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Sample records for agonist alleviates disease

  1. Melanocortin MC4 receptor agonists alleviate brain damage in abdominal compartment syndrome in the rat.

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    Liu, Dong; Zhang, Hong-Guang; Zhao, Zi-Ai; Chang, Ming-Tao; Li, Yang; Yu, Jian; Zhang, Ye; Zhang, Lian-Yang

    2015-02-01

    Intra-abdominal hypertension (IAH) is accompanied by high morbidity and mortality in surgical departments and ICUs. However, its specific pathophysiology is unclear. IAH not only leads to intra-abdominal tissue damage but also causes dysfunction in distal organs, such as the brain. In this study, we explore the protective effects of melanocortin 4 receptor agonists in IAH-induced brain injury. The IAH rat models were induced by hemorrhagic shock/resuscitation (with the mean arterial pressure (MAP) maintained at 30 mm Hg for 90 min followed by the reinfusion of the withdrawn blood with lactated Ringer's solution). Then, air was injected into the peritoneal cavity of the rats to maintain an intra-abdominal pressure of 20 mm Hg for 4 h. The effects of the melanocortin 4 receptor agonist RO27-3225 in alleviating the rats' IAH brain injuries were observed, which indicated that RO27-3225 could reduce brain edema, the expressions of the IL-1β and TNF-α inflammatory cytokines, the blood-brain barrier's permeability and the aquaporin4 (AQP4) and matrix metalloproteinase 9 (MMP9) levels. Moreover, the nicotinic acetylcholine receptor antagonist chlorisondamine and the selective melanocortin 4 receptor antagonist HS024 can negate the protective effects of the RO27-3225. The MC4R agonist can effectively reduce the intracerebral proinflammatory cytokine gene expression and alleviate the brain injury caused by blood-brain barrier damage following IAH. PMID:25616531

  2. PPAR Agonists and Cardiovascular Disease in Diabetes

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    Anna C. Calkin

    2008-01-01

    Full Text Available Peroxisome proliferators activated receptors (PPARs are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  3. Toll-like receptor activation by helminths or helminth products to alleviate inflammatory bowel disease

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    Song YanXia

    2011-09-01

    Full Text Available Abstract Helminth infection may modulate the expression of Toll like receptors (TLR in dendritic cells (DCs and modify the responsiveness of DCs to TLR ligands. This may regulate aberrant intestinal inflammation in humans with helminthes and may thus help alleviate inflammation associated with human inflammatory bowel disease (IBD. Epidemiological and experimental data provide further evidence that reducing helminth infections increases the incidence rate of such autoimmune diseases. Fine control of inflammation in the TLR pathway is highly desirable for effective host defense. Thus, the use of antagonists of TLR-signaling and agonists of their negative regulators from helminths or helminth products should be considered for the treatment of IBD.

  4. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

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    Yu, Shan; Li, Sijia; Henke, Adam; Muse, Evan D; Cheng, Bo; Welzel, Gustav; Chatterjee, Arnab K; Wang, Danling; Roland, Jason; Glass, Christopher K; Tremblay, Matthew

    2016-07-01

    Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. PMID:27025962

  5. β2-agonist therapy in lung disease.

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    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  6. Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.

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    Betti, Cecilia; Starnowska, Joanna; Mika, Joanna; Dyniewicz, Jolanta; Frankiewicz, Lukasz; Novoa, Alexandre; Bochynska, Marta; Keresztes, Attila; Kosson, Piotr; Makuch, Wioletta; Van Duppen, Joost; Chung, Nga N; Vanden Broeck, Jozef; Lipkowski, Andrzej W; Schiller, Peter W; Janssens, Frans; Ceusters, Marc; Sommen, François; Meert, Theo; Przewlocka, Barbara; Tourwé, Dirk; Ballet, Steven

    2015-12-10

    Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds. PMID:26713106

  7. Are Dopamine Agonists Neuroprotective in Parkinson′s Disease?

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Dopamine (DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson′s disease (PD) and in PD patient with levodopa (L-DOPA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoplasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer′s disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinical trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as 18 F-L-DOPA PET and 123 I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.``

  8. Screening for new agonists against Alzheimer's disease.

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    Zheng, Huiqin; Wei, Dong-Qing; Zhang, Rui; Wang, Chunfang; Wei, Huachun; Chou, Kuo-Chen

    2007-09-01

    To find new drug candidates for treating Alzheimer's disease, we used the similarity search technique and GTS-21 as a template to search the Traditional Chinese Medicines Database. The high-score molecules thus obtained were compared with the template through the flexible alignment. Those molecules which had good alignment with GTS-21 were selected for conducting the docking studies aimed at the alpha7 nicotinic acetylcholine receptor. The CHARMM22 force field was taken to compute the partial charge and the TABU search was adopted to operate the docking process. The docking results thus obtained were used to compare with that of GTS-21. Those molecules which had better docking results than that of GTS-21 were singled out for further consideration. Finally, it was found through an in-depth structural analysis that Mol 7235 might be a promising candidate for further modification by experiments to make it become an effective drug for treating Alzheimer's disease. PMID:17897076

  9. The treatment of Parkinson's disease with dopamine agonists

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    Frank, Wilhelm

    2008-06-01

    Full Text Available Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body. The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system. A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen. Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors, monoaminoxydase-inhibitors (MAO-inhibitors and NMDA-antagonists (N-Methyl-d-aspartat-antagonists. In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia. The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine

  10. Bilateral Thoracoscopic Splanchnotomy to Alleviate Pain in Chronic Pancreatic Disease.

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    Bosanquet, David C; Wilcox, Christopher R M; Rasheed, Ashraf

    2016-03-01

    Chronic intractable pain is a common problem in severe pancreatic disease. Bilateral thoracoscopic splanchnotomy, a thoracoscopic neurotomy of the splanchnic nerves, is rarely performed but may provide significant pain relief in these patients. We present a safe strategy that uses prone positioning and two thoracoscopic ports for either hemithorax, permitting easy exposure and simple dissection of the greater and lesser splanchnic nerves. In our experience, this technique provides excellent pain relief with a minimal postoperative stay and few postoperative adverse events. This intervention has the potential to reduce dependency on opioid agents and improve quality of life in carefully selected patients. PMID:26897240

  11. Arachnophobia alleviated by subthalamic nucleus stimulation for Parkinson's disease.

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    Allert, Niels; Gippert, Sabrina M; Sajonz, Bastian E A; Nelles, Christoph; Bewernick, Bettina; Schlaepfer, Thomas E; Coenen, Volker A

    2016-06-01

    We report on a Parkinson patient with motor fluctuations and dyskinesias in whom deep brain stimulation (DBS) of the subthalamic nucleus (STN) not only improved motor symptoms but also pre-existing arachnophobia. Arachnophobia had been unchanged by the course of Parkinson's disease but rapidly improved with STN-DBS. Both, motor effects and the improvement of arachnophobia were stable during 2 years follow-up. To our knowledge this is the first report on STN stimulation effects on a specific phobia. PMID:27198699

  12. Ku70 alleviates neurodegeneration in Drosophila models of Huntington's disease.

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    Takuya Tamura

    Full Text Available DNA damage accumulates in genome DNA during the long life of neurons, thus DNA damage repair is indispensable to keep normal functions of neurons. We previously reported that Ku70, a critical molecule for DNA double strand break (DSB repair, is involved in the pathology of Huntington's disease (HD. Mutant huntingtin (Htt impaired Ku70 function via direct interaction, and Ku70 supplementation recovered phenotypes of a mouse HD model. In this study, we generate multiple Drosophila HD models that express mutant huntingtin (Htt in eye or motor neuron by different drivers and show various phenotypes. In such fly models, Ku70 co-expression recovers lifespan, locomotive activity and eye degeneration. In contrast, Ku70 reduction by heterozygous null mutation or siRNA-mediated knock down accelerates lifespan shortening and locomotion disability. These results collectively support that Ku70 is a critical mediator of the HD pathology and a candidate therapeutic target in HD.

  13. Compound Formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson’s disease

    Institute of Scientific and Technical Information of China (English)

    Long Teng; Fang Hong; Chenguang Zhang; Jiancheng He; Haiying Wang

    2014-01-01

    Compound Formula Rehmannia has been shown to be clinically effective in treating Parkin-son’s disease and levodopa-induced dyskinesia;however, the mechanisms remain unclear. In this study, we established a model of Parkinson’s disease dyskinesia in rats, and treated these animals with Compound Formula Rehmannia. Compound Formula Rehmannia inhibited the increase in mRNA expression of N-methyl-D-aspartate receptor subunits 1 and 2 and excitatory amino acid neurotransmitter genes, and it inhibited the reduction in expression of γ-aminobutyric acid receptor B1, an inhibitory amino acid neurotransmitter gene, in the corpus striatum. In addition, Compound Formula Rehmannia alleviated dyskinesia symptoms in the Parkinson’s disease rats. These experimental findings indicate that Compound Formula Rehmannia alleviates levodo-pa-induced dyskinesia in Parkinson’s disease by modulating neurotransmitter signaling in the corpus striatum.

  14. Qing Re Liang Xue Decoction Alleviates Hypercoagulability in Kawasaki Disease

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    Jiao-yang Chen

    2015-01-01

    Full Text Available Objective. Kawasaki disease (KD is a multisystemic autoimmune vasculitis. Intravenous immunoglobulin (IVIG is the first-line treatment for KD. It is unclear whether traditional Chinese medicine (TCM has an effect on KD. We aimed to observe the clinical efficacy of TCM on acute KD via serum interleukin-33 (IL-33 and tumor necrosis factor alpha (TNF-α measurements. Methods. Thirty-one KD patients were treated with Qing Re Liang Xue decoction and Western medicine (integrative medicine treatment group, while 28 KD patients were treated with Western medicine only (Western medicine treatment group. Thirty patients were included in a febrile group and 28 healthy children were included in the control group. Clinical characteristics and laboratory findings were gathered and compared. Serum IL-33 and TNF-α levels were measured by multiplex Luminex assay. Results. The platelet count in the integrative medicine treatment group was significantly lower than that in the Western medicine treatment group. The integrative medicine group had a shorter fever duration and lower IL-33 and TNF-α levels than those in the Western medicine group, but there were no significant differences between the two KD groups after treatment. Conclusion. Qing Re Liang Xue decoction improved the hypercoagulable state of KD patients. Potential myocardial protective effects require further research.

  15. Studies on possibility for alleviation of lifestyle diseases by low-dose irradiation or radon inhalation

    International Nuclear Information System (INIS)

    Our previous studies showed the possibility that activation of the anti-oxidative function alleviates various oxidative damages, which are related to lifestyle diseases. Results showed that, low-dose X-ray irradiation activated superoxide dismutase and inhibits oedema following ischaemia-reperfusion. To alleviate ischaemia-reperfusion injury with transplantation, the changes of the anti-oxidative function in liver graft using low-dose X-ray irradiation immediately after exenteration were examined. Results showed that liver grafts activate the anti-oxidative function as a result of irradiation. In addition, radon inhalation enhances the anti-oxidative function in some organs, and alleviates alcohol-induced oxidative damage of mouse liver. Moreover, in order to determine the most effective condition of radon inhalation, mice inhaled radon before or after carbon tetrachloride (CCl4) administration. Results showed that radon inhalation alleviates CCl4-induced hepatopathy, especially prior inhalation. It is highly possible that adequate activation of anti-oxidative functions induced by low-dose irradiation can contribute to preventing or reducing oxidative damages, which are related to lifestyle diseases. (authors)

  16. Naringin Alleviates Diabetic Kidney Disease through Inhibiting Oxidative Stress and Inflammatory Reaction.

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    Fenqin Chen

    Full Text Available Naringin, a flavanone glycoside extracted from Citrus grandis Osbeck, has a wide range of pharmacological effects. In the present study we aimed at demonstrating the protective effect of naringin against diabetic kidney disease (DKD and elucidating its possible molecular mechanism underlying. The beneficial effect of naringin was assessed in rats with streptozotocin (STZ-induced diabetes and high glucose-induced HBZY-1 cells. According to our results, first we found that naringin relieved kidney injury, improved renal function and inhibited collagen formation and renal interstitial fibrosis. Second, we confirmed that naringin restrained oxidative stress by activating Nrf2 antioxidant pathway. Moreover, the results suggested that naringin significantly resisted inflammatory reaction by inhibiting NF- κ B signaling pathway. Taken together, our results demonstrate that naringin effectively alleviates DKD, which provide theoretical basis for naringin clinically used to treatment of DKD.

  17. Graft versus host disease: New insights into A2A receptor agonist therapy

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    Karlie R. Jones

    2015-01-01

    Full Text Available Allogeneic transplantation can cure many disorders, including sickle cell disease, chronic granulomatous disease (CGD, severe combined immunodeficiency (SCID and many types of cancers. However, there are several associated risks that can result in severe immunological reactions and, in some cases, death. Much of this morbidity is related to graft versus host disease (GVHD [1]. GVHD is an immune mediated reaction in which donor T cells recognize the host as antigenically foreign, causing donor T cells to expand and attack host tissues. The current method of treating recent transplant patients with immunosuppressants to prevent this reaction has met with only partial success, emphasizing a need for new methods of GVHD treatment and prevention. Recently, a novel strategy has emerged targeting adenosine A2A receptors (A2AR through the use of adenosine agonists. These agonists have been shown in vitro to increase the TGFβ-induced generation of FoxP3+ regulatory T cells (Tregs and in vivo to improve weight gain and mortality as well as inhibit the release of pro-inflammatory cytokines in GVHD murine models [2,3]. Positive results involving A2AR agonists in vitro and in vivo are promising, suggesting that A2AR agonists should be a part of the management of clinical GvHD.

  18. Acupuncture Alleviated the Nonmotor Symptoms of Parkinson’s Disease including Pain, Depression, and Autonomic Symptoms

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    Chifumi Iseki

    2014-01-01

    Full Text Available A woman started to feel intractable pain on her lower legs when she was 76. At the age of 78, she was diagnosed as having Parkinson’s disease (PD. The leg pain was suspected to be a symptom of PD after eliminating other causes. The patient also suffered from nonmotor symptoms, depression, anxiety, hot flashes, and paroxysmal sweating. Though the patient had received pharmacotherapy including levodopa for 5 years, she still suffered from the nonmotor symptoms and was referred to our department. We treated her with acupuncture based on the Chinese traditional medicine and electroacupuncture five times per week. After the 2-week treatment, the assessment for the symptoms was as follows; visual analogue scale (VAS score of the leg pain was 16 mm (70 mm, before, Hamilton’s rating scales for depression (HAM-D score was 9 (18, before, timed 3 m Up and Go took 20 steps in 30 sec (24 steps in 38 sec, before, and the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS Part 1 score was 13 (21, before. Autonomic symptoms, hot flashes and paroxysmal sweating, were also alleviated. Acupuncture may be a good treatment modality for nonmotor symptoms in PD.

  19. Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease

    OpenAIRE

    Li, Songtao; Sun, Baodong; Nilsson, Mats I.; Bird, Andrew; Mark A. Tarnopolsky; Thurberg, Beth L.; Bali, Deeksha; Koeberl, Dwight D.

    2013-01-01

    Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P

  20. The α7 nAChR selective agonists as drug candidates for Alzheimer's disease.

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    Fan, Huaimeng; Gu, Ruoxu; Wei, Dongqing

    2015-01-01

    The nicotinic acetylcholine receptors (nAChRs) are ion channels distribute in the central or peripheral nervous system. They are receptors of the neurotransmitter acetylcholine and activation of them by agonists mediates synaptic transmission in the neuron and muscle contraction in the neuromuscular junction. Current studies reveal relationship between the nAChRs and the learning and memory as well as cognation deficit in various neurological disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia and drug addiction. There are various subtypes in the nAChR family and the α7 nAChR is one of the most abundant subtypes in the brain. The α7 nAChR is significantly reduced in the patients of Alzheimer's disease and is believed to interact with the Aβ amyloid. Aβ amyloid is co-localized with α7 nAChR in the senile plaque and interaction between them induces neuron apoptosis and reduction of the α7 nAChR expression. Treatment with α7 agonist in vivo shows its neuron protective and procognation properties and significantly improves the learning and memory ability of the animal models. Therefore, the α7 nAChR agonists are excellent drug candidates for Alzheimer's disease and we summarized here the current agonists that have selectivity of the α7 nAChR over the other nAChR, introduced recent molecular modeling works trying to explain the molecular mechanism of their selectivity and described the design of novel allosteric modulators in our lab. PMID:25387975

  1. PPAR-γ agonists in polycystic kidney disease with frequent development of cardiovascular disorders.

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    Nagao, Shizuko; Yamaguchi, Tamio

    2012-06-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common of the monogenic disorders and is characterized by bilateral renal cysts; cysts in other organs including liver, pancreas, spleen, testis and ovary; vascular abnormalities including intracranial aneurysms and subarachnoid hemorrhage; and cardiac disorders such as left ventricular hypertrophy (LVH), mitral valve regurgitation, mitral valve prolapse and aortic regurgitation. Autosomal recessive polycystic kidney disease (ARPKD) is an early-onset multisystem disorder characterized by polycysts divided from the renal collecting ducts, congenital hepatic fibrosis, and ductal plate malformation complicated by pulmonary hyperplasia and systemic hypertension. In these polycystic kidney diseases (PKD), progressive enlargement of the cysts results from the aberrant proliferation of tubule epithelial cells and trans-epithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. PPAR-γ agonists ameliorate polycystic kidney, polycystic liver and cardiac defects through β-catenin, c-Myc, CFTR, MCP-1, S6, ERK, and TGF-β signaling pathways in animal models of PKD. In this review, we describe the possible therapeutic value of PPAR-γ agonists in the treatment of renal and hepatic manifestations, and cardiac defects in progressive PKD. PMID:22122459

  2. A non-peptide oxytocin receptor agonist, WAY-267,464, alleviates novelty-induced hypophagia in mice: insights into changes in c-Fos immunoreactivity.

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    Olszewski, Pawel K; Ulrich, Christine; Ling, Nicholas; Allen, Kerry; Levine, Allen S

    2014-09-01

    Anxiety caused by the novelty of food or of the environment where the food is presented leads to suppression of consumption (hyponeophagia) reflected by an increased latency to begin feeding and decreased food intake. Studies suggest that some anxiolytics, mainly benzodiazepines and SSRIs, resolve hyponeophagia. Though the neurohormone oxytocin (OT) affects both anxiety responsiveness and feeding-related homeostasis, the link between OT and hyponeophagia has not been established. The current experiments examined the effect of OT receptor stimulation on hyponeophagia in mice and associated changes in brain activity. We found that the OT receptor agonist, WAY-267,464, at 10 and 30 mg/kg b. wt. IP, reduced the latency to approach food and increased the amount of food eaten in hyponeophagia tests differing in animals' motivation to eat (hunger, reward) and the anxiogenic context of environmental novelty (illumination and type of the cage). This effect was abolished by the pretreatment with the OT receptor antagonist, L-368,899, at 10mg/kg b. wt. The antagonist also suppressed social transmission of preference for novel food. Mice subjected to novelty conditions causing hypophagia showed significant changes in c-Fos immunoreactivity in the hippocampus, lateral septum, cingulate and piriform cortex and in the bed nucleus of the stria terminalis, lateral division, posterolateral part (STLP). The pretreatment with WAY-267,464 restored c-Fos levels in the STLP to values detected in control animals subjected to non-anxiogenic conditions. We conclude that OT plays a role in shaping the magnitude of the novelty stress-provoked hypophagia and the activity of the relevant neural networks. PMID:25038444

  3. Agonists of the tissue-protective erythropoietin receptor in the treatment of Parkinson's disease.

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    Punnonen, Juha; Miller, James L; Collier, Timothy J; Spencer, Jeffrey R

    2015-01-01

    Parkinson's disease (PD) is a neurodegenerative disease affecting more than a million people in the USA alone. While there are effective symptomatic treatments for PD, there is an urgent need for new therapies that slow or halt the progressive death of dopaminergic neurons. Significant progress has been made in understanding the pathophysiology of PD, which has substantially facilitated the discovery efforts to identify novel drugs. The tissue-protective erythropoietin (EPO) receptor, EPOR/CD131, has emerged as one promising target for disease-modifying therapies. Recombinant human EPO (rhEPO), several variants of EPO, EPO-mimetic peptides, cell-based therapies using cells incubated with or expressing EPO, gene therapy vectors encoding EPO, and small molecule EPO mimetic compounds all show potential as therapeutic candidates. Agonists of the EPOR/CD131 receptor demonstrate potent anti-apoptotic, antioxidant, and anti-inflammatory effects and protect neurons, including dopaminergic neurons, from diverse insults in vitro and in vivo. When delivered directly to the striatum, rhEPO protects dopaminergic neurons in animal models of PD. Early-stage clinical trials testing systemic rhEPO have provided encouraging results, while additional controlled studies are required to fully assess the potential of the treatment. Poor CNS availability of proteins and challenges related to invasive delivery limit delivery of EPO protein. Several variants of EPO and small molecule agonists of the EPO receptors are making progress in preclinical studies and may offer solutions to these challenges. While EPO was initially discovered as the primary modulator of erythropoiesis, the discovery and characterization of the tissue-protective EPOR/CD131 receptor offer an opportunity to selectively target the neuroprotective receptor as an approach to identify disease-modifying treatments for PD. PMID:25832721

  4. Concomitant Cushing's Disease and Marked Hyperprolactinemia: Response to a Dopamine Receptor Agonist.

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    Shiraishi, Jun; Koyama, Hidenori; Shirakawa, Manabu; Ishikura, Reiichi; Okazaki, Hirokazu; Kurajoh, Masafumi; Shoji, Takuhito; Moriwaki, Yuji; Yamamoto, Tetsuya; Namba, Mitsuyoshi

    2016-01-01

    A 38-year-old woman was admitted to our hospital because of amenorrhea, multiple bone fractures, and a Cushingoid appearance. Endocrinological investigations revealed that she had co-existing Cushing's disease and prolactinoma, with a serum level of prolactin (PRL) at 1,480 ng/mL, corticotropin (ACTH) at 81.3 pg/mL, and cortisol at 16.6 μg/dL. Due to the lack of indication for transsphenoidal surgery, cabergoline monotherapy was initiated. A 6-month course of treatment resulted in only subtle amelioration of hypercortisolism, while hyperprolactinemia was dramatically improved. In 5 cases of bihormonal (ACTH/PRL) pituitary macroadenoma reported in the English literature, 2 were initially treated with dopaminergic agonists with substantial effectiveness for both PRL and ACTH. We herein report an extremely rare case of bihormonal macroadenoma in which only PRL was responsive to treatment. PMID:27086808

  5. A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease.

    Directory of Open Access Journals (Sweden)

    Daniel Todd

    Full Text Available Huntington's disease (HD is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.

