxiety-like behaviors. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Enhancing High Value Care in Gastroenterology Practice.

    Science.gov (United States)

    Camilleri, Michael; Katzka, David A

    2016-10-01

    The objective of this review is to identify common areas in gastroenterology practice where studies performed provide an opportunity for enhancing value or lowering costs. We provide examples of topics in gastroenterology where clinicians could enhance value by either using less invasive testing, choosing a single best test, or by using patient symptoms to guide additional testing. The topics selected for review are selected in esophageal, pancreatic, and colorectal cancer; functional gastrointestinal diseases (irritable bowel syndrome, bacterial overgrowth, constipation); immune-mediated gastrointestinal diseases; and pancreaticobiliary pathology. We propose guidance to alter practice based on current evidence. These studies support the need to review current practice and to continue performing research to further validate the proposed guidance to enhance value of care in gastroenterology and hepatology. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.