  6. How Can 1+1=3? beta(2)-Adrenergic and Glucocorticoid Receptor Agonist Synergism in Obstructive Airway Diseases

    NARCIS (Netherlands)

    Schmidt, Martina; Michel, Martin C.

    2011-01-01

    For a long time it was believed that beta(2)-adrenergic receptor agonists used in the treatment of obstructive airway diseases worked primarily on airway smooth muscle cells, causing relaxation, whereas glucocorticoids primarily improved airway function via their anti-inflammatory action, indicating

  7. AMPKα1 overexpression alleviates the hepatocyte model of nonalcoholic fatty liver disease via inactivating p38MAPK pathway.

    Science.gov (United States)

    Zhang, Hong-Ai; Yang, Xiao-Yan; Xiao, Yan-Feng

    2016-05-27

    Nonalcoholic fatty liver disease (NAFLD) has a wide spectrum of liver damage with a worldwide prevalence of almost 20%. AMP-activated protein kinase α1 (AMPKα1) is an energy sensor that plays a key role in regulating lipid metabolism of the liver. This study explores the role of AMPKα1 overexpression in a steatotic hepatocyte model. The results displayed that the AMPKα1 overexpression suppressed lipid accumulation in the cytoplasm, decreased triglyceride levels, maintained the survival of steatotic hepatocyte model with decreased cell apoptosis and increased survival rate. Besides, AMPKα1 overexpression promoted the expression of lipid catabolism-related genes, reduced the level of anabolism-related genes, alleviated the inflammatory response by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. Moreover, AMPKα1 overexpression could inhibit the activation of p38 mitogen-activated protein kinase (p38MAPK). Finally, Anisomycin, a frequently-used activator of p38MAPK, reversed the inhibitory effect of pc-AMPKα1 on the expression of p-p38MAPK, suggesting that AMPKα1 overexpression alleviates inflammatory response through the inactivation of p38MAPK. These results indicated that AMPKα1 may serve as a novel target for treatment of NAFLD. PMID:27109475

  8. Parkinson's disease fatigability and its correction with the dopamine receptor agonist pramipexole

    Directory of Open Access Journals (Sweden)

    Marina Romanovna Nodel

    2011-12-01

    Full Text Available Fatigability is a common nonmotor symptom in Parkinson's disease (PD, which worsens quality of life in patients. Objective: to analyze the association of fatigability with the duration of PD and the degree of movement and neuropsychic (depression, nocturnal sleep disorders, daytime sleepiness disorders; to evaluate changes in the manifestations of fatigability during therapy with the dopamine receptor agonist pramipexole (Mirapex. Patients and methods. Sixty patients with PD (disease duration 6.02±3.47 years; stage 2.68±0.62 without dementia were examined using the PD fatigue scale (PFS-16, unified PD rating scale (Part 2, the Beck depression inventory, the PD sleep scale, and the Epworth sleeping scale. Results. 66% of the patients were found to consider fatigability to be one of the three most daily life-limiting manifestations of the disease. The integrated rating of fatigability significantly correlated with total depression scores and sleep scores. During pramipexole therapy, there were statistically significant positive changes in fatigability, which did not correlate with those in motor functions, depression, and sleep problems. It is concluded that fatigability substantially impairs the daily activities of patients with PD and is associated with neuropsychic symptoms to a greater extent than with the degree of movement disorders in PD. This may be due to both the common pathophysiological mechanisms of these abnormalities and their comorbidity in PD. The fact that there is no significant association of the time course of changes in fatigability with alterations in the parameters of other neuropsychic functions during therapy conceivably indicated the independent genesis of this symptom.

  9. Normal aging in rats and pathological aging in human Alzheimer's disease decrease FAAH activity: modulation by cannabinoid agonists.

    Science.gov (United States)

    Pascual, A C; Martín-Moreno, A M; Giusto, N M; de Ceballos, M L; Pasquaré, S J

    2014-12-01

    Anandamide is an endocannabinoid involved in several physiological functions including neuroprotection. Anandamide is synthesized on demand and its endogenous level is regulated through its degradation, where fatty acid amide hydrolase plays a major role. The aim of this study was to characterize anandamide breakdown in physiological and pathological aging and its regulation by CB1 and CB2 receptor agonists. Fatty acid amide hydrolase activity was analyzed in an independent cohort of human cortical membrane samples from control and Alzheimer's disease patients, and in membrane and synaptosomes from adult and aged rat cerebral cortex. Our results demonstrate that fatty acid amide hydrolase activity decreases in the frontal cortex from human patients with Alzheimer's disease and this effect is mimicked by Aβ(1-40) peptide. This activity increases and decreases in aged rat cerebrocortical membranes and synaptosomes, respectively. Also, while the presence of JWH-133, a CB2 selective agonist, slightly increases anandamide hydrolysis in human controls, it decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. In the presence of WIN55,212-2, a mixed CB1/CB2 agonist, anandamide hydrolysis increases in Alzheimer's disease patients but decreases in human controls as well as in adult and aged rat cerebrocortical membranes and synaptosomes. Although a similar profile is observed in fatty acid amide hydrolase activity between aged rat synaptic endings and human Alzheimer's disease brains, it is differently modulated by CB1/CB2 agonists. This modulation leads to a reduced availability of anandamide in Alzheimer's disease and to an increased availability of this endocannabinoid in aging. PMID:25456842

  10. Genetic Engineering to Enhance Crop-Based Phytonutrients (Nutraceuticals) to Alleviate Diet-Related Diseases

    Science.gov (United States)

    Nutrition studies have provided unambiguous evidence that a number of human health maladies including chronic coronary artery, hypertension, diabetes, osteoporosis, cancer, and age- and lifestyle-related diseases are associated with the diet. Several favorable and a few deleterious natural dietary i...

  11. Lumbar Puncture Alleviates Chorea in a Patient with Huntington’s Disease and Normal Pressure Hydrocephalus

    OpenAIRE

    Peyman Shirani; Salamone, Alicia R.; Elham Lahijani; York, Michele K.; Schulz, Paul E.

    2009-01-01

    A 44-year-old African-American male was admitted to our hospital after a suicide attempt. He had depression, poor cognitive function, choreiform movements, difficulty pronouncing words, and difficulty walking. His symptoms had worsened markedly over several months. Chorea lead to genetic testing that confirmed a diagnosis of Huntington Disease (HD). A CT scan of the head showed wider ventricles than is typical of HD. The head CT and gait change suggested normal pressure hydrocephalus (NPH). L...

  12. Naringin Alleviates Diabetic Kidney Disease through Inhibiting Oxidative Stress and Inflammatory Reaction

    OpenAIRE

    Chen, Fenqin; Zhang, Ning; Ma, Xiaoyu; Huang, Ting; Shao, Ying; Wu, Can; Wang, Qiuyue

    2015-01-01

    Naringin, a flavanone glycoside extracted from Citrus grandis Osbeck, has a wide range of pharmacological effects. In the present study we aimed at demonstrating the protective effect of naringin against diabetic kidney disease (DKD) and elucidating its possible molecular mechanism underlying. The beneficial effect of naringin was assessed in rats with streptozotocin (STZ)-induced diabetes and high glucose-induced HBZY-1 cells. According to our results, first we found that naringin relieved k...

  13. Capacities of the dopamine receptor agonist pramipexole in the treatment of patients with Parkinson’s disease

    OpenAIRE

    ILLARIOSHKIN S.N.

    2012-01-01

    Dopaminergic stimulation with levodopa, a biological precursor of dopamine precursor, and dopamine receptor agonists (DRA) remains the leading pharmacotherapeutic strategy for Parkinson’s disease (PD). The long-term use of levodopa is associated with the development of characteristic fluctuations in its symptoms and drug-induced dyskinesias so DRA are the drugs of choice and may be used alone and as part of combination therapy in a number of cases of parkinsonism in young patients in particul...

  14. Lumbar Puncture Alleviates Chorea in a Patient with Huntington’s Disease and Normal Pressure Hydrocephalus

    Directory of Open Access Journals (Sweden)

    Peyman Shirani

    2009-01-01

    Full Text Available A 44-year-old African-American male was admitted to our hospital after a suicide attempt. He had depression, poor cognitive function, choreiform movements, difficulty pronouncing words, and difficulty walking. His symptoms had worsened markedly over several months. Chorea lead to genetic testing that confirmed a diagnosis of Huntington Disease (HD. A CT scan of the head showed wider ventricles than is typical of HD. The head CT and gait change suggested normal pressure hydrocephalus (NPH. Lumbar puncture (LP led to improved neuropsychologic test scores and walking thereby supporting the diagnosis of NPH. Surprisingly, the LP also led to an 80% improvement of chorea. There are two other reports of an association between HD and NPH. NPH should be considered in HD patients with atypical symptoms, such as the inability to walk or rapid progression, as its treatment may lead to improved cognition, gait, and chorea.

  15. Aortic valve calcification and mild tricuspid regurgitation but no clinical heart disease after 8 years of dopamine agonist therapy for prolactinoma

    NARCIS (Netherlands)

    M. Kars; V. Delgado (Victoria); E.R. Holman (Eduard); R.A. Feelders (Richard); J.W.A. Smit (Jan); J.A. Romijn (Johannes); J.J. Bax (Jeroen); A.M. Pereira (Alberto)

    2008-01-01

    textabstractObjective: Treatment with ergot-derived dopamine agonists, pergolide, and cabergoline has been associated with an increased frequency of valvular heart disease in Parkinson's disease. The aim of the present study was to assess the prevalence of valvular heart disease in patients treated

  16. Dopamine agonist withdrawal syndrome: implications for patient care.

    Science.gov (United States)

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID:23686524

  17. The Roles of Opioid Receptors and agonists in health and disease Conditions

    Directory of Open Access Journals (Sweden)

    A.O. Ibegbu

    Full Text Available Opioid receptors are found in the central nervous system (CNS and are classified as mu (µ, kappa (κ, delta (δ and sigma (σ opioid receptors. Opioid receptors belong to the large family of G protein coupled receptors (GPCRs, and have diverse and important physiological roles. Opioid receptors are not uniformly distributed in the CNS and are found in areas concerned with pain, with the highest concentration in the cerebral cortex, followed by the amygdala, septum, thalamus, hypothalamus, midbrain and spinal cord. Activated delta opioid receptors are coupled to Gi1 while activated mu opioid receptors are coupled to Gi3 in neuroblastoma cells. Mu opioid receptors are activated by mu receptor agonists and are coupled through the Gαi1 and GαoA. Both mu and kappa opioid receptors are coupled via both Gi and Gz and opioid receptors are important targets for thousands of pharmacological agents. GPCRs typically require activation by agonists for their signalling activity to be initiated but some of the GPCRs may display basal or spontaneous signalling activity in the absence of an agonist. The stimulation of these receptors triggers analgesic effects and affects the function of the nervous system, gastrointestinal tract and other body systems. Hundreds of analogs of opioid peptides have been synthesized in an effort to make the compounds more active, selective, and resistant to biodegradation than the endogenous ligands. All these modifications resulted in obtaining very selective agonists and antagonists with high affinity at mu-, delta-, and kappa-opioid receptors, which are useful in further studies on the pharmacology of opioid receptors in a mammalian organism.

  18. Prevalence of hypersexual behavior in Parkinson’s disease patients: Not restricted to males and dopamine agonist use

    Directory of Open Access Journals (Sweden)

    Christine A Cooper

    2009-03-01

    Full Text Available Christine A Cooper, Armon Jadidian, Michelle Paggi, Janet Romrell, Michael S Okun, et alDepartment of Neurology, University of Florida, Gainesville, FL, USAAbstract: This study investigates the prevalence and demographic characteristics of hypersexuality in Parkinson’s disease (PD. Impulse control disorders in PD patients have been associated with dopamine agonist therapy. Moreover, hypersexuality and pathological gambling have been associated with males, while females may be inherently thought to be more likely to participate in compulsive shopping and binge-eating behaviors. In this study, a screening mail-in survey was sent to all PD patients at a single Movement Disorders Center. One  hundred forty one of 400 (35.3% research packets were returned completed. Fifteen of 141 patients met initial screening criteria for hypersexual behavior. After detailed interview, only 6/141 (4.3% of PD patients met criteria for pathologic hypersexual behavior. These behaviors included: compulsive masturbation, prostitution, and paraphilias. Patients with a younger age of PD onset were more likely to exhibit hypersexual behavior. Unlike previous report, no significant association was found between hypersexuality and gender or dopamine agonist use. Rather, this study suggests that physicians should be vigilant for hypersexual behavior in all PD patients, regardless of gender and PD medication regimen. Ultimately, given the innate sensitivity of the topic and survey limitations, it is very likely that hypersexual behavior in our cohort, as it is in the general PD population, has been under-reported.Keywords: Parkinson’s disease, hypersexuality, impulsive behavior, dopamine agonists

  19. From the cell to the clinic: a comparative review of the partial D₂/D₃receptor agonist and α2-adrenoceptor antagonist, piribedil, in the treatment of Parkinson's disease.

    Science.gov (United States)

    Millan, Mark J

    2010-11-01

    Though L-3,4-dihydroxyphenylalanine (L-DOPA) is universally employed for alleviation of motor dysfunction in Parkinson's disease (PD), it is poorly-effective against co-morbid symptoms like cognitive impairment and depression. Further, it elicits dyskinesia, its pharmacokinetics are highly variable, and efficacy wanes upon long-term administration. Accordingly, "dopaminergic agonists" are increasingly employed both as adjuncts to L-DOPA and as monotherapy. While all recognize dopamine D(2) receptors, they display contrasting patterns of interaction with other classes of monoaminergic receptor. For example, pramipexole and ropinirole are high efficacy agonists at D(2) and D(3) receptors, while pergolide recognizes D(1), D(2) and D(3) receptors and a broad suite of serotonergic receptors. Interestingly, several antiparkinson drugs display modest efficacy at D(2) receptors. Of these, piribedil displays the unique cellular signature of: 1), signal-specific partial agonist actions at dopamine D(2)and D(3) receptors; 2), antagonist properties at α(2)-adrenoceptors and 3), minimal interaction with serotonergic receptors. Dopamine-deprived striatal D(2) receptors are supersensitive in PD, so partial agonism is sufficient for relief of motor dysfunction while limiting undesirable effects due to "over-dosage" of "normosensitive" D(2) receptors elsewhere. Further, α(2)-adrenoceptor antagonism reinforces adrenergic, dopaminergic and cholinergic transmission to favourably influence motor function, cognition, mood and the integrity of dopaminergic neurones. In reviewing the above issues, the present paper focuses on the distinctive cellular, preclinical and therapeutic profile of piribedil, comparisons to pramipexole, ropinirole and pergolide, and the core triad of symptoms that characterises PD-motor dysfunction, depressed mood and cognitive impairment. The article concludes by highlighting perspectives for clarifying the mechanisms of action of piribedil and other

  20. Therapeutic Potentials and uses of Cannabinoid Agonists in Health and Disease Conditions

    Directory of Open Access Journals (Sweden)

    A.O. Ibegbu

    2012-04-01

    Full Text Available Cannabis and its derivatives have great therapeutic potential and have been used for centuries for medicinal purposes. The side effects of cannabinoids include euphoric mood changes, acute psychotic episodes, initiation and exacerbation of schizophrenic psychosis in predisposed persons, impaired cognitive and psychomotor performance, tachycardia and hypotension. The production of complex behavioural effects by cannabinoids are mediated by cannabinoid receptors (CB1 and CB2 and by interactions with other neurochemical systems. It has been shown that the therapeutic and physiological effects of cannabinoids are dependent upon whether the administration is acute or chronic and on the route of administration. The physiological effects of cannabis and its derivatives include: reduction in psychomotor coordination and performance, alterations in thermoregulation, endocrine and reproductive functions and gut motility. There is also evidence of agonist selectivity for CB1 receptors coupled to different subtypes of Gi proteins or to Gi versus Go proteins. Cannabinoid-activated receptors distinct from CB1 or CB2 exist in the central nervous system. Cannabinoids are known to inhibit GABA-mediated inhibitory postsynaptic currents in the hippocampus via a presynaptic action at CB1 receptors located on GABAergic terminals. CB1 receptors have also been implicated in the inhibition of glutamatergic excitatory postsynaptic currents. The synthetic cannabinoid, Win 55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was found to attenuate hyperalgesia in a rat model of neuropathic pain and suppress opioid-induced emesis in ferrets.

  1. A genome-wide analysis of the response to inhaled β2-agonists in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Hardin, M; Cho, M H; McDonald, M-L; Wan, E; Lomas, D A; Coxson, H O; MacNee, W; Vestbo, J; Yates, J C; Agusti, A; Calverley, P M A; Celli, B; Crim, C; Rennard, S; Wouters, E; Bakke, P; Bhatt, S P; Kim, V; Ramsdell, J; Regan, E A; Make, B J; Hokanson, J E; Crapo, J D; Beaty, T H; Hersh, C P

    2016-08-01

    Short-acting β2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled β2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65. PMID:26503814

  2. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet

    OpenAIRE

    Lau, Wei Ling; Leaf, Elizabeth M.; Hu, Ming Chang; Takeno, Marc M.; Kuro-o, Makoto; Moe, Orson W.; Giachelli, Cecilia M.

    2012-01-01

    Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times p...

  3. HISTAMINE H3 RECEPTOR INVERSE AGONISTS ON COGNITIVE AND MOTOR PROCESSES: RELEVANCE TO ALZHEIMER’S DISEASE, ADHD, SCHIZOPHRENIA AND DRUG ABUSE

    Directory of Open Access Journals (Sweden)

    Divya Vohora

    2012-10-01

    Full Text Available Histamine H3 receptor antagonists/ inverse agonists possess potential to treat diverse disease states of the central nervous system (CNS. Cognitive dysfunction and motor impairments are the hallmark of multifarious neurodegenerative and/or psychiatric disorders. This review presents the various neurobiological/ neurochemical evidences available so far following H3 receptor inverse agonists/ antagonists in the pathophysiology of Alzheimer’s disease (AD, attention-deficit hyperactivity disorder (ADHD, schizophrenia and drug abuse each of which is accompanied by deficits of some aspects of cognitive and/or motor functions. Whether the H3 receptor inverse agonism modulates the neurochemical basis underlying the disease condition or affects only the cognitive/motor component of the disease process is discussed with the aim to provide a rationale for their use in diverse disease states that are interlinked and are accompanied by some common motor, cognitive and attentional deficits.

  4. The safety of long-acting ß2-agonists in the treatment of stable chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Decramer ML

    2013-01-01

    Full Text Available Marc L Decramer,1 Nicola A Hanania,2 Jan O Lötvall,3 Barbara P Yawn41Respiratory Division, University Hospital, KU Leuven, Belgium; 2Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA; 3Krefting Research Centre, University of Gothenburg, Gothenburg, Sweden; 4Department of Research, Olmsted Medical Center, Rochester, MN, USABackground: Inhaled long-acting bronchodilators are the mainstay of pharmacotherapy for chronic obstructive pulmonary disease (COPD. Both the twice-daily long-acting ß2-adrenoceptor agonists (LABAs salmeterol and formoterol and the once-daily LABA indacaterol are indicated for use in COPD. This review examines current evidence for the safety of LABAs in COPD, focusing on their effect on exacerbations and deaths.Methods: We searched PubMed for placebo-controlled studies evaluating long-term (≥24 weeks use of formoterol, salmeterol, or indacaterol in patients with stable COPD, published between January 1990 and September 2012. We summarized data relating to exacerbations and adverse events, particularly events related to COPD.Results: From 20 studies examined (8774 LABA-treated patients, there was no evidence of an association between LABA treatment and increased exacerbations, COPD-related adverse events, or deaths. Where analyzed as an efficacy outcome, LABA treatment was generally associated with significant or numerical reductions in COPD exacerbations compared with placebo. Incidences of COPD-related adverse events were similar for active and placebo treatments. The incidence of adverse events typically associated with the ß2-agonist drug class such as skeletal muscle tremors and palpitations was low (often <1% of patients, and there were no reports of increased incidence of cardiac arrhythmias. The systemic effects of ß2-adrenoceptor stimulation, such as high glucose and potassium levels, were considered minor.Conclusion: Current evidence from clinical studies of the

  5. Achieving therapeutic benefits of inhaled corticosteroids/beta2 agonist in chronic obstructive airway disease

    Institute of Scientific and Technical Information of China (English)

    WANG Zeng-li

    2007-01-01

    @@ Asthma and chronic obstructive pulmonary disease (COPD) are the two commonest causes of adult airflow obstruction. The fundamental differences and similarities between the pathological mechanisms of asthma and COPD are well recognized.1

  6. Autoantibodies enhance agonist action and binding to cardiac muscarinic receptors in chronic Chagas' disease.

    Science.gov (United States)

    Hernandez, Ciria C; Nascimento, Jose H; Chaves, Elen A; Costa, Patricia C; Masuda, Masako O; Kurtenbach, Eleonora; Campos DE Carvalho, Antonio C; Gimenez, Luis E

    2008-01-01

    Chronic Chagasic patient immunoglobulins (CChP-IgGs) recognize an acidic amino acid cluster at the second extracellular loop (el2) of cardiac M(2)-muscarinic acetylcholine receptors (M(2)AChRs). These residues correspond to a common binding site for various allosteric agents. We characterized the nature of the M(2)AChR/CChP-IgG interaction in functional and radioligand binding experiments applying the same mainstream strategies previously used for the characterization of other allosteric agents. Dose-response curves of acetylcholine effect on heart rate were constructed with data from isolated heart experiments in the presence of CChP or normal blood donor (NBD) sera. In these experiments, CChP sera but not NBD sera increased the efficacy of agonist action by augmenting the onset of bradyarrhythmias and inducing a Hill slope of 2.5. This effect was blocked by gallamine, an M(2)AChR allosteric antagonist. Correspondingly, CChP-IgGs increased acetylcholine affinity twofold and showed negative cooperativity for [(3)H]-N-methyl scopolamine ([(3)H]-NMS) in allosterism binding assays. A peptide corresponding to the M(2)AChR-el2 blocked this effect. Furthermore, dissociation assays showed that the effect of gallamine on the [(3)H]-NMS off-rate was reverted by CChP-IgGs. Finally, concentration-effect curves for the allosteric delay of W84 on [(3)H]-NMS dissociation right shifted from an IC(50) of 33 nmol/L to 78 nmol/L, 992 nmol/L, and 1670 nmol/L in the presence of 6.7 x 10(- 8), 1.33 x 10(- 7), and 2.0 x 10(- 7) mol/L of anti-el2 affinity-purified CChP-IgGs. Taken together, these findings confirmed a competitive interplay of these ligands at the common allosteric site and revealed the novel allosteric nature of the interaction of CChP-IgGs at the M(2)AChRs as a positive cooperativity effect on acetylcholine action. PMID:18702010

  7. Autoantibodies Enhance Agonist Action and Binding to Cardiac Muscarinic Receptors in Chronic Chagas’ Disease

    Science.gov (United States)

    Hernández, Ciria C.; Nascimento, José H.; Chaves, Elen A.; Costa, Patrícia C.; Masuda, Masako O.; Kurtenbach, Eleonora; Campos de Carvalho, Antônio C.; Giménez, Luis E.

    2009-01-01

    Chronic Chagasic patient immunoglobulins (CChP-IgGs) recognize an acidic amino acid cluster at the second extracellular loop (el2) of cardiac M2-muscarinic acetylcholine receptors (M2AChRs). These residues correspond to a common binding site for various allosteric agents. We characterized the nature of the M2AChR/CChP-IgG interaction in functional and radioligand binding experiments applying the same mainstream strategies previously used for the characterization of other allosteric agents. Dose-response curves of acetylcholine effect on heart rate were constructed with data from isolated heart experiments in the presence of CChP or normal blood donor (NBD) sera. In these experiments, CChP sera but not NBD sera increased the efficacy of agonist action by augmenting the onset of bradyarrhythmias and inducing a Hill slope of 2.5. This effect was blocked by gallamine, an M2AChR allosteric antagonist. Correspondingly, CChP-IgGs increased acetylcholine affinity twofold and showed negative cooperativity for [3H]-N-methyl scopolamine ([3H]-NMS) in allosterism binding assays. A peptide corresponding to the M2AChR-el2 blocked this effect. Furthermore, dissociation assays showed that the effect of gallamine on the [3H]-NMS off-rate was reverted by CChP-IgGs. Finally, concentration-effect curves for the allosteric delay of W84 on [3H]-NMS dissociation right shifted from an IC50 of 33 nmol/L to 78 nmol/L, 992 nmol/L, and 1670 nmol/L in the presence of 6.7 × 10−8, 1.33 × 10−7, and 2.0 × 10−7 mol/L of anti-el2 affinity-purified CChP-IgGs. Taken together, these findings confirmed a competitive interplay of these ligands at the common allosteric site and revealed the novel allosteric nature of the interaction of CChP-IgGs at the M2AChRs as a positive cooperativity effect on acetylcholine action. PMID:18702010

  8. Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease.

    Science.gov (United States)

    Han, Sang-oh; Li, Songtao; Bird, Andrew; Koeberl, Dwight

    2015-11-01

    Pompe disease (glycogen storage disease type II; acid maltase deficiency) is a devastating myopathy resulting from acid α-glucosidase (GAA) deficiency in striated and smooth muscle. Despite the availability of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the limitations of ERT have prompted the preclinical development of gene therapy. Gene therapy has the advantage of continuously producing GAA, in contrast to ERT, which requires frequent injections of rhGAA. An adeno-associated viral (AAV) vector containing a muscle-specific promoter, AAV-MHCK7hGAApA, achieved high GAA expression in heart and skeletal muscle in mice with Pompe disease. However, elevated GAA activity was not sufficient to completely clear accumulated glycogen in skeletal muscle. The process of glycogen clearance from lysosomes might require improved trafficking of GAA to the lysosomes in skeletal muscle, previously achieved with the β(2)-agonist clenbuterol that enhanced glycogen clearance in skeletal muscle without increasing GAA activity. Glycogen clearance was clearly enhanced by treatment with a nondepleting anti-CD4 monoclonal antibody (anti-CD4 mAb) along with muscle-specific GAA expression in cardiac muscle, but that treatment was not effective in skeletal muscle. Furthermore, anti-CD4 mAb treatment along with clenbuterol achieved synergistic therapeutic efficacy in both cardiac and skeletal muscle. This triple therapy increased both muscle strength and weight gain. Overall, triple therapy to enhance GAA trafficking and to suppress immune responses significantly improved the efficacy of muscle-targeted gene therapy in murine Pompe disease. PMID:26417913

  9. GLP-1 Receptor Agonist and Non-Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Jinmi Lee

    2012-08-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD, one of the most common liver diseases, is caused by the disruption of hepatic lipid homeostasis. It is associated with insulin resistance as seen in type 2 diabetes mellitus. Glucagon-like peptide-1 (GLP-1 is an incretin that increases insulin sensitivity and aids glucose metabolism. In recent in vivo and in vitro studies, GLP-1 presents a novel therapeutic approach against NAFLD by increasing fatty acid oxidation, decreasing lipogenesis, and improving hepatic glucose metabolism. In this report, we provide an overview of the role and mechanism of GLP-1 in relieving NAFLD.

  10. Capacities of the dopamine receptor agonist pramipexole in the treatment of patients with Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    S N Illarioshkin

    2012-01-01

    Full Text Available Dopaminergic stimulation with levodopa, a biological precursor of dopamine precursor, and dopamine receptor agonists (DRA remains the leading pharmacotherapeutic strategy for Parkinson’s disease (PD. The long-term use of levodopa is associated with the development of characteristic fluctuations in its symptoms and drug-induced dyskinesias so DRA are the drugs of choice and may be used alone and as part of combination therapy in a number of cases of parkinsonism in young patients in particular. Pramipexole (mirapex is one of the most effective representatives of non-ergoline DRA, which has an extensive evidence base. The paper analyzes the heterodirectional properties of pramipexole in detail and its effect on motor (including tremor and nonmotor (depression manifestations of PD and discusses the possible neuroprotective action of the drug. It also separately considers the potential of the new unique 24-hour controlled release formulation: the administration of the drug considerably reduces the dose titration period and enhances patient compliance.

  11. Beyond acetylcholinesterase inhibitors for treating Alzheimer's disease: α7-nAChR agonists in human clinical trials.

    Science.gov (United States)

    Russo, Patrizia; Del Bufalo, Alessandra; Frustaci, Alessandra; Fini, Massimo; Cesario, Alfredo

    2014-01-01

    The neuronal nicotinic alpha7-acetylcholine receptor (α7-nAChR) is a promising and attractive drug target for improving cognitive deficits in neuropsychiatric and neurological disorders such as Alzheimer's disease (AD). α7-nAChR belongs to the family of ligand gated ion channels. α7-nAChR is expressed in key brain regions (e.g. pre- and frontal cortex, hippocampus). It is involved in essential cognitive functions such as memory, thinking, comprehension, learning capacity, calculation, orientation, language, and judgment. α7-nAChR binds to amyloid peptide (Aβ) inducing either receptor activation or inhibition in an Aβ concentration-dependent mode. Aβ oligomers induce τ phosphorylation via α7-nAChR activation. α7-nAChR agonists and/or α7-nAChR positive allosteric modulators may be useful in AD therapy. The current review enlightens: (i) α7-nAChR neurobiology, (ii) α7-nAChR role in cognition and (iii) in AD, and (iv) the clinical status of the most promising molecules for the treatment of cognitive dysfunction in AD. PMID:24641224

  12. GW501516, a PPARδ agonist, ameliorates tubulointerstitial inflammation in proteinuric kidney disease via inhibition of TAK1-NFκB pathway in mice.

    Directory of Open Access Journals (Sweden)

    Xu Yang

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA-bound albumin or PBS(-. In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases.

  13. Transcriptional Modulation of the Immune Response by Peroxisome Proliferator-Activated Receptor-α Agonists in Autoimmune Disease1

    OpenAIRE

    Gocke, Anne R.; Hussain, Rehana Z.; Yang, Yuhong; Peng, Haiyan; Weiner, Jeffrey; Ben, Li-Hong; Drew, Paul D.; Stuve, Olaf; Lovett-Racke, Amy E.; Racke, Michael K.

    2009-01-01

    Peroxisome proliferator-activated receptor-α (PPARα) agonists have been shown to have a therapeutic benefit in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). In this study, we investigated the mechanism by which the PPARα agonist gemfibrozil induces immune deviation and protects mice from EAE. We demonstrated that treatment with gemfibrozil increases expression of the Th2 transcription factor GATA-3 and decreases expression of the Th1 transcripti...

  14. Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study

    OpenAIRE

    Pinter, M.; Pogarell, O.; Oertel, W.

    1999-01-01

    OBJECTIVES—Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance.
METHODS—Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pra...

  15. Efficacy and safety of the long-acting β2-agonist olodaterol over 4 weeks in Japanese patients with chronic obstructive pulmonary disease

    OpenAIRE

    Ichinose, Masakazu; Takizawa, Ayako; Izumoto, Toshiyasu; Tadayasu, Yusuke; Hamilton, Alan L; Kunz, Christina; Fukuchi, Yoshinosuke

    2015-01-01

    Background Olodaterol is a novel long-acting β2-agonist with proven ≥24-hour duration of action in preclinical and clinical studies. Objective This randomized, double-blind, placebo-controlled, parallel-group study evaluated the dose response of once-daily (QD) olodaterol based on bronchodilator efficacy, safety, and pharmacokinetics over 4 weeks in Japanese patients with chronic obstructive pulmonary disease (COPD). Methods All eligible patients were randomized to receive 2 µg, 5 µg, or 10 µ...

  16. Distinct efficacy of pre-differentiated versus intact fetal mesencephalon-derived human neural progenitor cells in alleviating rat model of Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    XuanWang; YanyanLu; HuanqingZhang; KunWang; QihuaHe; YueWang; XianyuLiu; LinsongLi; XiaominWang

    2005-01-01

    Neural progenitor cells have shown tile effectiveness in the treatment of Parkinson's disease, but tile therapeutic efficacy remains variable. One of important factors that determine the efficacy is the necessity ofpre-differentiation of progenitor cells into dopaminergic neurons before transplantation. This study therefore investigated the therapeutic efficacy of mesencephalon-derived human neural progenitor cells with or without the pre-differentiation in alleviating a rat model of Parkinson's disease. We found that a combination of 50ng/ml fibroblast growth factor 8, 10ng/ml glial cell line-derived neurotrophic factor and 10μM forskolin facilitated the differentiation of human fetal mesencephalic progenitor cells into dopaminergic neurons in vitro. More importantly, after transplanted into the striatum ofparkinsonian rats, only pre-differentiated grafts resulted in an elevated production ofdopamine in the transplanted site and the amelioration of behavioral impairments of the parkinsonian rats. Unlike pre-differentiated progenitors, grafted intactprogenitors rarely differentiated into dopaminergic neurons in vivo and emigrated actively away from the transplanted site. These data demonstrates the importance ofpre-differentiation of human progenitor cells before transplantation in enhancing therapeutic potency for Parkinson's disease.

  17. Long-term dietary supplementation of pomegranates, figs and dates alleviate neuroinflammation in a transgenic mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Musthafa Mohamed Essa

    Full Text Available Alzheimer's disease (AD is a devastating age-related neurodegenerative disease with no specific treatment at present. The APPsw/Tg2576 mice exhibit age-related deterioration in memory and learning as well as amyloid-beta (Aβ accumulation, and this mouse strain is considered an effective model for studying the mechanism of accelerated brain aging and senescence. The present study was aimed to investigate the beneficial effects of dietary supplements pomegranate, figs, or the dates on suppressing inflammatory cytokines in APPsw/Tg2576 mice. Changes in the plasma cytokines and Aβ, ATP, and inflammatory cytokines were investigated in the brain of transgenic mice. Significantly enhanced levels of inflammatory cytokines IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, TNF-α and Eotaxin activity were decreased by administration of the diet supplements containing pomegranates, figs, or dates. In addition, putative delays in the formation of senile plaques, as indicated by a decreasing tendency of brain Aβ1-40 and Aβ1-42 contents, were observed. Thus, novel results mediated by reducing inflammatory cytokines during aging may represent one mechanism by which these supplements exert their beneficial effects against neurodegenerative diseases such as AD.

  18. Combined aerobic exercise and enzyme replacement therapy rejuvenates the mitochondrial-lysosomal axis and alleviates autophagic blockage in Pompe disease.

    Science.gov (United States)

    Nilsson, M I; MacNeil, L G; Kitaoka, Y; Suri, R; Young, S P; Kaczor, J J; Nates, N J; Ansari, M U; Wong, T; Ahktar, M; Brandt, L; Hettinga, B P; Tarnopolsky, M A

    2015-10-01

    A unifying feature in the pathogenesis of aging, neurodegenerative disease, and lysosomal storage disorders is the progressive deposition of macromolecular debris impervious to enzyme catalysis by cellular waste disposal mechanisms (e.g., lipofuscin). Aerobic exercise training (AET) has pleiotropic effects and stimulates mitochondrial biogenesis, antioxidant defense systems, and autophagic flux in multiple organs and tissues. Our aim was to explore the therapeutic potential of AET as an ancillary therapy to mitigate autophagic buildup and oxidative damage and rejuvenate the mitochondrial-lysosomal axis in Pompe disease (GSD II/PD). Fourteen weeks of combined recombinant acid α-glucosidase (rhGAA) and AET polytherapy attenuated mitochondrial swelling, fortified antioxidant defense systems, reduced oxidative damage, and augmented glycogen clearance and removal of autophagic debris/lipofuscin in fast-twitch skeletal muscle of GAA-KO mice. Ancillary AET potently augmented the pool of PI4KA transcripts and exerted a mild restorative effect on Syt VII and VAMP-5/myobrevin, collectively suggesting improved endosomal transport and Ca(2+)- mediated lysosomal exocytosis. Compared with traditional rhGAA monotherapy, AET and rhGAA polytherapy effectively mitigated buildup of protein carbonyls, autophagic debris/lipofuscin, and P62/SQSTM1, while enhancing MnSOD expression, nuclear translocation of Nrf-2, muscle mass, and motor function in GAA-KO mice. Combined AET and rhGAA therapy reactivates cellular clearance pathways, mitigates mitochondrial senescence, and strengthens antioxidant defense systems in GSD II/PD. Aerobic exercise training (or pharmacologic targeting of contractile-activity-induced pathways) may have therapeutic potential for mitochondrial-lysosomal axis rejuvenation in lysosomal storage disorders and related conditions (e.g., aging and neurodegenerative disease). PMID:26001726

  19. Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype.

    Science.gov (United States)

    Conceição, Mariana; Mendonça, Liliana; Nóbrega, Clévio; Gomes, Célia; Costa, Pedro; Hirai, Hirokazu; Moreira, João Nuno; Lima, Maria C; Manjunath, N; Pereira de Almeida, Luís

    2016-03-01

    Others and we showed that RNA interference holds great promise for the treatment of dominantly inherited neurodegenerative disorders such as Machado-Joseph disease (MJD), for which there is no available treatment. However, successful experiments involved intracranial administration of viral vectors and there is a need for a safer and less invasive procedure. In this work, we successfully generated stable nucleic acid lipid particles (SNALPs), incorporating a short peptide derived from rabies virus glycoprotein (RVG-9r) and encapsulating small interfering RNAs (siRNAs), which can target mutant ataxin-3. The developed formulation exhibited important features that make it adequate for systemic administration: high encapsulation efficiency of siRNAs, ability to protect the encapsulated siRNAs, appropriate and homogeneous particle size distribution. Following optimization of the formulation and in vitro validation of its efficacy to silence the MJD-causing protein - mutant ataxin-3 - in neuronal cells, in vivo experiments showed that intravenous administration of RVG-9r-targeted SNALPs efficiently silenced mutant ataxin-3 reducing neuropathology and motor behavior deficits in two mouse models of MJD. To our knowledge, this is the first report showing beneficial impact of a non-viral gene silencing strategy in MJD and the first time that a non-invasive systemic administration proved to be beneficial on a polyglutamine disorder. Our study opens new avenues towards MJD therapy that can also be applied to other neurodegenerative diseases linked to the production of pathogenic proteins. PMID:26757259

  20. Salicylic acid and cysteine contribute to arbutin-induced alleviation of angular leaf spot disease development in cucumber.

    Science.gov (United States)

    Kuźniak, Elżbieta; Wielanek, Marzena; Chwatko, Grażyna; Głowacki, Rafał; Libik-Konieczny, Marta; Piątek, Milena; Gajewska, Ewa; Skłodowska, Maria

    2015-06-01

    Arbutin induced suppression of angular leaf spot disease in cucumber resulting from lower populations of Pseudomonas syringae pv lachrymans in the infected tissues. This study provides insight into mechanisms that may potentially account for this effect. In the absence of the pathogen, exogenous arbutin-induced expression of PR1, the marker of salicylic acid signaling, increased the content of salicylic acid and modulated the cysteine pool. This suggested that arbutin promoted cucumber plants to a "primed" state. When challenged with the pathogen, the arbutin-treated plants showed strongly reduced infection symptoms 7 days after inoculation. At this time point, they were characterized by higher contents of free and protein-bound cysteine due to higher cysteine biosynthetic capacity related to increased activities of serine acetyltransferase and cysteine synthase when compared with plants infected without arbutin treatment. Moreover, in the arbutin-treated and infected plants the contents of free salicylic acid and its conjugates were also increased, partly owing to its biosynthesis via the phenylpropanoid pathway. We suggest that arbutin-induced abrogation of angular leaf spot disease in cucumber could be mediated by salicylic acid and cysteine-based signaling. PMID:25955697

  1. A novel acylaminoimidazole derivative, WN1316, alleviates disease progression via suppression of glial inflammation in ALS mouse model.

    Directory of Open Access Journals (Sweden)

    Kazunori Tanaka

    Full Text Available Amyotrophic lateral sclerosis (ALS is an adult-onset motor neuron degenerative disease. Given that oxidative stress and resulting chronic neuronal inflammation are thought to be central pathogenic, anti-oxidative agents and modulators of neuronal inflammation could be potential therapies for ALS. We report here that the novel small molecular compound, 2-[mesityl(methylamino]-N-[4-(pyridin-2-yl-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316 selectively suppresses oxidative stress-induced cell death and neuronal inflammation in the late-stage ALS mice. WN1316 has high blood-brain-barrier permeability and water solubility, and boosts both neuronal apoptosis inhibitory protein (NAIP and NF-E2-related factor 2 (Nrf2 which governed glutathione (GSH-related anti-oxidation pathway protecting motor neurons against oxidative injuries. Post-onset oral administration of low dose (1-100 µg/kg/day WN1316 in ALS(SOD1(H46R and ALS(SOD1(G93A mice resulted in sustained improved motor function and post onset survival rate. Immunohistochemical analysis revealed less DNA oxidative damage and motor neuronal inflammation as well as repression of both microgliosis and astrocytosis, concomitant down regulation of interleukin-1β and inducible nitric oxide synthase, and preservation of the motoneurons in anterior horn of lumbar spinal cord and skeletal muscle (quadriceps femoris. Thus, WN1316 would be a novel therapeutic agent for ALS.

  2. Combined pharmacological therapy of the acute radiation disease using a cyclooxygenase-2 inhibitor and an adenosine A(3) receptor agonist

    Czech Academy of Sciences Publication Activity Database

    Hofer, Michal; Pospíšil, Milan; Dušek, L.; Hoferová, Zuzana; Komůrková, Denisa

    2014-01-01

    Roč. 9, č. 6 (2014), s. 642-646. ISSN 1895-104X R&D Projects: GA ČR(CZ) GAP303/11/0128 Institutional support: RVO:68081707 Keywords : Hematopoiesis * Cyclooxygenase inhibition * Adenosine receptor agonist Subject RIV: BO - Biophysics Impact factor: 0.710, year: 2014

  3. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents

    Directory of Open Access Journals (Sweden)

    Fabbri Leonardo M

    2010-10-01

    Full Text Available Abstract Chronic obstructive pulmonary disease (COPD is characterized by progressive airflow limitation and debilitating symptoms. For patients with moderate-to-severe COPD, long-acting bronchodilators are the mainstay of therapy; as symptoms progress, guidelines recommend combining bronchodilators from different classes to improve efficacy. Inhaled long-acting β2-agonists (LABAs have been licensed for the treatment of COPD since the late 1990s and include formoterol and salmeterol. They improve lung function, symptoms of breathlessness and exercise limitation, health-related quality of life, and may reduce the rate of exacerbations, although not all patients achieve clinically meaningful improvements in symptoms or health related quality of life. In addition, LABAs have an acceptable safety profile, and are not associated with an increased risk of respiratory mortality, although adverse effects such as palpitations and tremor may limit the dose that can be tolerated. Formoterol and salmeterol have 12-hour durations of action; however, sustained bronchodilation is desirable in COPD. A LABA with a 24-hour duration of action could provide improvements in efficacy, compared with twice-daily LABAs, and the once-daily dosing regimen could help improve compliance. It is also desirable that a new LABA should demonstrate fast onset of action, and a safety profile at least comparable to existing LABAs. A number of novel LABAs with once-daily profiles are in development which may be judged against these criteria. Indacaterol, a LABA with a 24-hour duration of bronchodilation and fast onset of action, is the most advanced of these. Preliminary results from large clinical trials suggest indacaterol improves lung function compared with placebo and other long-acting bronchodilators. Other LABAs with a 24-hour duration of bronchodilation include carmoterol, vilanterol trifenatate and oldaterol, with early results indicating potential for once-daily dosing in

  4. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.

    Directory of Open Access Journals (Sweden)

    Nicolas Maurice

    Full Text Available Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD. Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure in pharmacological (neuroleptic treatment and lesional (unilateral intranigral 6-hydroxydopamine injection PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease.

  5. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.

    Science.gov (United States)

    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane; Amalric, Marianne; Kerkerian-Le Goff, Lydia

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID:26571268

  6. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson’s Disease

    Science.gov (United States)

    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID:26571268

  7. Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists in patients with chronic obstructive pulmonary disease.

    Science.gov (United States)

    Levin, D C; Little, K S; Laughlin, K R; Galbraith, J M; Gustman, P M; Murphy, D; Kram, J A; Hardie, G; Reuter, C; Ostransky, D; McFarland, K; Petty, T L; Silvers, W; Rennard, S I; Mueller, M; Repsher, L H; Zuwallack, R L; Vale, R

    1996-01-29

    A randomized, double-blind placebo-controlled clinical trial was designed to assess the safety, efficacy, and duration of the bronchodilation resulting from the addition of 500 micrograms of ipratropium bromide (Atrovent; Boehringer Ingelheim, CT) inhalation solution to standard small volume nebulizer treatments with 2.5 mg albuterol inhalation solution. A total of 195 patients (63% men, average age 64 years) with > 10 pack-year smoking histories and stable, moderate-to- severe chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 second [FEV1] 1.02 liter, 38.8% predicted) from eight university-affiliated chest clinics in seven U.S. cities were enrolled into the study. Asthma, rhinitis, and eosinophilia were exclusions, as was daily use of > 10 mg of prednisone (or 20 mg on alternate days). There was a 2-week stabilization period during which the patients were instructed in the use of the small volume nebulizers, which they used three times daily with albuterol alone. They were asked to keep daily logs of peak flow rates, pulmonary symptoms, and additional medication usage. On their test day 1 the subjects came to the pulmonary function laboratory having been off theophylline for 24 hours and beta 2-agonists for 12 hours and performed a baseline spirometry. They then received their morning small volume nebulizer treatment of albuterol to which was added either 500 micrograms if ipratropium bromide or a saline placebo. Spirometry was repeated at 15, 30, and 60 minutes, and then hourly for 8 hours. Subjects then took home a 2-week supply of albuterol and test drug for thrice daily use in their small volume nebulizer. They were evaluated for pulmonary symptoms and adverse effects every 14 days. The 8-hour spirometry was repeated on test day 43 and finally on test day 85. Primary data evaluated were the peak increase in FEV1 and the area between the FEV1 baseline value and the 8-hour FEV1 curve. Similar calculations were made for forced vital

  8. Genome Analysis of Pseudomonas fluorescens PCL1751: A Rhizobacterium that Controls Root Diseases and Alleviates Salt Stress for Its Plant Host.

    Directory of Open Access Journals (Sweden)

    Shu-Ting Cho

    Full Text Available Pseudomonas fluorescens PCL1751 is a rod-shaped Gram-negative bacterium isolated from the rhizosphere of a greenhouse-grown tomato plant in Uzbekistan. It controls several plant root diseases caused by Fusarium fungi through the mechanism of competition for nutrients and niches (CNN. This mechanism does not rely on the production of antibiotics, so it avoids the concerns of resistance development and is environmentally safe. Additionally, this bacterium promotes plant growth by alleviating salt stress for its plant host. To investigate the genetic mechanisms that may explain these observations, we determined the complete genome sequence of this bacterium, examined its gene content, and performed comparative genomics analysis with other Pseudomonas strains. The genome of P. fluorescens PCL1751 consisted of one circular chromosome that is 6,143,950 base-pairs (bp in size; no plasmid was found. The annotation included 19 rRNA, 70 tRNA, and 5,534 protein-coding genes. The gene content analysis identified a large number of genes involved in chemotaxis and motility, colonization of the rhizosphere, siderophore biosynthesis, and osmoprotectant production. In contrast, the pathways involved in the biosynthesis of phytohormones or antibiotics were not found. Comparison with other Pseudomonas genomes revealed extensive variations in their genome size and gene content. The presence and absence of secretion system genes were highly variable. As expected, the synteny conservation among strains decreased as a function of phylogenetic divergence. The integration of prophages appeared to be an important driver for genome rearrangements. The whole-genome gene content analysis of this plant growth-promoting rhizobacterium (PGPR provided some genetic explanations to its phenotypic characteristics. The extensive and versatile substrate utilization pathways, together with the presence of many genes involved in competitive root colonization, provided further support

  9. Genome Analysis of Pseudomonas fluorescens PCL1751: A Rhizobacterium that Controls Root Diseases and Alleviates Salt Stress for Its Plant Host.

    Science.gov (United States)

    Cho, Shu-Ting; Chang, Hsing-Hua; Egamberdieva, Dilfuza; Kamilova, Faina; Lugtenberg, Ben; Kuo, Chih-Horng

    2015-01-01

    Pseudomonas fluorescens PCL1751 is a rod-shaped Gram-negative bacterium isolated from the rhizosphere of a greenhouse-grown tomato plant in Uzbekistan. It controls several plant root diseases caused by Fusarium fungi through the mechanism of competition for nutrients and niches (CNN). This mechanism does not rely on the production of antibiotics, so it avoids the concerns of resistance development and is environmentally safe. Additionally, this bacterium promotes plant growth by alleviating salt stress for its plant host. To investigate the genetic mechanisms that may explain these observations, we determined the complete genome sequence of this bacterium, examined its gene content, and performed comparative genomics analysis with other Pseudomonas strains. The genome of P. fluorescens PCL1751 consisted of one circular chromosome that is 6,143,950 base-pairs (bp) in size; no plasmid was found. The annotation included 19 rRNA, 70 tRNA, and 5,534 protein-coding genes. The gene content analysis identified a large number of genes involved in chemotaxis and motility, colonization of the rhizosphere, siderophore biosynthesis, and osmoprotectant production. In contrast, the pathways involved in the biosynthesis of phytohormones or antibiotics were not found. Comparison with other Pseudomonas genomes revealed extensive variations in their genome size and gene content. The presence and absence of secretion system genes were highly variable. As expected, the synteny conservation among strains decreased as a function of phylogenetic divergence. The integration of prophages appeared to be an important driver for genome rearrangements. The whole-genome gene content analysis of this plant growth-promoting rhizobacterium (PGPR) provided some genetic explanations to its phenotypic characteristics. The extensive and versatile substrate utilization pathways, together with the presence of many genes involved in competitive root colonization, provided further support for the finding

  10. Synthesis and SAR of Imidazo[1,5-a]pyridine derivatives as 5-HT4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease.

    Science.gov (United States)

    Nirogi, Ramakrishna; Mohammed, Abdul Rasheed; Shinde, Anil K; Bogaraju, Narsimha; Gagginapalli, Shankar Reddy; Ravella, Srinivasa Rao; Kota, Laxman; Bhyrapuneni, Gopinadh; Muddana, Nageswara Rao; Benade, Vijay; Palacharla, Raghava Chowdary; Jayarajan, Pradeep; Subramanian, Ramkumar; Goyal, Vinod Kumar

    2015-10-20

    Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition. PMID:26363507

  11. Restoration of Haemoglobin Level Using Hydrodynamic Gene Therapy with Erythropoietin Does Not Alleviate the Disease Progression in an Anaemic Mouse Model for TGFβ1-Induced Chronic Kidney Disease

    DEFF Research Database (Denmark)

    Pedersen, Lea; Wogensen, Lise; Marcussen, Niels;

    2015-01-01

    expressed in non-haematopoietic tissue and today, Epo is recognised as a cytokine with many pleiotropic effects. We hypothesize that hydrodynamic gene therapy with Epo can restore haemoglobin levels in anaemic transgenic mice and that this will attenuate the extracellular matrix accumulation in the kidneys....... The experiment is conducted by hydrodynamic gene transfer of a plasmid encoding murine Epo in a transgenic mouse model that overexpresses TGF-β1 locally in the kidneys. This model develops anaemia due to chronic kidney disease characterised by thickening of the glomerular basement membrane, deposition...... of mesangial matrix and mild interstitial fibrosis. A group of age matched wildtype littermates are treated accordingly. After a single hydrodynamic administration of plasmid DNA containing murine EPO gene, sustained high haemoglobin levels are observed in both transgenic and wildtype mice from 7...

  12. PPARγ agonist pioglitazone improves cerebellar dysfunction at pre-Aβ deposition stage in APPswe/PS1dE9 Alzheimer's disease model mice.

    Science.gov (United States)

    Toba, Junya; Nikkuni, Miyu; Ishizeki, Masato; Yoshii, Aya; Watamura, Naoto; Inoue, Takafumi; Ohshima, Toshio

    2016-05-13

    Alzheimer's disease (AD) is one of the best known neurodegenerative diseases; it causes dementia and its pathological features include accumulation of amyloid β (Aβ) and neurofibrillary tangles (NFTs) in the brain. Elevated Cdk5 activity and CRMP2 phosphorylation have been reported in the brains of AD model mice at the early stage of the disease, but the significance thereof in human AD remains unelucidated. We have recently reported that Aβ accumulation in the cerebellum of AD model APPswe/PS1dE9 (APP/PS1) mice, and cerebellar dysfunctions, such as impairment of motor coordination ability and long-term depression (LTD) induction, at the pre-Aβ accumulation stage. In the present study, we found increased phosphorylation levels of CRMP2 as well as increased p35 protein levels in the cerebellum of APP/PS1 mice. Interestingly, we show that pioglitazone, an agonist of peroxisome proliferator-activated receptor γ, normalized the p35 protein and CRMP2 phosphorylation levels in the cerebellum. Impaired motor coordination ability and LTD in APP/PS1 mice were ameliorated by pioglitazone treatment at the pre-Aβ accumulation stage. These results suggest a correlation between CRMP2 phosphorylation and AD pathophysiology, and indicate the effectiveness of pioglitazone treatment at the pre-Aβ accumulation stage in AD model mice. PMID:27059136

  13. Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson's disease.

    Science.gov (United States)

    Pisanu, Augusta; Lecca, Daniela; Mulas, Giovanna; Wardas, Jadwiga; Simbula, Gabriella; Spiga, Saturnino; Carta, Anna R

    2014-11-01

    Neuroinflammatory changes play a pivotal role in the progression of Parkinson's disease (PD) pathogenesis. Recent findings have suggested that activated microglia may polarize similarly to peripheral macrophages in the central nervous system (CNS), assuming a pro-inflammatory M1 phenotype or the alternative anti-inflammatory M2 phenotype via cytokine production. A skewed M1 activation over M2 has been related to disease progression in Alzheimer disease, and modulation of microglia polarization may be a therapeutic target for neuroprotection. By using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-probenecid (MPTPp) mouse model of progressive PD, we investigated dynamic changes in the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and anti-inflammatory cytokines, such as transforming growth factor (TGF)-β and IL-10, within Iba-1-positive cells in the substantia nigra compacta (SNc). In addition, to further characterize changes in the M2 phenotype, we measured CD206 in microglia. Moreover, in order to target microglia polarization, we evaluated the effect of the peroxisome-proliferator-activated receptor (PPAR)-γ agonist rosiglitazone, which has been shown to exert neuroprotective effects on nigral dopaminergic neurons in PD models, and acts as a modulator of cytokine production and phenotype in peripheral macrophages. Chronic treatment with MPTPp induced a progressive degeneration of SNc neurons. The neurotoxin treatment was associated with a gradual increase in both TNF-α and IL-1β colocalization with Iba-1-positive cells, suggesting an increase in pro-inflammatory microglia. In contrast, TGF-β colocalization was reduced by the neurotoxin treatment, while IL-10 was mostly unchanged. Administration of rosiglitazone during the full duration of MPTPp treatment reverted both TNF-α and IL-1β colocalization with Iba-1 to control levels. Moreover, rosiglitazone induced an increase in TGF-β and IL-10

  14. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

    Science.gov (United States)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Mikkelsen, Jens D; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-09-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD. PMID:27233809

  15. The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer’s Disease

    Science.gov (United States)

    Hansen, Henrik H.; Fabricius, Katrine; Barkholt, Pernille; Niehoff, Michael L.; Morley, John E.; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Farr, Susan A.; Vrang, Niels

    2015-01-01

    Abstract Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer’s disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by amyloid plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of amyloid-β plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD. PMID:25869785

  16. The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Niehoff, Michael L; Morley, John E; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Farr, Susan A; Vrang, Niels

    2015-01-01

    Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer's disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by amyloid plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of amyloid-β plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD. PMID:25869785

  17. Impact of beta2-agonists, beta-blockers, and their combination on cardiac function in elderly male patients with chronic obstructive pulmonary disease

    OpenAIRE

    Zeng LH; Hu YX; Liu L; Zhang M; Cui H

    2013-01-01

    Long-Huan Zeng,1,* Yi-Xin Hu,2,* Lin Liu,2 Meng Zhang,1 Hua Cui1 1Second Geriatric Cardiology Division, 2Clinical Department of Geriatrics, Chinese PLA General Hospital, Beijing, People's Republic of China *These authors contributed equally to this work Purpose: This study was undertaken to determine the association between cardiac function and therapy with beta2-adrenoceptor agonists (β2-agonists), β-blockers, or β-blocker–β2-agonist com...

  18. Global Gene Expression Profiling in PPAR-γ Agonist-Treated Kidneys in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

    Science.gov (United States)

    Yoshihara, Daisuke; Kugita, Masanori; Yamaguchi, Tamio; Aukema, Harold M.; Kurahashi, Hiroki; Morita, Miwa; Hiki, Yoshiyuki; Calvet, James P.; Wallace, Darren P.; Toyohara, Takafumi; Abe, Takaaki; Nagao, Shizuko

    2012-01-01

    Kidneys are enlarged by aberrant proliferation of tubule epithelial cells leading to the formation of numerous cysts, nephron loss, and interstitial fibrosis in polycystic kidney disease (PKD). Pioglitazone (PIO), a PPAR-γ agonist, decreased cell proliferation, interstitial fibrosis, and inflammation, and ameliorated PKD progression in PCK rats (Am. J. Physiol.-Renal, 2011). To explore genetic mechanisms involved, changes in global gene expression were analyzed. By Gene Set Enrichment Analysis of 30655 genes, 13 of the top 20 downregulated gene ontology biological process gene sets and six of the top 20 curated gene set canonical pathways identified to be downregulated by PIOtreatment were related to cell cycle and proliferation, including EGF, PDGF and JNK pathways. Their relevant pathways were identified using the Kyoto Encyclopedia of Gene and Genomes database. Stearoyl-coenzyme A desaturase 1 is a key enzyme in fatty acid metabolism found in the top 5 genes downregulated by PIO treatment. Immunohistochemical analysis revealed that the gene product of this enzyme was highly expressed in PCK kidneys and decreased by PIO. These data show that PIO alters the expression of genes involved in cell cycle progression, cell proliferation, and fatty acid metabolism. PMID:22666229

  19. Dose-response relationships and time course of the response to systemic beta adrenoreceptor agonists in infants with bronchopulmonary disease.

    OpenAIRE

    Kraemer, R; Birrer, P; Schöni, M H

    1988-01-01

    The lung function response to three doses of salbutamol 0.075 mg/kg given at 10 minute intervals by gastric tube was studied in 31 infants aged 2-22 months with bronchopulmonary disease (eight after the respiratory distress syndrome, 15 with wheezy bronchitis, and eight with cystic fibrosis). Lung function was measured by whole body plethysmography. Seven of 31 infants had normal lung function and 10 of the remaining 24 had an increase in thoracic gas volume (TGV), 10 an increase in airway re...

  20. Long acting β2 agonists for stable chronic obstructive pulmonary disease with poor reversibility: a systematic review of randomised controlled trials

    Directory of Open Access Journals (Sweden)

    Mensinkai Shaila

    2004-08-01

    Full Text Available Abstract Background The long acting β2-agonists, salmeterol and formoterol, have been recommended, by some, as first line treatment of stable chronic obstructive pulmonary disease (COPD. We reviewed evidence of efficacy and safety when compared with placebo or anticholinergic agents in patients with poorly reversible COPD. Methods After searching MEDLINE, EMBASE, HealthSTAR, BIOSIS Previews, PASCAL, ToxFile, SciSearch, the Cochrane Library, and PubMed, as well as Web sites, selected journals, reference lists, and contacting drug manufacturers, two reviewers independently screened reports of randomised controlled trials of parallel or crossover design lasting four weeks or longer and including patients with a forced expiratory volume in one second (FEV1 ≤ 75% of predicted, a ratio of FEV1 to forced vital capacity (FVC ≤ 88% of predicted, and Results Twelve trials satisfied our inclusion criteria; eight were high quality (Jadad score >2 and four were low quality (≤ 2. The adequacy of allocation concealment was unclear in all of them. We did not perform a meta-analysis due to differences in trial design and how outcomes were reported. Two trials comparing salmeterol with ipratropium did not detect differences; one trial comparing formoterol and ipratropium described greater improvement with formoterol in morning PEFR (15.3 versus 7.1 l/min, p = 0.040. Of twelve trials comparing long acting β2 agonists with placebo, six reported no improvement in exercise capacity, eleven reported improvements in FEV1 lung function (one reported no improvement, six reported less rescue inhaler usage (one reported no difference and five reported improved dyspnea scores (two reported no improvement. Differences in quality of life were detected in one salmeterol trial ; however, two salmeterol, and one formoterol trial reported no differences. Adverse effects of interest were not reported. Conclusion In terms of clinical outcomes and safety, we could not find

  1. Oral supplements of aqueous extract of tomato seeds alleviate motor abnormality, oxidative impairments and neurotoxicity induced by rotenone in mice: relevance to Parkinson's disease.

    Science.gov (United States)

    Gokul, Krishna; Muralidhara

    2014-07-01

    Although tomato seeds (an industrial by-product) are known to contain several bioactive compounds, studies describing their health effects are limited. Previously, we evidenced that aqueous extract of tomato seeds (TSE) markedly attenuated rotenone (ROT)-induced oxidative stress and neurotoxicity in Drosophila system. This study investigated the neuroprotective effect of TSE in a chronic ROT model of neurotoxicity in mice. Initially, we assessed the potential of oral supplements of TSE to modulate the levels of endogenous markers of oxidative stress in brain regions of mice. Subsequently, employing a co-exposure paradigm, the propensity of TSE (100 mg/kg bw, 3 weeks) to attenuate ROT-induced behavioral phenotype (gait abnormalities, anxiety-like state), oxidative dysfunctions and neurotoxicity was examined. We found that mice provided with TSE supplements exhibited progressive improvement in gait pattern and exploratory behavior. TSE markedly offset ROT-induced oxidative impairments, restored reduced glutathione levels, antioxidant defenses (superoxide dismutase, glutathione peroxidase) and protein carbonyls content in brain regions. Specifically, TSE effectively diminished ROT induced elevation in the activity levels of acetylcholinesterase and restored the dopamine levels in striatum. Interestingly, in mitochondria, TSE was able to restore the activity of mitochondrial complexes and redox state. Collectively, our findings in the chronic ROT model demonstrate the ability of TSE to alleviate behavioral phenotype, oxidative stress, mitochondrial dysfunction and neurotoxicity. Further studies in dopaminergic cell models are necessary to understand the precise molecular mechanism/s by which tomato seed bioactives offer significant neuroprotection. PMID:24831121

  2. Time-dependent propensity score and collider-stratification bias: an example of beta2-agonist use and the risk of coronary heart disease

    International Nuclear Information System (INIS)

    Stratification and conditioning on time-varying cofounders which are also intermediates can induce collider-stratification bias and adjust-away the (indirect) effect of exposure. Similar bias could be expected when one conditions on time-dependent PS. We explored collider-stratification and confounding bias due to conditioning or stratifying on time-dependent PS using a clinical example on the effect of inhaled short- and long-acting beta2-agonist use (SABA and LABA, respectively) on coronary heart disease (CHD). In an electronic general practice database we selected a cohort of patients with an indication for SABA and/or LABA use and ascertained potential confounders and SABA/LABA use per three month intervals. Hazard ratios (HR) were estimated using PS stratification as well as covariate adjustment and compared with those of Marginal Structural Models (MSMs) in both SABA and LABA use separately. In MSMs, censoring was accounted for by including inverse probability of censoring weights.The crude HR of CHD was 0.90 [95 % CI: 0.63, 1.28] and 1.55 [95 % CI: 1.06, 2.62] in SABA and LABA users respectively. When PS stratification, covariate adjustment using PS, and MSMs were used, the HRs were 1.09 [95 % CI: 0.74, 1.61], 1.07 [95 % CI: 0.72, 1.60], and 0.86 [95 % CI: 0.55, 1.34] for SABA, and 1.09 [95 % CI: 0.74, 1.62], 1.13 [95 % CI: 0.76, 1.67], 0.77 [95 % CI: 0.45, 1.33] for LABA, respectively. Results were similar for different PS methods, but higher than those of MSMs. When treatment and confounders vary during follow-up, conditioning or stratification on time-dependent PS could induce substantial collider-stratification or confounding bias; hence, other methods such as MSMs are recommended.

  3. Gluten-free diet may alleviate depressive and behavioural symptoms in adolescents with coeliac disease: a prospective follow-up case-series study

    Directory of Open Access Journals (Sweden)

    Sipilä Ilkka

    2005-03-01

    Full Text Available Abstract Background Coeliac disease in adolescents has been associated with an increased prevalence of depressive and disruptive behavioural disorders, particularly in the phase before diet treatment. We studied the possible effects of a gluten-free diet on psychiatric symptoms, on hormonal status (prolactin, thyroidal function and on large neutral amino acid serum concentrations in adolescents with coeliac disease commencing a gluten-free diet. Methods Nine adolescents with celiac disease, aged 12 to 16 years, were assessed using the semi-structured K-SADS-Present and Lifetime Diagnostic interview and several symptom scales. Seven of them were followed at 1 to 2, 3, and 6 months on a gluten-free diet. Results Adolescent coeliac disease patients with depression had significantly lower pre-diet tryptophan/ competing amino-acid (CAA ratios and free tryptophan concentrations, and significantly higher biopsy morning prolactin levels compared to those without depression. A significant decrease in psychiatric symptoms was found at 3 months on a gluten-free diet compared to patients' baseline condition, coinciding with significantly decreased coeliac disease activity and prolactin levels and with a significant increase in serum concentrations of CAAs. Conclusion Although our results of the amino acid analysis and prolactin levels in adolescents are only preliminary, they give support to previous findings on patients with coeliac disease, suggesting that serotonergic dysfunction due to impaired availability of tryptophan may play a role in vulnerability to depressive and behavioural disorders also among adolescents with untreated coeliac disease.

  4. Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Watterson, Kenneth R.; Stocker, Claire J.; Sokol, Elena; Jenkins, Laura; Simon, Katharina; Grundmann, Manuel; Petersen, Rasmus Koefoed; Wargent, Edward T.; Hudson, Brian D.; Kostenis, Evi; Ejsing, Christer S.; Cawthorne, Michael A.; Milligan, Graeme; Ulven, Trond

    2015-01-01

    Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and...... in concentration-response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and....... In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic...

  5. Heart valve disease associated with treatment with ergot-derived dopamine agonists: a clinical and echocardiographic study of patients with Parkinson's disease

    DEFF Research Database (Denmark)

    Rasmussen, Vibeke Guldbrand; Poulsen, Steen Hvitfeldt; Dupont, E;

    2007-01-01

    .2% (P < 0.05). The sensitivity of detecting at least moderate valvular disease by cardiac murmur, dyspnoea, or the heart failure marker NT-proBNP (natriuretic peptide) was 62% for the neurologists and 93% for the cardiologist but with equally low specificity (30-35%). CONCLUSION: EDDA was associated...

  6. Action Research for Poverty Alleviation

    OpenAIRE

    D. Rajasekhar

    2002-01-01

    This paper documents the process adopted in an action research project for poverty alleviation undertaken in two project areas of NGOs. After describing the process adopted to initiate action research, the paper discusses the methods conducted to acquire knowledge on processes generating poverty, and strategies adopted to alleviate poverty both by the poor and local organisations. Methods adopted to translate the knowledge into action are also discussed. Conclusions are provided at the end.

  7. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson’s Disease

    OpenAIRE

    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane; Amalric, Marianne; Kerkerian-Le Goff, Lydia

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological...

  8. Non-Ergot Dopamine Agonists Do Not Increase the Risk of Heart Failure in Parkinson’s Disease Patients: A Meta-Analysis of Randomized Controlled Trials

    Science.gov (United States)

    De Vecchis, Renato; Cantatrione, Claudio; Mazzei, Damiana; Baldi, Cesare; Di Maio, Marco

    2016-01-01

    Background In recent years, some observational studies suggested that pramipexole, a non-ergot dopamine agonist (DA) used for the treatment of Parkinson’s disease (PD), may increase the risk of heart failure (HF). However, the limitations inherent in observational studies made it difficult to determine whether the excess of incident HF was related to the drug or to other determinants. Thus, some concerns remained regarding the increased putative HF risk associated with non-ergot DAs as a class or individually. Methods In our meta-analysis, primary endpoint was the risk of incident HF in patients with PD treated with non-ergot DAs compared to those treated with monotherapy with levodopa. Secondary outcome measures were all-cause mortality and cardiovascular events. For these purposes, only randomized controlled trials (RCTs) were considered, provided that they offered complete outcome data pertaining to the incident HF, all-cause mortality and risk of cardiovascular events. Systematic searches were performed in the databases of PubMed, Embase and ClinicalTrial.gov up to May 2015. The effect size was estimated using the pooled relative risk (RR) of non-ergot DAs versus placebo on incident HF as well as on all-cause mortality or cardiovascular events. Results Six out of 27 RCTs reported at least one case of incident HF; therefore, we included them in the RR estimate, whereas 13 RCTs were included in the meta-analysis for mortality rates and 22 RCTs were included to evaluate cardiovascular events. Treatment with non-ergot DAs did not reveal an increase in the risk of incident HF as compared with the placebo group (pooled RR: 0.95; 95% CI: 0.30 - 2.90; P = 0.893). Similarly, patients treated with non-ergot DAs did not show any significant differences compared to controls with regard to all-cause mortality (pooled RR: 0.617; 95% CI: 0.330 - 1.153; P = 0.13) as well as with regard to cardiovascular events (pooled RR: 1.067; 95% CI: 0.663 - 1.717; P = 0.789). Conclusions

  9. Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: an indirect comparison of olodaterol and indacaterol

    Directory of Open Access Journals (Sweden)

    Roskell NS

    2014-07-01

    Full Text Available Neil S Roskell,1 Antonio Anzueto,2 Alan Hamilton,3 Bernd Disse,4 Karin Becker5 1Statistics, Bresmed Health Solutions Ltd, Sheffield, UK; 2School of Medicine, University of Texas Health Science Center, San Antonio, TX, USA; 3Medical Department, Boehringer Ingelheim (Canada Ltd, Burlington, ON, Canada; 4Medical Department, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany; 5Global Health Economics and Outcomes Research, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany Purpose: In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD, an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted. Methods: A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1, Transition Dyspnea Index, St George’s Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations. Results: Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol. Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters, the following mean differences (95% confidence interval were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, –0.005 (–0.077 to 0.067, and indacaterol 150 mcg

  10. Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer's disease.

    Science.gov (United States)

    Yahiaoui, Samir; Hamidouche, Katia; Ballandonne, Céline; Davis, Audrey; de Oliveira Santos, Jana Sopkova; Freret, Thomas; Boulouard, Michel; Rochais, Christophe; Dallemagne, Patrick

    2016-10-01

    5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip. PMID:27266998

  11. 多巴胺受体激动药治疗帕金森病的新进展%New Advances of Dopaminergic Agonists for Treatment of Parkinsons Disease

    Institute of Scientific and Technical Information of China (English)

    孙斌

    2001-01-01

    Parkinson's disease (PD) caused by the deficiency of DA in the substantial nigra-striatum system in the brain is a chronically progressive disease. Early diagnosis and prompt treatment PD can prolong work time and improve life quality of the patient. There are three primary approaches to increase activity of dopaminergic system:vicarious treatment to compensate DA; promote releasing DA in nerve endings of dopamine neurons and to prevent decreasing DA metabolism,as well as application of agonists that stimulate dopamine receptors. Some specialists suggest that application of dopaminergic agonists in the initial stage can not only delay the occurrence of syndrome on side effects with long-term use of levodopa,but also prevent the damage of dopaminergic cell caused by levodopa or its metabolite,and delay the development of PD. There are positive and adverse effects with DA agonists. This paper discussed the usage and side effects of classic and new dopaminergic agonists.%由于脑内黑质-纹状体系统中缺少多巴胺(DA)所致的帕金森病(PD)为慢性进展性疾病。对帕金森病尽早诊断和及时治疗的意义,在于能够延长患者的可工作时间和提高生存质量。增加DA能系统的活性,有三种途径:即DA替代疗法;促进DA神经元末端释放DA和阻止DA的降解代谢;应用DA受体激动药。一些作者主张在PD的早期先用DA能受体激动药,不但使“左旋多巴长期综合征”的出现延迟,并且可防止左旋多巴或其代谢产物损害DA能细胞和迟滞病情发展。应用DA受体激动药有利也有弊。介绍了常用和新型的DA能受体激动药的特点、用法和副作用等。

  12. β2-Adrenergic agonist-induced hypertrophy of the quadriceps skeletal muscle does not modulate disease severity in the rodent meniscectomy model of osteoarthritis

    OpenAIRE

    Tonge, D. P.; S. W. Jones; Parr, T.; Bardsley, R.; Doherty, M; Maciewicz, R.A.

    2010-01-01

    Summary Objective To examine whether β2-adrenergic agonist-induced hypertrophy of the quadriceps skeletal muscle can modulate the severity of osteoarthritis (OA) in the rodent meniscectomy (MNX) model. Methods Male Lewis rats were subcutaneously administered with 1.5 mg/kg/day clenbuterol hydrochloride (n = 15) or saline vehicle (n = 20) for 14 days. Following pre-treatment, five animals from each group were sacrificed to assess the immediate effects of clenbuterol. The remaining animals unde...

  13. Effects of dexmedetomidine on oxygenation and lung mechanics in patients with moderate chronic obstructive pulmonary disease undergoing lung cancer surgery

    OpenAIRE

    Lee, Su Hyun; Kim, Namo; Lee, Chang Yeong; Ban, Min Gi; Oh, Young Jun

    2015-01-01

    BACKGROUND Chronic obstructive pulmonary disease (COPD) is a risk factor that increases the incidence of postoperative cardiopulmonary morbidity and mortality after lung resection. Dexmedetomidine, a selective α2-adrenoreceptor agonist, has been reported previously to attenuate intrapulmonary shunt during one-lung ventilation (OLV) and to alleviate bronchoconstriction. OBJECTIVE The objective is to determine whether dexmedetomidine improves oxygenation and lung mechanics in patients with mode...

  14. Islam, Globalization, and Poverty Alleviation

    Directory of Open Access Journals (Sweden)

    Dwi Sulastyawati

    2015-11-01

    Full Text Available Globalization is globab as well condition and situation, neither economically, politically, and socially. All countries that embrace open economic system have participated in the system of globalization. Today the world is under the influence of super power world. For instance, using dollar as the official currency for international transactions, so that dollar dominates in international transactions. As a result, the value of the debt of developing countries has increased due to the rising price of dollar. The increment of the debt value in developing countries led the government reduces subsidies for the community. Thus economic hardship perceived more and more for poor people. This resulted that poverty is hard to be alleviated. This article analyzes the various Islamic perspective and thoughts on the impact of globalization on poverty alleviation.DOI: 10.15408/aiq.v5i2.2123

  15. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Luis F Razgado-Hernandez

    Full Text Available The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old, immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy

  16. Exploring prospects of β3-adrenoceptor agonists and inverse agonists for colon mobility control

    Directory of Open Access Journals (Sweden)

    Maria Grazia Perrone

    2013-07-01

    Full Text Available Inverse agonists are useful active ingredient of drugs clinically used to treat diseases mainly involving receptors endowed with non-endogenous agonist induced activity (constitutive or basal activity. SP-1e and SP-1g are the first two potent and highly selective β3-adrenoceptor inverse agonists [EC50=181 nM (IA=- 64% and 136 nM (IA=-73%, respectively], which their peculiar activity seems due to the absolute configurations of the two stereogenic centres present in each molecule. Rat proximal colon motility measurements allowed their further pharmacological characterization and pA2 values determination by Schild analysis (7.89 and 8.16, respectively. The purpose of our work is a further characterization of our novel β3-adrenoceptor agonists (SP-1a-d, SP-1f,1h and inverse agonists (SP-1e and SP-1g on rat proximal colon motility and a confirmation of their inverse agonist nature in a more complex system like the functional test on rat proximal colon. Male Wistar rats segment of the proximal colon were placed in organ baths containing Krebs solution. Muscle tension was recorded isotonically. Cumulative β3-AR agonists doses experiments were performed for each test compound: isoprenaline, BRL37344, SP-1a-d, SP-1f and SP-1h were dissolved in Krebs. The EC50 values of each agonists and pA2 of inverse agonists were determined. SP- 1a-d, SP-1f and SP-1h in rat colon have a muscle relaxing effect thus confirming their partial agonist activity found in CHO-K1 cell line. SP-1e and SP-1g behaved as antagonists with pA2 values of 7.89 and 8.16, respectively. In conclusion, experiments carried out by using isolated rat proximal colon allowed us to determine the pA2 values of the two β3-AR inverse agonists and add knowledge on the behavior of a novel set of compounds and their possible value as agents useful whenever is necessary to also control the colon motility.

  17. Alleviating energy poverty: Indian experience

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Garima

    2010-09-15

    Energy services play an important role in human welfare. India faces acute energy poverty indicating lack of access of clean energy fuels. Access to electricity is limited to 56% households in India and about 89% of rural households depend on polluting energy sources. Energy poverty impacts income poverty as poor find it difficult to acquire high priced cleaner fuels. It also adversely impacts the socio economic conditions of women. The paper highlights the linkage of energy poverty with income poverty and gender inequality. It analyses measures taken to alleviate energy poverty and recommends regulatory and policy measures as way forward.

  18. Identification of Selective ERRγ Inverse Agonists

    Directory of Open Access Journals (Sweden)

    Jina Kim

    2016-01-01

    Full Text Available GSK5182 (4 is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively. Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

  19. Perspectives for design of selective muscarinic agonists

    Czech Academy of Sciences Publication Activity Database

    Jakubík, Jan; Doležal, Vladimír; El-Fakahany, E. E.; Janíčková, Helena; Randáková, Alena; Šantrůčková, Eva

    Vol. 1. Martin: Jessenius Faculty of Medicine, 2011 - (Babušiková, E.; Dobrota, D.; Lehotský, J.), s. 154-168 ISBN 978-80-88866-99-2 R&D Projects: GA ČR(CZ) GA305/09/0681; GA AV ČR(CZ) IAA500110703; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : muscarinic acetylcholine receptor agonists * Alzheimer's disease * schizophrenia Subject RIV: FH - Neurology

  20. Adverse effects of beta-agonists: are they clinically relevant?

    Science.gov (United States)

    Abramson, Michael J; Walters, Julia; Walters, E Haydn

    2003-01-01

    Inhaled beta(2)-adrenoceptor agonists (beta(2)-agonists) are the most commonly used asthma medications in many Western countries. Minor adverse effects such as palpitations, tremor, headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective beta-agonist fenoterol and asthma deaths. Three case-control studies confirmed that among patients prescribed fenoterol, the risk of death was significantly elevated even after controlling for the severity of asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed fenoterol, but also suggested this might be a class effect of beta(2)-agonists. However, in subsequent studies, the long-acting beta(2)-agonist salmeterol was not associated with increased asthma mortality. In a case-control study blood albuterol (salbutamol) concentrations were found to be 2.5 times higher among patients who died of asthma compared with controls. It is speculated that such toxic concentrations could cause tachyarrhythmias under conditions of hypoxia and hypokalemia. The risk of asthma exacerbations and near-fatal attacks may also be increased among patients dispensed fenoterol, but this association may be largely due to confounding by severity. Although salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized beta(2)-agonists. Nebulized and oral beta(2)-agonists are also associated with an increased risk of cardiovascular death, ischemic heart disease and cardiac failure. Caution should be exercised when first prescribing a beta-agonist for patients with cardiovascular disease. A potential mechanism for adverse effects with regular use of beta(2)-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting beta(2)-agonists can occur, but has been consistently demonstrated only for formoterol (eformoterol) a full agonist, rather

  1. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    Science.gov (United States)

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. PMID:20579229

  2. Assessment of the Protection of Dopaminergic Neurons by an α7 Nicotinic Receptor Agonist, PHA 543613 Using [18F]LBT-999 in a Parkinson’s Disease Rat Model

    Science.gov (United States)

    Sérrière, Sophie; Doméné, Aurélie; Vercouillie, Johnny; Mothes, Céline; Bodard, Sylvie; Rodrigues, Nuno; Guilloteau, Denis; Routier, Sylvain; Page, Guylène; Chalon, Sylvie

    2015-01-01

    The inverse association between nicotine intake and Parkinson’s disease (PD) is well established and suggests that this molecule could be neuroprotective through anti-inflammatory action mediated by nicotinic receptors, including the α7-subtype (α7R). The objective of this study was to evaluate the effects of an agonist of α7R, PHA 543613, on striatal dopaminergic neurodegeneration and neuroinflammation in a rat model of PD induced by 6-hydroxydopamine (6-OHDA) lesion. Adult male Wistar rats were lesioned in the right striatum and assigned to either the PHA group (n = 7) or the Sham group (n = 5). PHA 543613 hydrochloride at the concentration of 6 mg/kg (PHA group) or vehicle (Sham group) was intra-peritoneally injected 2 h before 6-OHDA lesioning and then at days 2, 4, and 6 post-lesion. Positron emission tomography (PET) imaging was performed at 7 days post-lesion using [18F]LBT-999 to quantify the striatal dopamine transporter (DAT). After PET imaging, neuroinflammation was evaluated in same animals in vitro through the measurement of the microglial activation marker 18 kDa translocator protein (TSPO) by quantitative autoradiography with [3H]PK-11195. The DAT density reflecting the integrity of dopaminergic neurons was significantly decreased while the intensity of neuroinflammation measured by TSPO density was significantly increased in the lesioned compared to intact striatum in both groups. However, these both modifications were partially reversed in the PHA group compared to Sham. In addition, a significant positive correlation between the degree of lesion and the intensity of neuroinflammation was evidenced. These findings indicate that PHA 543613 exerts neuroprotective effects on the striatal dopaminergic neurons associated with a reduction in microglial activation in this model of PD. This reinforces the hypothesis that an α7R agonist could provide beneficial effects for the treatment of PD. PMID:26389120

  3. Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington’s disease

    OpenAIRE

    Jin, Jing; Albertz, Jennifer; Guo, Zhihong; Peng, Qi; Rudow, Gay; Troncoso, Juan C.; Ross, Christopher A.; Duan, Wenzhen

    2013-01-01

    Huntington’s disease (HD) is a devastating genetic neurodegenerative disease caused by CAG trinucleotide expansion in the exon-1 region of the huntingtin gene. Currently, no cure is available. It is becoming increasingly apparent that mutant HTT impairs metabolic homeostasis and causes transcriptional dysregulation. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a transcriptional factor that plays a key role in regulating genes involved in energy metabolism; recent studies d...

  4. Dopaminergic agonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy....

  5. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...... presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide and...... liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  6. Hypoxic Preconditioning Alleviates Ethanol Neurotoxicity: the Involvement of Autophagy

    OpenAIRE

    Wang, Haiping; Bower, Kimberly A.; Frank, Jacqueline A.; Xu, Mei; Luo, Jia

    2013-01-01

    Ethanol is a neuroteratogen and neurodegeneration is the most devastating consequence of developmental exposure to ethanol. A sublethal preconditioning has been proposed as a neuroprotective strategy against several central nervous system (CNS) neurodegenerative diseases. We have recently demonstrated that autophagy is a protective response to alleviate ethanol toxicity. A modest hypoxic preconditioning (1% oxygen) did not cause neurotoxicity but induced autophagy (Tzeng et al., 2010). We the...

  7. Deep Brain Stimulation Alleviates Parkinsonian Bradykinesia by Regularizing Pallidal Activity

    OpenAIRE

    Dorval, Alan D.; Kuncel, Alexis M.; Birdno, Merrill J.; Turner, Dennis A.; Grill, Warren M.

    2010-01-01

    Deep brain stimulation (DBS) of the basal ganglia can alleviate the motor symptoms of Parkinson's disease although the therapeutic mechanisms are unclear. We hypothesize that DBS relieves symptoms by minimizing pathologically disordered neuronal activity in the basal ganglia. In human participants with parkinsonism and clinically effective deep brain leads, regular (i.e., periodic) high-frequency stimulation was replaced with irregular (i.e., aperiodic) stimulation at the same mean frequency ...

  8. INFECTION WITH FOOT-AND-MOUTH DISEASE VIRUS CAUSES LOSS OF CIRCULATING PLASMACYTOID DENDRITIC CELLS AND ABROGATES THE INTERFERON ALPHA RESPONSE TO TLR AGONISTS

    Science.gov (United States)

    Immune evasion by pathogens is often critical to virulence and spread of the infectious agent. Foot-and-mouth disease virus (FMDV) is considered one of the most contagious infections known yet is very sensitive to both type I and type II interferons (IFN). In many species including swine, plasmacyto...

  9. Harnessing motivation to alleviate neglect

    Directory of Open Access Journals (Sweden)

    Charlotte eRussell

    2013-06-01

    Full Text Available The syndrome of spatial neglect results from the combination of a number of deficits in attention, with patients demonstrating both spatially lateralised and non-lateralised impairments. Previous reports have hinted that there may be a motivational component to neglect and that modulating this might alleviate some of the debilitating symptoms. Additionally, recent work on the effects of reward on attention in healthy participants has revealed improvements across a number of paradigms. As the primary deficit in neglect has been associated with attention, this evidence for reward’s effects is potentially important. However, until very recently there have been few empirical studies addressing this potential therapeutic avenue. Here we review the growing body of evidence that attentional impairments in neglect can be reduced by motivation, for example in the form of preferred music or anticipated monetary reward, and discuss the implications of this for treatments for these patients. Crucially these effects of positive motivation are not observed in all patients with neglect, suggesting that the consequences of motivation may relate to individual lesion anatomy. Given the key role of dopaminergic systems in motivational processes, we suggest that motivational stimulation might act as a surrogate for dopaminergic stimulation. In addition, we consider the relationship between clinical post stroke apathy and lack of response to motivation.

  10. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide and...... liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  11. Are Dopamine Agonists Neuroprotective in Parkinson‘s disease?

    Institute of Scientific and Technical Information of China (English)

    乐卫东; Jank.J

    2002-01-01

    Dopamine(DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson's disease(PD) and in PD patient with levodopa(L-DO-PA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoylasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer's disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinal trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as18F-L-DOPA PET and123I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.

  12. AGONISTIC BEHAVIOR OF LABORATORY MICE

    OpenAIRE

    D. Cinghiţă; D. Stănescu

    2005-01-01

    In this work we study agonistic behavior of laboratory white mice when they are kept in captivity. For all this experimental work we used direct observation of mice, in small lists, because we need a reduced space to emphasize characteristics of agonistic behavior. Relations between members of the same species that live in organized groups are based in most cases on hierarchical structure. Relations between leader and subservient, decided by fighting, involve a thorough observation between i...

  13. Dihydrocodeine / Agonists for Alcohol Dependents

    Directory of Open Access Journals (Sweden)

    Albrecht eUlmer

    2012-03-01

    Full Text Available Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients.Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC to 102 heavily alcohol addict-ed patients, later, also Buprenorphine, Clomethiazole (>6 weeks, Baclofen and in one case Amphetamine, each on individual indication. This paper focuses on the data with DH, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC-treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-step scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details.Conclusions: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around ¼ of the patients already. Many further

  14. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Science.gov (United States)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  15. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1 Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Henrik H Hansen

    Full Text Available One of the major histopathological hallmarks of Alzheimer's disease (AD is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1 receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP and presenilin-1 (PS1 are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9 of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c., or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.. In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

  16. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

    Science.gov (United States)

    Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  17. Alleviating Stress In Police Agencies

    Directory of Open Access Journals (Sweden)

    Phillip Neely

    2013-05-01

    Full Text Available Policestress has been examined in many studies, many of which have focused upon thedevelopment of prevention and treatment programs for the police officers(Maslach, 1982; Maslach & Jackson, 1979; Mitchell, 1983; Mitchell &Everly, 1993. The trend of combating stress began with the police agenciesusing employee assistance programs, funding conferences, conducting research,and establishing prevention programs, but the fact remains that the health ofpolice officers and their families becomes a large concern as most officerstend not use free counseling due to concerns regarding confidentiality and thecompetence of the counselors. An example of one program is the New JerseyCOP-2-COP confidential hotline for police officers and their families (Ussery& Waters, 2006. COP-2-COP was a volunteer program and its usefulness wasseen post-September 11, 2001, in its response to the needs of the survivors ofthe World Trade Center disaster and also after the New Orleans disaster in theCritical Incident Stress Debriefing process after Hurricane Katrina.  Police stress can have a bad influence onpolice performance and can cause many problems such as poor job performance,increased accidents, sleep disturbances, marital discord, domestic violence,posttraumatic stress disorder, depression, suicide, alcohol and other drugabuse, ulcers and other digestive disorders, respiratory ailments, andcardiovascular disease.

  18. Strategies for designing synthetic immune agonists.

    Science.gov (United States)

    Wu, Tom Y-H

    2016-08-01

    Enhancing the immune system is a validated strategy to combat infectious disease, cancer and allergy. Nevertheless, the development of immune adjuvants has been hampered by safety concerns. Agents that can stimulate the immune system often bear structural similarities with pathogen-associated molecular patterns found in bacteria or viruses and are recognized by pattern recognition receptors (PRRs). Activation of these PRRs results in the immediate release of inflammatory cytokines, up-regulation of co-stimulatory molecules, and recruitment of innate immune cells. The distribution and duration of these early inflammatory events are crucial in the development of antigen-specific adaptive immunity in the forms of antibody and/or T cells capable of searching for and destroying the infectious pathogens or cancer cells. However, systemic activation of these PRRs is often poorly tolerated. Hence, different strategies have been employed to modify or deliver immune agonists in an attempt to control the early innate receptor activation through temporal or spatial restriction. These approaches include physicochemical manipulation, covalent conjugation, formulation and conditional activation/deactivation. This review will describe recent examples of discovery and optimization of synthetic immune agonists towards clinical application. PMID:27213842

  19. Curcumin alleviates oxidative stress and mitochondrial dysfunction in astrocytes.

    Science.gov (United States)

    Daverey, Amita; Agrawal, Sandeep K

    2016-10-01

    Oxidative stress plays a critical role in various neurodegenerative diseases, thus alleviating oxidative stress is a potential strategy for therapeutic intervention and/or prevention of neurodegenerative diseases. In the present study, alleviation of oxidative stress through curcumin is investigated in A172 (human glioblastoma cell line) and HA-sp (human astrocytes cell line derived from the spinal cord) astrocytes. H2O2 was used to induce oxidative stress in astrocytes (A172 and HA-sp). Data show that H2O2 induces activation of astrocytes in dose- and time-dependent manner as evident by increased expression of GFAP in A172 and HA-sp cells after 24 and 12h respectively. An upregulation of Prdx6 was also observed in A172 and HA-sp cells after 24h of H2O2 treatment as compared to untreated control. Our data also showed that curcumin inhibits oxidative stress-induced cytoskeleton disarrangement, and impedes the activation of astrocytes by inhibiting upregulation of GFAP, vimentin and Prdx6. In addition, we observed an inhibition of oxidative stress-induced inflammation, apoptosis and mitochondria fragmentation after curcumin treatment. Therefore, our results suggest that curcumin not only protects astrocytes from H2O2-induced oxidative stress but also reverses the mitochondrial damage and dysfunction induced by oxidative stress. This study also provides evidence for protective role of curcumin on astrocytes by showing its effects on attenuating reactive astrogliosis and inhibiting apoptosis. PMID:27423629

  20. GnRH agonist triggering

    DEFF Research Database (Denmark)

    Kol, Shahar; Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2013-01-01

    The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages...... triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. Routinely, human chorionic gonadotrophin (HCG) is used to induce ovulation in fertility treatments. This approach deviates...... significantly from physiology and often results in insufficient hormonal support in early pregnancy and in ovarian hyperstimulation syndrome (OHSS). An alternative approach is to use a gonadotrophin-releasing hormone (GnRH) agonist which allows a more physiological trigger of ovulation and, most importantly...

  1. Gust Alleviation Using Direct Gust Measurement

    Science.gov (United States)

    Hoppe, Sven Marco

    2000-01-01

    The increasing competition in the market of civil aircraft leads to operating efficiency and passenger comfort being very important sales arguments. Continuous developments in jet propulsion technology helped to reduce energy consumption, as well as noise and vibrations due to the engines. The main problem with respect to ride comfort is, however, the transmittance of accelerations and jerkiness imposed by atmospheric turbulence from the wings to the fuselage. This 'gust' is also a design constraint: Light airplane structures help to save, energy, but are more critical to resist the loads imposed by turbulence. For both reasons, efficient gust alleviation is necessary to improve the performance of modern aircraft. Gust can be seen as a change in the angle of attack or as an additional varying vertical component of the headwind. The effect of gust can be very strong, since the same aerodynamic forces that keep the airplane flying are involved. Event though the frequency range of those changes is quite low, it is impossible for the pilot to alleviate gust manually. Besides, most of the time during the flight, the, autopilot maintains course and the attitude of flight. Certainly, most autopilots should be capable of damping the roughest parts of turbulence, but they are unable to provide satisfactory results in that field. A promising extension should be the application of subsidiary, control, where the inner (faster) control loop alleviates turbulence and the outer (slower) loop controls the attitude of flight. Besides the mentioned ride comfort, another reason for gust alleviation with respect to the fuselage is the sensibility of electrical devices to vibration and high values of acceleration. Many modern airplane designs--especially inherently instable military aircraft--are highly dependent on avionics. The lifetime and the reliability of these systems is thus essential.

  2. poverty and poverty alleviation in globalised cities

    OpenAIRE

    Verena Ast

    2014-01-01

    In the light of increasing "division of the cities" and its underlying process of socio-spatial segregation researches focus more and more on the consequences of this process: the development of advantaged and disadvantaged districts within contemporary cities. Thereby especially poverty alleviation respectively poverty eradication in disadvantaged districts becomes an emerging and central field of intervention in social policies. This is due to the broad impact of poverty like higher risk of...

  3. Foveation-based Mechanisms Alleviate Adversarial Examples

    OpenAIRE

    Luo, Yan; Boix, Xavier; Roig, Gemma; Poggio, Tomaso; Zhao, Qi

    2015-01-01

    We show that adversarial examples, i.e., the visually imperceptible perturbations that result in Convolutional Neural Networks (CNNs) fail, can be alleviated with a mechanism based on foveations---applying the CNN in different image regions. To see this, first, we report results in ImageNet that lead to a revision of the hypothesis that adversarial perturbations are a consequence of CNNs acting as a linear classifier: CNNs act locally linearly to changes in the image regions with objects reco...

  4. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    Science.gov (United States)

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics. PMID:26675887

  5. Inhibition of BET bromodomains alleviates inflammation in human RPE cells.

    Science.gov (United States)

    Hytti, M; Tokarz, P; Määttä, E; Piippo, N; Korhonen, E; Suuronen, T; Honkakoski, P; Kaarniranta, K; Lahtela-Kakkonen, M; Kauppinen, A

    2016-06-15

    Bromodomain-containing proteins are vital for controlling the expression of many pro-inflammatory genes. Consequently, compounds capable of inhibiting specific bromodomain-facilitated protein-protein interactions would be predicted to alleviate inflammation, making them valuable agents in the treatment of diseases caused by dysregulated inflammation, such as age-related macular degeneration. Here, we assessed the ability of known inhibitors JQ-1, PFI-1, and IBET-151 to protect from the inflammation and cell death caused by etoposide exposure in the human retinal pigment epithelial cell line, ARPE-19. The potential anti-inflammatory effects of the bromodomain inhibitors were assessed by ELISA (enzyme-linked immunosorbent assay) profiling. The involvement of NF-κB and SIRT1 in inflammatory signaling was monitored by ELISA and western blotting. Furthermore, SIRT1 was knocked down using a specific siRNA or inhibited by EX-527 to elucidate its role in the inflammatory reaction. The bromodomain inhibitors effectively decreased etoposide-induced release of IL-6 and IL-8. This anti-inflammatory effect was not related to SIRT1 activity, although all bromodomain inhibitors decreased the extent of acetylation of p53 at the SIRT1 deacetylation site. Overall, since bromodomain inhibitors display anti-inflammatory properties in human retinal pigment epithelial cells, these compounds may represent a new way of alleviating the inflammation underlying the onset of age-related macular degeneration. PMID:27106081

  6. Immunotherapy with Agonistic Anti-CD137: Two Sides of a Coin

    Institute of Scientific and Technical Information of China (English)

    YonglianSun; JonathanH.Chen; YangxinFu

    2004-01-01

    CD137 (4-1BB), a member of the TNF receptor superfamily, is an inducible T cell costimulatory receptor primarily expressed on activated CD4+ and CD8+ T cells. Agonistic monoclonal antibodies (mAbs) against CD137 greatly enhance T cell-mediated immune responses against many types of tumors and viruses. Surprisingly, these agonists also showed therapeutic effects in several autoimmune diseases. These findings suggest that in different disease environments, CD137 engagement with agonist mAb in vivo can diametrically modulate immune response outcomes. Therefore, CD137 agonists represent a promising immunotherapeutic approach to a wide array of disparate immune disorders. However, CD137's potency in modulating immune response necessitates caution when targeting CD137 clinically. Cellular & Molecular Immunology. 2004;1(1):31-36.

  7. Immunotherapy with Agonistic Anti-CD137: Two Sides of a Coin

    Institute of Scientific and Technical Information of China (English)

    Yonglian Sun; Jonathan H.Chen; Yangxin Fu

    2004-01-01

    CD137 (4-1BB), a member of the TNF receptor superfamily, is an inducible T cell costimulatory receptor primarily expressed on activated CD4+ and CD8+ T cells. Agonistic monoclonal antibodies (mAbs) against CD137 greatly enhance T cell-mediated immune responses against many types of tumors and viruses. Surprisingly, these agonists also showed therapeutic effects in several autoimmune diseases. These findings suggest that in different disease environments, CD137 engagement with agonist mAb in vivo can diametrically modulate immune response outcomes. Therefore, CD137 agonists represent a promising immunotherapeutic approach to a wide array of disparate immune disorders. However, CD137's potency in modulating immune response necessitates caution when targeting CD137 clinically. Cellular & Molecular Immunology. 2004;1(1):31-36.

  8. PPARγ Agonist Beyond Glucose Lowering Effect

    OpenAIRE

    Sugawara, Akira; Uruno, Akira; Kudo, Masataka; Matsuda, Ken; Yang, Chul Woo; Ito, Sadayoshi

    2011-01-01

    The nuclear hormone receptor PPARγ is activated by several agonists, including members of the thiazolidinedione group of insulin sensitizers. Pleiotropic beneficial effects of these agonists, independent of their blood glucose-lowering effects, have recently been demonstrated in the vasculature. PPARγ agonists have been shown to lower blood pressure in animals and humans, perhaps by suppressing the renin-angiotensin (Ang)-aldosterone system (RAAS), including the inhibition of Ang II type 1 re...

  9. Absence of functional alternative complement pathway alleviates lupus cerebritis.

    Science.gov (United States)

    Alexander, Jessy J; Jacob, Alexander; Vezina, Paul; Sekine, Hideharu; Gilkeson, Gary S; Quigg, Richard J

    2007-06-01

    The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB-/-MRL/lpr) compared to fB-sufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16+/-0.02 vs. 0.35+/-0.13, pcerebritis. PMID:17523212

  10. Dopamine Agonist Increases Risk Taking but Blunts Reward-Related Brain Activity

    OpenAIRE

    Jordi Riba; Krämer, Ulrike M.; Marcus Heldmann; Sylvia Richter; Münte, Thomas F.

    2008-01-01

    The use of D2/D3 dopaminergic agonists in Parkinson's disease (PD) may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of the reward system, following unexpected high gains and therefo...

  11. Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination.

    Science.gov (United States)

    Du, Changsheng; Duan, Yanhui; Wei, Wei; Cai, Yingying; Chai, Hui; Lv, Jie; Du, Xiling; Zhu, Jian; Xie, Xin

    2016-01-01

    Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches. PMID:27040771

  12. Beta-agonists and animal welfare

    Science.gov (United States)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  13. [Adrenergic beta-agonist intoxication].

    Science.gov (United States)

    Carrola, Paulo; Devesa, Nuno; Silva, José Manuel; Ramos, Fernando; Alexandrino, Mário B; Moura, José J

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestión of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a ß-adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency. PMID:22226216

  14. Alleviating Media Bias Through Intelligent Agent Blogging

    CERN Document Server

    Diaz-Aviles, Ernesto

    2009-01-01

    Consumers of mass media must have a comprehensive, balanced and plural selection of news to get an unbiased perspective; but achieving this goal can be very challenging, laborious and time consuming. News stories development over time, its (in)consistency, and different level of coverage across the media outlets are challenges that a conscientious reader has to overcome in order to alleviate bias. In this paper we present an intelligent agent framework currently facilitating analysis of the main sources of on-line news in El Salvador. We show how prior tools of text analysis and Web 2.0 technologies can be combined with minimal manual intervention to help individuals on their rational decision process, while holding media outlets accountable for their work.

  15. Alleviate Cellular Congestion Through Opportunistic Trough Filling

    Directory of Open Access Journals (Sweden)

    Yichuan Wang

    2014-04-01

    Full Text Available The demand for cellular data service has been skyrocketing since the debut of data-intensive smart phones and touchpads. However, not all data are created equal. Many popular applications on mobile devices, such as email synchronization and social network updates, are delay tolerant. In addition, cellular load varies significantly in both large and small time scales. To alleviate network congestion and improve network performance, we present a set of opportunistic trough filling schemes that leverage the time-variation of network congestion and delay-tolerance of certain traffic in this paper. We consider average delay, deadline, and clearance time as the performance metrics. Simulation results show promising performance improvement over the standard schemes. The work shed lights on addressing the pressing issue of cellular overload.

  16. Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist.

    Science.gov (United States)

    Lin, Hsiang-Ru

    2015-01-01

    Lepidozenolide is a sesquiterpenoid isolated from the liverwort Lepidozia fauriana and its possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and hyperglycemia. In this study, whether lepidozenolide may act as a FXR agonist was determined. Indeed, in mammalian one-hybrid and transient transfection reporter assays, lepidozenolide transactivated FXR to modulate promoter action including GAL4, CYP7A1, and PLTP promoters in a dose-dependent manner, while it exhibited slightly less agonistic activity than chenodeoxycholic acid, an endogenous FXR agonist. Through the molecular modeling docking studies lepidozenolide was shown to bind to FXR ligand binding pocket fairly well. All these results indicate that lepidozenolide acts as a FXR agonist. PMID:25315435

  17. Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells.

    Science.gov (United States)

    Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C; Hershfeld, Alena; Kenyon, Lawrence C; Deshpande, Deepak A

    2016-02-15

    Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K(+) channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as

  18. Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children

    Directory of Open Access Journals (Sweden)

    Chenhong Zhang

    2015-08-01

    Research in context: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader–Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

  19. The selective nicotinic acetylcholine receptor alpha7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain.

    Science.gov (United States)

    Feuerbach, Dominik; Lingenhoehl, Kurt; Olpe, Hans-Rudolf; Vassout, Annick; Gentsch, Conrad; Chaperon, Frederique; Nozulak, Joachim; Enz, Albert; Bilbe, Graeme; McAllister, Kevin; Hoyer, Daniel

    2009-01-01

    Several lines of evidence suggest that the nicotinic acetylcholine receptor alpha7 (nAChR alpha7) is involved in central nervous system disorders like schizophrenia and Alzheimer's disease as well as in inflammatory disorders like sepsis and pancreatitis. The present article describes the in vivo effects of JN403, a compound recently characterized to be a potent and selective partial nAChR alpha7 agonist. JN403 rapidly penetrates into the brain after i.v. and after p.o. administration in mice and rats. In the social recognition test in mice JN403 facilitates learning/memory performance over a broad dose range. JN403 shows anxiolytic-like properties in the social exploration model in rats and the effects are retained after a 6h pre-treatment period and after subchronic administration. The effect on sensory inhibition was investigated in DBA/2 mice, a strain with reduced sensory inhibition under standard experimental conditions. Systemic administration of JN403 restores sensory gating in DBA/2 mice, both in anaesthetized and awake animals. Furthermore, JN403 shows anticonvulsant potential in the audiogenic seizure paradigm in DBA/2 mice. In the two models of permanent pain tested, JN403 produces a significant reversal of mechanical hyperalgesia. The onset was fast and the duration lasted for about 6h. Altogether, the present set of data suggests that nAChR alpha7 agonists, like JN403 may be beneficial for improving learning/memory performance, restoring sensory gating deficits, and alleviating pain, epileptic seizures and conditions of anxiety. PMID:18793655

  20. Cryptochinones from Cryptocarya chinensis act as farnesoid X receptor agonists.

    Science.gov (United States)

    Lin, Hsiang-Ru; Chou, Tsung-Hsien; Huang, Din-Wen; Chen, Ih-Sheng

    2014-09-01

    Cryptochinones A-D are tetrahydroflavanones isolated from the leaves of Cryptocarya chinensis, an evergreen tree whose extracts are believed to have a variety of health benefits. The origin of their possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and for hyperglycemia. We studied whether cryptochinones A-D, which are structurally similar to known FXR ligands, may act at this target. Indeed, in mammalian one-hybrid and transient transfection reporter assays, cryptochinones A-D transactivated FXR to modulate promoter action including GAL4, SHP, CYP7A1, and PLTP promoters in dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid (CDCA), an endogenous FXR agonist. Through molecular modeling docking studies we evaluated their ability to bind to the FXR ligand binding pocket. Our results indicate that cryptochinones A-D can behave as FXR agonists. PMID:25127166

  1. Alleviating soil acidity through plant organic compounds

    Directory of Open Access Journals (Sweden)

    Anderson R. Meda

    2001-06-01

    Full Text Available A laboratory experiment was conducted to evaluate the effects of water soluble plant extracts on soil acidity. The plant materials were: black oat, oil seed radish, white and blue lupin, gray and dwarf mucuna, Crotalaria spectabilis and C. breviflora, millet, pigeon pea, star grass, mato grosso grass, coffee leaves, sugar cane leaves, rice straw, and wheat straw. Plant extracts were added on soil surface in a PVC soil column at a rate of 1.0 ml min-1. Both soil and drainage water were analyzed for pH, Ca, Al, and K. Plant extracts applied on the soil surface increased soil pH, exchangeable Ca ex and Kex and decreased Al ex. Oil seed radish, black oat, and blue lupin were the best and millet the worst materials to alleviate soil acidity. Oil seed radish markedly increased Al in the drainage water. Chemical changes were associated with the concentrations of basic cations in the plant extract: the higher the concentration the greater the effects in alleviating soil acidity.Foram conduzidos experimentos de laboratórios para avaliar os efeitos de extratos de plantas solúveis em água na acidez do solo. Os materiais de plantas foram: aveia preta, nabo, tremoço branco e azul, mucuna cinza e anã, Crotalaria spectabilis e C. breviflora, milheto, guandu, grama estrela, grama mato grosso, folhas de café, folhas de cana-de-açúcar, palhada de arroz e palhada de trigo. Foi utilizado o seguinte procedimento para o extrato da planta solúvel em água: pesar 3g de material de planta, adicionar 150 ml de água, agitar por 8h e filtrar. Os extratos de plantas foram adicionados na superfície do solo em uma coluna de PVC (1 ml min-1. Após, adicionou-se água deionizada em quantidade equivalente a três volumes de poros. Os extratos de plantas aumentaram o pH, Ca e K trocável e diminuíram Al. Nabo, aveia preta e tremoço azul foram os melhores e milheto o pior material para amenizar a acidez do solo. Nabo aumentou Al na água de drenagem. As altera

  2. Dyskinesias and Treatment with Pramipexole in Patients with Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    John C. P. Piedad

    2012-01-01

    Full Text Available Dopamine agonists such as pramipexole (PPX have first been proposed as adjunctive treatment to levodopa (L-DOPA for patients with Parkinson’s disease (PD and then as a monotherapy alternative to alleviate dyskinesia. Treatment with PPX has overall been associated with improvement in parkinsonian symptoms. Although the majority of placebo-controlled studies demonstrated that dyskinesia was more prevalent in the PPX compared to the placebo groups, some studies did not detect any dyskinesia as a side effect of this medication. PPX was consistently associated with lower risk for developing dyskinesia compared to L-DOPA. Moreover, the presence of these symptoms in the placebo groups suggests involvement of non-PPX-related factors for developing dyskinesia. It is suggested that future research should aim at ascertaining whether cotherapy with L-DOPA, PPX dosage, and other patient characteristics are contributory factors for the development of PPX-related dyskinesia in patients with PD.

  3. Innovation of Tourism Poverty Alleviation Model: Stakeholder Perspective

    OpenAIRE

    Guoqing HUANG

    2015-01-01

    The research has included the stakeholder theory in regional tourism poverty alleviation study and emphasized the significance of community residents’ involvement in tourism managing process as a core stakeholder and their equal chance of the shared interests. In addition, to construct a new model of tourism poverty alleviation and clarify its mechanism through the comprehensive analysis of other stakeholders’ interest appeals. 

  4. Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy

    OpenAIRE

    Jakubík, J; Janíčková, H; El-Fakahany, EE; Doležal, V

    2011-01-01

    BACKGROUND AND PURPOSE Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5′-γ−thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M2 muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. EXPERIMENTAL APPROACH Filtration and scintillation proximity ass...

  5. Thrombopoietin Receptor Agonists in Primary ITP

    OpenAIRE

    Siegal, Deborah; Crowther, Mark; Cuker, Adam

    2013-01-01

    Thrombopoietin (TPO) regulates thrombopoiesis through activation of TPO receptors on the megakaryocyte cell surface, resulting in increased platelet production. The TPO receptor agonists are novel treatments for patients with chronic ITP aimed at increasing platelet production through interactions with the TPO receptor on megakaryocytes. Two TPO receptor agonists, romiplostim and eltrombopag, have received regulatory approval. In patients with chronic ITP who remain at risk of bleeding follow...

  6. An Online Alternative to Alleviate Communication Apprehension

    Directory of Open Access Journals (Sweden)

    Seyit Ahmet Çapan

    2013-05-01

    Full Text Available Anxiety is an affective factor commonly associated with one’s overall performance in a foreign language. As a component of foreign language anxiety, communication apprehension specifically correlates with successful oral production. A plethora of research (Bailey, Onwuegbuzie & Daley, 2003; Foss & Reitzel, 1988 has indicated that high levels of communication apprehension negatively affects one’s L2 communication abilities. Thus, this study intends to remedy negative effects of communication apprehension on EFL learners by virtual meetings held through computer-mediated communication. The participants (N: 18 in this study were selected through purposive sampling. The study employed both quantitative and qualitative techniques. To analyze the data collected, a non-parametric test, Wilcoxon Signed Rank Test, was utilized. The results indicated that computer-mediated communication via voice over IP tools made a significant contribution to alleviate communication apprehension levels in the participants with varying degrees of apprehension levels. The study yielded the most drastic reduction in the high apprehension group, since the participants in this group made a significant progress and ended up with moderate levels of communication apprehension. Also, the participants’ self-reports revealed that computer-mediated communication yielded remarkably positive changes in their attitudes towards communicating in the target language. Moreover, the study revealed that computer-mediated communication helped to increase their intercultural awareness. Finally, participants provided a bunch of practical suggestions as possible solutions for reducing communication apprehension.Keywords: apprehension, communication, computer-mediated, attitudes

  7. Alleviating energy poverty for the world's poor

    International Nuclear Information System (INIS)

    Improving energy services for poor households in developing countries remains one of the most pressing challenges facing the development community. The dependence of these households on traditional forms of energy leads to significant health impacts as well as other major disbenefits, yet there has been little progress in meeting this challenge. This viewpoint argues for an 'energy-poverty alleviation' fund to help provide modern energy services to these households. It also proposes an approach through which to create such a fund, namely by introducing an incremental levy on petroleum. Notably, this scheme does not need a global agreement since a levy could be introduced by major oil-exporting countries. The implementation of this mechanism would result in a climate-friendly outcome (even before taking into account the elimination of products of incomplete combustion resulting from the traditional household use of biomass-based fuels) while providing immense socio-economic benefits to the world's poor. Such an approach would allow significant progress on the sustainable development front while reducing global greenhouse gas emissions, and therefore is very much consistent with the United Nations Framework Convention on Climate Change

  8. Targeted Delivery of LXR Agonist Using a Site-Specific Antibody-Drug Conjugate.

    Science.gov (United States)

    Lim, Reyna K V; Yu, Shan; Cheng, Bo; Li, Sijia; Kim, Nam-Jung; Cao, Yu; Chi, Victor; Kim, Ji Young; Chatterjee, Arnab K; Schultz, Peter G; Tremblay, Matthew S; Kazane, Stephanie A

    2015-11-18

    Liver X receptor (LXR) agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been hindered by on-target adverse effects in the liver mediated by excessive lipogenesis. Herein, we report a novel site-specific antibody-drug conjugate (ADC) that selectively delivers a LXR agonist to monocytes/macrophages while sparing hepatocytes. The unnatural amino acid para-acetylphenylalanine (pAcF) was site-specifically incorporated into anti-CD11a IgG, which binds the α-chain component of the lymphocyte function-associated antigen 1 (LFA-1) expressed on nearly all monocytes and macrophages. An aminooxy-modified LXR agonist was conjugated to anti-CD11a IgG through a stable, cathepsin B cleavable oxime linkage to afford a chemically defined ADC. The anti-CD11a IgG-LXR agonist ADC induced LXR activation specifically in human THP-1 monocyte/macrophage cells in vitro (EC50-27 nM), but had no significant effect in hepatocytes, indicating that payload delivery is CD11a-mediated. Moreover, the ADC exhibited higher-fold activation compared to a conventional synthetic LXR agonist T0901317 (Tularik) (3-fold). This novel ADC represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis. PMID:25945727

  9. Discovery of a potent and selective GPR120 agonist

    DEFF Research Database (Denmark)

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel;

    2012-01-01

    GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is...... however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist....

  10. Attenuation by a sigma1 (σ1) receptor agonist of the learning and memory deficits induced by a prenatal restraint stress in juvenile rats

    OpenAIRE

    Meunier, Johann; Gué, Michèle; Récasens, Max; Maurice, Tangui

    2004-01-01

    Stress during pregnancy results in complex neurochemical and behavioral alterations throughout the offspring lifetime. We here examined the impact of prenatal stress (PS) on memory functions in male and female offspring and report the efficacy of a selective sigma1 (σ1) receptor agonist, igmesine, in alleviating the observed deficits.Dams received an unpredictable 90-min duration restraint stress from gestational day E17 to E20. Learning was examined in offspring between day P24 and P36 using...

  11. Arctigenin alleviates ER stress via activating AMPK

    Institute of Scientific and Technical Information of China (English)

    Yuan GU; Xiao-xiao SUN; Ji-ming YE; Li HE; Shou-sheng YAN; Hao-hao ZHANG; Li-hong HU; Jun-ying YUAN; Qiang YU

    2012-01-01

    Aim:To investigate the protective effects of arctigenin (ATG),a phenylpropanoid dibenzylbutyrolactone lignan from Arctium lappa L (Compositae),against ER stress in vitro and the underlying mechanisms.Methods:A cell-based screening assay for ER stress regulators was established.Cell viability was measured using MTT assay.PCR and Western blotting were used to analyze gene and protein expression.Silencing of the CaMKKβ,LKB1,and AMPKα1 genes was achieved by RNA interference (RNAi).An ATP bioluminescent assay kit was employed to measure the intracellular ATP levels.Results:ATG (2.5,5,and 10 μmol/L) inhibited cell death and unfolded protein response (UPR) in a concentration-dependent manner in cells treated with the ER stress inducer brefeldin A (100 nmol/L).ATG (1,5,and 10 μmol/L) significantly attenuated protein synthesis in cells through inhibiting mTOR-p7OS6K signaling and eEF2 activity,which were partially reversed by silencing AMPKα1 with RNAi.ATG (1-50 μmol/L) reduced intracellular ATP level and activated AMPK through inhibiting complex I-mediated respiration.Pretreatment of cells with the AMPK inhibitor compound C (25 μmol/L) rescued the inhibitory effects of ATG on ER stress.Furthermore,ATG (2.5 and 5μmol/L) efficiently activated AMPK and reduced the ER stress and cell death induced by palmitate (2 mmol/L) in INS-1 β cells.Conclusion:ATG is an effective ER stress alleviator,which protects cells against ER stress through activating AMPK,thus attenuating protein translation and reducing ER load.

  12. Sodium butyrate alleviates adipocyte inflammation by inhibiting NLRP3 pathway.

    Science.gov (United States)

    Wang, Xukai; He, Gang; Peng, Yan; Zhong, Weitian; Wang, Yan; Zhang, Bo

    2015-01-01

    Insulin resistance (IR) is a common feature of Type II diabetes, metabolic disorders, hypertension and other vascular diseases. Recent studies showed that obesity-induced inflammation may be critical for IR. To investigate the anti-inflammatory effect of sodium butyrate (NaB) on obesity-induced inflammation, the db/db mice were intraperitoneally injected with NaB for 6 weeks. Glucose control was evaluated by glucose tolerance test (GTT) and insulin tolerance test (ITT). Adipose tissue was harvested for gene expression analysis. 3T3-L1 adipocytes were treated with Tnf-α to mimic the inflammatory state and gene expression was detected by realtime PCR and Western blotting. Our results showed that NaB treatment improved glucose control in db/db mice as determined by GTT and ITT tests. Gene expression analysis showed that NaB inhibited cytokines and immunological markers including CD68, Interferon-γ and Mcp in adipose tissues in db/db mice. Moreover, NaB inhibited cytokine releasing in 3T3-L1 adipocytes treated with TNF-α. Further analysis of inflammation pathway showed that NLRP3 was activated in db/db mice, which was efficiently inhibited by NaB treatment. Our data suggest that inhibition of obesity-induced inflammation alleviates IR, and NaB might be a potential anti-inflammatory agent for obesity. PMID:26234821

  13. Observation on the Efficacy of Small Dose of Esmolol Intravenous Pre-injection Alleviating the Reac-tion of Tracheal Intubation for Patients with Hypertension and Coronary Heart Disease%小剂量艾司洛尔预先静脉注射减轻高血压冠心病患者气管插管反应的疗效观察

    Institute of Scientific and Technical Information of China (English)

    王光福; 徐小波; 李河志; 赵辉; 刘绍靖

    2016-01-01

    目的 观察小剂量艾司洛尔预先静脉注射在减轻高血压冠心病患者气管插管反应的作用. 方法 选取2009年2月至2012年10月在武装警察部队四川总队成都医院行全身麻醉手术的高血压冠心病患者60例,根据随机数字表法分为艾司洛尔组和对照组,各30 例. 艾司洛尔组在麻醉插管前5 min给予小剂量艾司洛尔(0.7 mg/kg);对照组仅给予0.9%NaCl注射液,两组麻醉诱导和维持方法相同,分别监测并记录麻醉诱导前、诱导后、插管即刻、插管后1、3、5 min时心率和平均动脉压变化. 结果 对照组插管即刻、插管1、3、5 min 的平均动脉压较诱导前有明显升高[ ( 120 ± 15)mmHg(1 mmHg=0.133 kPa)、(118 ±23) mmHg、(115 ±10) mmHg、(112 ±14) mmHg 比(98 ± 14) mmHg],心率明显增快[(88 ±8)次/min、(94 ±15)次/min、(91 ±10)次/min、(93 ±10)次/min比(76 ±4)次/min],艾司洛尔组的平均动脉压[(101 ±11) mmHg、(104 ±18) mmHg、(101 ± 10) mmHg、(98 ±10) mmHg比(98 ±14) mmHg],心率[(78 ±4)次/min、(81 ±12)次/min、(80 ± 7)次/min、(78 ±5)次/min比(75 ±7)次/min]分别较诱导前有轻度升高,但变化幅度不大. 两组比较差异有统计学意义( P<0.05 ). 结论 小剂量艾司洛尔预先注射能够有效减轻高血压冠心病患者气管插管时的心血管反应.%Objective To observe the effect of intravenous pre-injection of small dose of esmolol on alle-viating the impact of tracheal intubation on patients with hypertension and coronary heart disease .Methods Total of 60 patients with hypertension and coronary heart disease undergoing general anesthesia operations at Chengdu Armed Police Corps Hospital from Feb.2009 to Oct.2012 were selected, and were divide into esmolol group and control group according to random number table method,with 30 patients in each group. The esmolol group was injected with small dose of esmolol(0.7 mg/kg) 5 minutes prior to the anesthetic intubation;the control

  14. Effects of FGF receptor peptide agonists on animal behavior under normal and pathological conditions

    DEFF Research Database (Denmark)

    Rudenko, Olga; Tkach, Vadym; Berezin, Vladimir;

    2010-01-01

    . Employing an R6/2 mouse model of Huntington's disease (HD), we found that although hexafin2 did not affect the progression of motor symptoms, it alleviated deficits in activity related to social behavior, including sociability and social novelty. Thus, hexafin2 may have therapeutic potential for the...

  15. Can Earth Sciences Help Alleviate Global Poverty?

    Science.gov (United States)

    Mutter, J. C.

    2004-12-01

    essential and could hold the key to making gains toward alleviating the burden of global poverty.

  16. Single mothers empowerment through small business development projects in Gweru, Zimbabwe : the case of the GWAPA Poverty Alleviation Programme / Maxwell Constantine Chando Musingafi

    OpenAIRE

    Musingafi, Maxwell

    2008-01-01

    This study sought to evaluate the effectiveness of the GWAPA Single Mothers Poverty alleviation Programme. The study hypothesized that women in Gweru are among the most vulnerable to poverty and disease and GWAPA project may be an effective source to their poverty alleviation. Main objectives of the study were to explain selected development concepts, to explore the relationship between gender and poverty, to investigate the effectiveness of the GWAPA Programme, to outline the challenges face...

  17. Bioanalysis and pharmacokinetics of the dopamine D2 agonist N-0923

    NARCIS (Netherlands)

    Swart, Pieter Jacob

    1992-01-01

    This thesis describes the bioanalysis and pharmacokinetics of the S(-) enantiomer (N-0923) of the selective and potent dopamine D2 agonist 2-(N-propyl-N-2-thienylethyl-amino)-5-hydroxytetralin, N-0437 which has possible applications in the treatment of Parkinson’s disease. The R(+) enantiomer (N-092

  18. Local immunotherapy based on agonistic CD40 antibodies effectively inhibits experimental bladder cancer

    OpenAIRE

    Sandin, Linda C; Tötterman, Thomas H; Sara M. Mangsbo

    2014-01-01

    Local immunotherapy resurfaces in the field of cancer as a potential way to cure localized and metastatic disease with limited toxic effects. We have recently demonstrated that local administration of agonistic CD40 antibodies can cure localized as well as disseminated bladder neoplasms. This approach reduces the circulating concentrations of antibodies that would result from systemic delivery, hence resulting in limited toxicity.

  19. How to alleviate perineal pain following an episiotomy.

    Science.gov (United States)

    Steen, Mary; Cummins, Bernie

    2016-03-30

    Rationale and key points An episiotomy increases maternal morbidity in the postnatal period. Alleviating perineal pain is an important aspect of maternal health care. ▶ A combination of pain relief methods, systemic and localised, may be required to alleviate perineal pain associated with an episiotomy. ▶ It is important that midwives and doctors advise women on how to alleviate perineal pain, prevent infection and promote healing following an episiotomy. Reflective activity Clinical skills articles can help update your practice and ensure it remains evidence based. Apply this article to your practice. Reflect on and write a short account of: 1. The advice you would give to a woman who has recently given birth to alleviate perineal pain. 2. The short and long-term problems associated with perineal pain. Subscribers can upload their reflective accounts at rcni.com/portfolio . PMID:27027195

  20. Cariprazine:New dopamine biased agonist for neuropsychiatric disorders.

    Science.gov (United States)

    De Deurwaerdère, P

    2016-02-01

    Cariprazine (RGH-188, MP-214, Vraylar[TM]) is a new dopamine receptor ligand developed for the treatment of several neuropsychiatric diseases including schizophrenia and bipolar disorders. Cariprazine displays higher affinity at dopamine D3 receptors and a similar affinity at D2 and 5-HT2B receptors. At variance with some atypical antipsychotics, its affinity at 5-HT1A, 5-HT2A and histamine H1 receptors is modest compared with its three main targets. Cariprazine could correspond to a biased agonist at dopamine receptors, displaying either antagonist or partial agonist properties depending on the signaling pathways linked to D2/D3 receptors. The compound crosses the blood-brain barrier, as revealed by positron emission tomography and pharmacokinetic studies in various species. Two main metabolites result mainly from the activity of CYP34A and display properties similar to those of the parent drug. Behavioral data report that cariprazine is efficacious in animal models addressing positive, negative and cognitive symptoms of schizophrenia with no extrapyramidal side effects. In September 2015, the FDA approved the use of cariprazine for the treatment of schizophrenia and type I bipolar disorder. The efficacy of cariprazine in other neuropsychiatric diseases is currently being evaluated in preclinical and clinical studies. Side effects have been observed in humans, including extrapyramidal side effects and akathisia of mild to moderate intensity. PMID:27092339

  1. The potential and the pitfalls of beta-adrenoceptor agonists for the management of skeletal muscle wasting.

    Science.gov (United States)

    Ryall, James G; Lynch, Gordon S

    2008-12-01

    The beta-adrenergic signaling pathway represents a novel therapeutic target for skeletal muscle wasting and weakness due to its role in the mechanisms controlling protein synthesis and degradation and in modulating fiber type. Stimulation of the pathway with beta-adrenoceptor agonists (beta-agonists) has therapeutic potential for muscle wasting disorders including: sarcopenia, cancer cachexia, disuse and inactivity, unloading or microgravity, sepsis and other metabolic disorders, denervation, burns, HIV-AIDS, chronic kidney or heart failure, and neuromuscular diseases. However, there are also pitfalls associated with beta-agonist administration and clinical applications have so far been limited, largely because of cardiovascular side effects. In rats and mice, newer generation beta-agonists (such as formoterol) can elicit an anabolic response in skeletal muscle even at very low doses, with reduced effects on the heart and cardiovascular system compared with older generation beta-agonists (such as fenoterol and clenbuterol). However, the potentially deleterious cardiovascular side effects of beta-agonists have not been obviated completely and so it is important to refine their development and therapeutic approach in order to overcome these obstacles. This review describes the therapeutic potential of stimulating the beta-adrenergic signaling pathway with beta-agonists, highlighting the beneficial effects on skeletal muscle structure and function and identifying some of the pitfalls associated with short- and long-term beta-agonist administration. The review also identifies some important, but as yet unanswered questions, regarding the importance of beta-adrenoceptor signaling in muscle health and disease and the strategies needed to improve the efficacy and safety of beta-agonists for muscle wasting disorders. PMID:18834902

  2. Study of Driving Fatigue Alleviation by Transcutaneous Acupoints Electrical Stimulations

    OpenAIRE

    Fuwang Wang; Hong Wang

    2014-01-01

    Driving fatigue is more likely to bring serious safety trouble to traffic. Therefore, accurately and rapidly detecting driving fatigue state and alleviating fatigue are particularly important. In the present work, the electrical stimulation method stimulating the Láogóng point (劳宫PC8) of human body is proposed, which is used to alleviate the mental fatigue of drivers. The wavelet packet decomposition (WPD) is used to extract θ, α, and β subbands of drivers' electroencephalogram (EEG) signals....

  3. beta2-Agonists at the Olympic Games.

    Science.gov (United States)

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  4. D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice.

    Science.gov (United States)

    Palazzo, Enza; Luongo, Livio; Guida, Francesca; Marabese, Ida; Romano, Rosaria; Iannotta, Monica; Rossi, Francesca; D'Aniello, Antimo; Stella, Luigi; Marmo, Federica; Usiello, Alessandro; de Bartolomeis, Andrea; Maione, Sabatino; de Novellis, Vito

    2016-07-01

    D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. D-Asp also restored the levels of extracellular D-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike D-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that D-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice. PMID:27115160

  5. The discovery of a selective and potent A2a agonist with extended lung retention

    OpenAIRE

    Åstrand, Annika B. M.; Lamm Bergström, Eva; Hui ZHANG; Börjesson, Lena; Söderdahl, Therese; Wingren, Cecilia; Jansson, Anne-Helene; Smailagic, Amir; Johansson, Camilla; Bladh, Håkan; Shamovsky, Igor; Tunek, Anders; Drmota, Tomas

    2015-01-01

    Although the anti-inflammatory role of the A2a receptor is well established, controversy remains with regard to the therapeutic value for A2a agonists in treatment of inflammatory lung diseases, also as a result of unwanted A2a-mediated cardiovascular effects. In this paper, we describe the discovery and characterization of a new, potent and selective A2a agonist (compound 2) with prolonged lung retention and limited systemic exposure following local administration. To support the lead optimi...

  6. Dopamine agonist increases risk taking but blunts reward-related brain activity.

    Directory of Open Access Journals (Sweden)

    Jordi Riba

    Full Text Available The use of D2/D3 dopaminergic agonists in Parkinson's disease (PD may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of the reward system, following unexpected high gains and therefore propose that pathological gambling in PD results from the need to seek higher rewards to overcome the blunted response in this system.

  7. Discovery of biaryls as RORγ inverse agonists by using structure-based design.

    Science.gov (United States)

    Enyedy, Istvan J; Powell, Noel A; Caravella, Justin; van Vloten, Kurt; Chao, Jianhua; Banerjee, Daliya; Marcotte, Douglas; Silvian, Laura; McKenzie, Andres; Hong, Victor Sukbong; Fontenot, Jason D

    2016-05-15

    RORγ plays a critical role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including T cells, γδ T cells, and innate lymphoid cells. RORγ-mediated inflammation has been linked to susceptibility to Crohn's disease, arthritis, and psoriasis. Thus inverse agonists of RORγ have the potential of modulating inflammation. Our goal was to optimize two RORγ inverse agonists: T0901317 from literature and 1 that we obtained from internal screening. We used information from internal X-ray structures to design two libraries that led to a new biaryl series. PMID:27080181

  8. Endogenous Receptor Agonists: Resolving Inflammation

    OpenAIRE

    Gerhard Bannenberg; Makoto Arita; Serhan, Charles N.

    2007-01-01

    Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and ω-3 polyunsa...

  9. Recent advances in the development of farnesoid X receptor agonists.

    Science.gov (United States)

    Ali, Ahmad H; Carey, Elizabeth J; Lindor, Keith D

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  10. Periodontal Probe Improves Exams, Alleviates Pain

    Science.gov (United States)

    2008-01-01

    Dentists, comedian Bill Cosby memorably mused, tell you not to pick your teeth with any sharp metal object. Then you sit in their chair, and the first thing they grab is an iron hook!" Conventional periodontal probing is indeed invasive, uncomfortable for the patient, and the results can vary greatly between dentists and even for repeated measurements by the same dentist. It is a necessary procedure, though, as periodontal disease is the most common dental disease, involving the loss of teeth by the gradual destruction of ligaments that hold teeth in their sockets in the jawbone. The disease usually results from an increased concentration of bacteria in the pocket, or sulcus, between the gums and teeth. These bacteria produce acids and other byproducts, which enlarge the sulcus by eroding the gums and the periodontal ligaments. The sulcus normally has a depth of 1 to 2 millimeters, but in patients with early stages of periodontal disease, it has a depth of 3 to 5 millimeters. By measuring the depth of the sulcus, periodontists can have a good assessment of the disease s progress. Presently, there are no reliable clinical indicators of periodontal disease activity, and the best available diagnostic aid, periodontal probing, can only measure what has already been lost. A method for detecting small increments of periodontal ligament breakdown would permit earlier diagnosis and intervention with less costly and time-consuming therapy, while overcoming the problems associated with conventional probing. The painful, conventional method for probing may be destined for the archives of dental history, thanks to the development of ultrasound probing technologies. The roots of ultrasound probes are in an ultrasound-based time-of-flight technique routinely used to measure material thickness and length in the Nondestructive Evaluation Sciences Laboratory at Langley Research Center. The primary applications of that technology have been for corrosion detection and bolt tension

  11. Effects of glucagon-like peptide-1 receptor agonists on renal function

    Institute of Scientific and Technical Information of China (English)

    Theodosios; D; Filippatos; Moses; S; Elisaf

    2013-01-01

    Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.

  12. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

    Science.gov (United States)

    Sun, Yiyi; Zang, Zhihe; Zhong, Ling; Wu, Min; Su, Qing; Gao, Xiurong; Zan, Wang; Lin, Dong; Zhao, Yan; Zhang, Zhonglin

    2013-01-01

    Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (-)-arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases. PMID:23691032

  13. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

    Directory of Open Access Journals (Sweden)

    Yiyi Sun

    Full Text Available Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (--arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases.

  14. Reciprocity of agonistic support in ravens.

    Science.gov (United States)

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  15. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

    OpenAIRE

    Rogue, Alexandra; Anthérieu, Sébastien; Vluggens, Aurore; Umbdenstock, Thierry; Claude, Nancy; De La Moureyre-Spire, Catherine; Weaver, Richard J; Guillouzo, André

    2014-01-01

    Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various ...

  16. Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists.

    Science.gov (United States)

    Smalley, Terrence L; Boggs, Sharon; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Kaldor, Istvan; Parks, Derek J

    2015-01-15

    The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs. PMID:25499883

  17. Pharmacokinetic and pharmacodynamic characterization of inhaled β2 - agonists using the isolated human lung perfusion model

    OpenAIRE

    Gnadt, Mirjam

    2011-01-01

    The inhaled pharmacotherapy is fundamental in the management of obstructive lung diseases such as asthma bronchiale or chronic obstructive pulmonary disease. In this context short- and long-acting β2-agonists play a prominent role as relieve and control medication. Regarding the risk-benefit profile of an inhaled drug, the pattern of pulmonary deposition and the rate and extent of absorption into systemic circulation are essential parameters. New developments of drugs are characterized by hig...

  18. Immediate haemodynamic effects of a novel partial agonist, beta 1-adrenoceptor blocking drug ICI 141,292 after intravenous administration to healthy young volunteers and patients with ischaemic heart disease

    DEFF Research Database (Denmark)

    Bonde, J; Svendsen, T L; Lyngborg, K;

    1987-01-01

    decreased approximately 8% following all three doses of ICI 141,292 and 14.9% after atenolol 5 mg. No changes in blood pressure were observed under resting conditions after any of the drugs. In six patients with ischaemic heart disease the intrinsic sympathomimetic activity following intravenous...... significant changes were observed in mean arterial blood pressure, stroke volume or total peripheral resistance whereas an increase in supine resting mean pulmonary arterial pressure of 3.4 mm Hg (P less than 0.05) could be demonstrated. ICI 141,292 seems to be a potent (at least five times as potent as...

  19. FXR agonist activity of conformationally constrained analogs of GW 4064

    Energy Technology Data Exchange (ETDEWEB)

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  20. Experimental study of G-CSF alleviating graft-versus-host disease after mixed bone marrow transplantation in mice%粒细胞集落刺激因子减轻混合骨髓移植后移植物抗宿主病的实验研究

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: How to reduce the incidence and severity of acute graft-versus-host disease (aGVHD) is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (allo-BMT). The low incidence of severe aGVHD observed in allogeneic peripheral blood stem cell transplantation (allo-PBSCT), which may be related to modulating immune function of T lymphocytes by granulocyte colony-stimulating factor (G-CSF) primed donors. The study aimed to explore whether aGVHD could be alleviated by syngeneic bone marrow mixed with G-CSF-mobilized H-2 haploidentical marrow grafting. Methods: Female BALB/c mice and neonatal BALB/c mice were recipients and male (BALB/c × C57BL/6)F1(BCF1)mice were donor mice respectively. Donor mice were injected subcutaneously with G-CSF daily at 0.01 μg/g body weight or saline for 6 days, and splenocytes were harvested on day 6. Spleen index (SI) represented GVHD in neonatal mice after the intraperitoneal injection of mixed spleen cells. Lethally irradiated (60Co, 8.5 Gy) adult mice were transplanted with a mixture of syngeneic plus G-CSF-mobilized (control diluents) H-2 haploidentical marrow cells. Survival time and survival rate of the recipients were observed after mixed marrow transplantation (MBMT). GVHD was assessed by observing signs of weight loss, ruffled fur, diarrhea and histological change of skin, liver and small intestines. Enzyme-linked immunosorbent assay (ELISA) method was used to detect cytokines (IL-2, IL-4 and INF-Y). Fluorescence-activated cell sorting (FACS) analysis was used to detect T cells phenotype. Results: (1) The neonatal mice subject to injection of 2:1 and 1:1 mixed spleen cells and H-2 haploidentical spleen cells all suffered from aGVHD. The severity of aGVHD in recipient mice receiving G-CSF-mobilized splenocytes was dramatically reduced. (2) The aGVHD signs and histological change were observed in most mice of 2:1 and 1:1 MBMT groups. However, the survival time of G-CSF-mobilized MBMT was

  1. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon

    2011-01-01

    Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

  2. Research Progress of Tourism-oriented Poverty Alleviation in China

    Institute of Scientific and Technical Information of China (English)

    Guoqing; HUANG; Pengfei; XIE

    2013-01-01

    Through systematic summary of domestic research documents about China’s tourism-oriented poverty alleviation in recent 10 years,it is found that researches mainly focus on 5 aspects:effect of tourism-oriented poverty alleviation,model and development strategy,benefit of poverty stricken people,practice of tourism-oriented poverty alleviation in specific region,and other related problems.At present,academic circle mainly has weak points of research content,method,object and region in tourism-oriented poverty alleviation.Finally,it points out key research interests:(1)Strengthening combination of qualitative and quantitative researches;(2)Expanding research fields and scope and promoting in-depth researches;(3)Analyzing benefiting mechanism of poverty-stricken people participating in tourism development in depth with poverty-stricken people as research objects;(4)Increasing scale development of perception research on effect of tourism-oriented poverty alleviation and research on measurement testing,to make subsequent research have reliability and comparability.

  3. Alleviating anemia and thrombocytopenia in myelofibrosis patients.

    Science.gov (United States)

    Cervantes, Francisco; Correa, Juan-Gonzalo; Hernandez-Boluda, Juan Carlos

    2016-05-01

    Anemia and thrombocytopenia are frequent clinical manifestations of myelofibrosis as well as important prognostic factors of the disease. Concerning the treatment of anemia, the first step should be the correction of reversible contributing factors, such as possible iron, folate and vitamin B12 deficiency. Then, treatment options include erythropoiesis stimulating agents, androgens, immunomodulating drugs, corticosteroids, and splenectomy. Anemia responses may also be observed in some patients treated with JAK inhibitors. However, most patients eventually fail to such therapies and become transfusion dependent. Some of the aforementioned therapies can also improve thrombocytopenia, but the responses are usually observed in patients with moderate platelet count decrease. Allogeneic hematopoietic stem cell transplantation, the only curative treatment of myelofibrosis, can be an alternative for selected patients with cytopenias who are refractory to conventional therapies. However, for the majority of patients, the management of anemia and severe thrombocytopenia remains an unmet need. PMID:26891375

  4. Elevatated CO2 alleviates heat stress tolerance in wheat

    DEFF Research Database (Denmark)

    Kjær, Katrine Heinsvig; Rosenqvist, Eva S. K.; Ottosen, Carl-Otto;

    2014-01-01

    Title: The alleviating effect of elevated CO2 on heat stress susceptibility of two wheat (Triticum aestivum L.) cultivars Session: Plant response and adaptation to abiotic stress Sindhuja Shanmugam1, Katrine Heinsvig Kjaer2*, Carl-Otto Ottosen2, Eva Rosenqvist3, Dew Kumari Sharma3 and Bernd Wolle...... crop performance under various climatic stresses.......Title: The alleviating effect of elevated CO2 on heat stress susceptibility of two wheat (Triticum aestivum L.) cultivars Session: Plant response and adaptation to abiotic stress Sindhuja Shanmugam1, Katrine Heinsvig Kjaer2*, Carl-Otto Ottosen2, Eva Rosenqvist3, Dew Kumari Sharma3 and Bernd......Institute for Agroecology, Aarhus University, Forsøgsvej 1, 4200 Slagelse, Denmark *Presenting author This study analysed the alleviating effect of elevated CO2 on stress-induced decreases in photosynthesis and changes in carbohydrate metabolism in two wheat cultivars (Triticum aestivum L.) of different...

  5. Experimental investigations on wake vortices and their alleviation

    Science.gov (United States)

    Savaş, Ömer

    2005-05-01

    Recent wake vortex research in the laboratory has benefited considerably from concurrent analytical and numerical research on the instability of vortex systems. Tow tank, with dye flow visualization and particle image velocimetry is the most effective combination for laboratory research. Passive and active wake alleviation schemes have been successfully demonstrated in the laboratory. The passive alleviation systems exploit the natural evolution of vortex instabilities while the active systems rely on hastening selected instabilities by forcing the vortices individually or as a system. Their practical applicability, however, will have to meet further criteria beyond those dictated by fluid dynamics. To cite this article: Ö. Savaş, C. R. Physique 6 (2005).

  6. GLP-1 agonists for type 2 diabetes

    DEFF Research Database (Denmark)

    Jespersen, Maria J; Knop, Filip K; Christensen, Mikkel

    2013-01-01

    Within recent years, glucagon-like peptide 1 receptor agonists (GLP-1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles. AREAS COVERED: This review describes the pharmacokinetics and...... safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches...... and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration. EXPERT OPINION: GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes and...

  7. Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain.

    Science.gov (United States)

    Seltzman, Herbert H; Shiner, Craig; Hirt, Erin E; Gilliam, Anne F; Thomas, Brian F; Maitra, Rangan; Snyder, Rod; Black, Sherry L; Patel, Purvi R; Mulpuri, Yatendra; Spigelman, Igor

    2016-08-25

    Alleviation of neuropathic pain by cannabinoids is limited by their central nervous system (CNS) side effects. Indole and indene compounds were engineered for high hCB1R affinity, peripheral selectivity, metabolic stability, and in vivo efficacy. An epithelial cell line assay identified candidates with <1% blood-brain barrier penetration for testing in a rat neuropathy induced by unilateral sciatic nerve entrapment (SNE). The SNE-induced mechanical allodynia was reversibly suppressed, partially or completely, after intraperitoneal or oral administration of several indenes. At doses that relieve neuropathy symptoms, the indenes completely lacked, while the brain-permeant CB1R agonist HU-210 (1) exhibited strong CNS side effects, in catalepsy, hypothermia, and motor incoordination assays. Pharmacokinetic findings of ∼0.001 cerebrospinal fluid:plasma ratio further supported limited CNS penetration. Pretreatment with selective CB1R or CB2R blockers suggested mainly CB1R contribution to an indene's antiallodynic effects. Therefore, this class of CB1R agonists holds promise as a viable treatment for neuropathic pain. PMID:27482723

  8. Response of Macroprolactinemia to Dopamine Agonists

    Directory of Open Access Journals (Sweden)

    Gonca Tamer

    2008-01-01

    Full Text Available Macroprolactinemia, defined as hyperprolactinemia with a predominance of the big big prolactin (macroprolactin isoform, is considered idiopathic and poorly symptomatic. Although macroprolactinemia has been considered to be a cause of apparent resistance to antiprolactinemic drugs, prolactin (PRL normalization with dopaminergic treatment cannot exclude macroprolactinemia.We report three cases with macroprolactinemia, whose PRL and macroprolactin levels were decreased and hyperprolactinemic symptoms were improved with dopamine agonists. Turk Jem 2008; 12: 83-5

  9. Signal Use by Octopuses in Agonistic Interactions.

    Science.gov (United States)

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  10. Treatment of Parkinson's disease.

    OpenAIRE

    Aminoff, M J

    1994-01-01

    Pharmacotherapy with levodopa for Parkinson's disease provides symptomatic benefit, but fluctuations in (or loss of) response may eventually occur. Dopamine agonists are also helpful and, when taken with low doses of levodopa, often provide sustained benefit with fewer side effects; novel agonists and new methods for their administration are therefore under study. Other therapeutic strategies are being explored, including the use of type B monoamine oxidase inhibitors to reduce the metabolic ...

  11. Alleviation Effects of Rare Earth on Cd Stress to Rape

    Institute of Scientific and Technical Information of China (English)

    马建军; 张淑侠; 朱京涛; 吴贺平

    2004-01-01

    Using rapes as test materials, the fastness expression and alleviation effect of rapes were studied under Cd stress condition, as the rapeseeds were dipped in the single element(La, Ce, Nd, Pr)and mixed rare earth(RE). The results indicate that, under Cd stress, the dry and fresh weight are increased by both the single element and mixed rare earth treatment, and the fastness of rape is improved.The single element of rare earth decreases the Cd content in rape roots and transmits Cd to the edible parts above the ground in which the alleviation effect of Ce is most significant.La treatment takes the second place, so that the poisonous effect of heavy metal Cd is eased.The mixed rare earth doesn't alleviate the assimilation of Cd in rape roots, but accelerates the transfer of Cd to the parts above the ground. The research puts forward that the alleviation of rare earth on Cd stress has connection with the decrease of Ca content.

  12. Urban agriculture and urban poverty alleviation: South African debates

    OpenAIRE

    Christian M. Rogerson

    1998-01-01

    Growing international attention has focussed on the potential role of urban agriculture in poverty alleviation. The aim in this paper is to analyse the existing challenge of urban poverty in South Africa and examine the potential role of urban agriculture as a component of a pro-poor urban development strategy.

  13. Alleviating Stress in Parents of High-Risk Preterm Infants.

    Science.gov (United States)

    Lowenthal, Barbara

    1989-01-01

    Possible sources of stress for parents of preterm high-risk infants are reviewed from a research perspective. Stages of parental attachment to their premature baby are spelled out. Strategies for special education teachers to use in alleviating parental stress are described. (JDD)

  14. Elder Abuse and Neglect Risk Alleviation in Protective Services.

    Science.gov (United States)

    Burnes, David P R; Rizzo, Victoria M; Courtney, Erin

    2014-01-01

    Little is known about conditions associated with favorable elder mistreatment (EM) case outcomes. The fundamental goal of EM protective service programs is to alleviate risk associated with substantiated cases of elder abuse and neglect. Using the EM socio-cultural model, this study examined victim, perpetrator, victim-perpetrator relationship, social embeddedness, and socio-cultural factors predicting risk alleviation of EM cases. Data from a random sample of EM protective social service cases (n = 250) at a large community agency in New York City were collected and coded by multiple, independent raters. Multinomial and binary logistic regression were used to examine undifferentiated risk alleviation for the entire sample of EM cases as well as differentiated financial, emotional, and physical abuse sub-types. Undifferentiated EM risk alleviation was associated with male victim gender, older victim age, previous community help-seeking, and victim-perpetrator dyads characterized by a separate living arrangement and shorter term abuse longevity. Financial abuse cases with younger perpetrators were less likely to have risk reduction. Physical abuse risk reduction was less likely when the perpetrator was male and the victim-perpetrator dyad included different genders. Distinct findings across EM sub-types suggest a need to develop targeted practice strategies with clients experiencing different forms of EM. Findings highlight a need to develop EM protective service infrastructure around perpetrator rehabilitation. PMID:24407144

  15. Training Teachers as Key Players in Poverty Alleviation

    Science.gov (United States)

    Benavente, Ana; Ralambomanana, Stangeline; Mbanze, Jorge

    2008-01-01

    This article presents several questions, reflections and suggestions on pre-service and in-service teacher training that arose during the project "Curricular innovation and poverty alleviation in sub-Saharan Africa". While recognizing that the situation in the nine countries taking part in the project, and in many other countries in the southern…

  16. Mapping the effects of three dopamine agonists with different dyskinetogenic potential and receptor selectivity using pharmacological functional magnetic resonance imaging.

    Science.gov (United States)

    Delfino, Marina; Kalisch, Raffael; Czisch, Michael; Larramendy, Celia; Ricatti, Jimena; Taravini, Irene R E; Trenkwalder, Claudia; Murer, Mario Gustavo; Auer, Dorothee P; Gershanik, Oscar S

    2007-09-01

    The mechanisms underlying dopamine agonist-induced dyskinesia in Parkinson's disease remain poorly understood. Similar to patients, rats with severe nigrostriatal degeneration induced by 6-hydroxydopamine are more likely to show dyskinesia during chronic treatment with unselective dopamine receptor agonists than with D2 agonists, suggesting that D1 receptor stimulation alone or in conjunction with D2 receptor stimulation increases the chances of experiencing dyskinesia. As a first step towards disclosing drug-induced brain activation in dyskinesia, we examined the effects of dopamine agonists on behavior and blood oxygenation level-dependent (BOLD) signal in the striatum and motor cortex of rats with unilateral nigrostriatal lesions. Rats were rendered dyskinetic before pharmacologic functional magnetic resonance imaging by means of a repeated treatment regime with dopamine agonists. The unselective agonist apomorphine and the selective D1/D5 agonist SKF-81297 induced strong forelimb dyskinesia (FD) and axial dystonia and increased BOLD signal in the denervated striatum. Besides, SKF-81297 produced a significant but smaller BOLD increase in the intact striatum and a symmetric bilateral increase in the motor cortex. The D2 family agonist quinpirole, which induced mild dyskinesia on chronic treatment, did not produce BOLD changes in the striatum or motor cortex. Further evidence to support an association between BOLD changes and dyskinesia comes from a direct correlation between scores of FD and magnitude of drug-induced BOLD increases in the denervated striatum and motor cortex. Our results suggest that striatal and cortical activation induced by stimulation of D1/D5 receptors has a primary role in the induction of peak dose dyskinesia in parkinsonism. PMID:17287822

  17. Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics

    Directory of Open Access Journals (Sweden)

    Liu L

    2013-04-01

    Full Text Available Lei Liu,1 Ying Ma,2 Run-Ling Wang,2 Wei-Ren Xu,3 Shu-Qing Wang,2,5 Kuo-Chen Chou4,5 1PET/CT Center, General Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 2Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics, School of Pharmacy, Tianjin Medical University, Tianjin, People’s Republic of China; 3Tianjin Institute of Pharmaceutical Research (TIPR, Tianjin, People’s Republic of China; 4Center of Excellence in Genomic Medicine Research (CEGMR, King Abdulaziz University, Jeddah, Saudi Arabia; 5Gordon Life Science Institute, Belmont, MA, USA Abstract: The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPARα agonists (such as fibrates and the glycemic advantages of the PPARγ agonists (such as thiazolidinediones, are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type

  18. Alleviation and prevention of severe allergic rhinitis and conjunctivitis following long-term lemon juice use: a case report

    OpenAIRE

    Vazouras, Konstantinos GI; Partheniou, Jota; Dimoliatis, Ioannis DK

    2009-01-01

    Allergic rhinitis (often coexisting with allergic conjunctivitis) is a highly prevalent, chronic, inflammatory disease. Most cases are not extraordinary; however, they may result in significant impairment in quality of life of patients, as well as in economical damage for both health-care system and patients. This case report describes the experiences of a middle-aged woman with the illness, who managed to completely alleviate and prevent her symptoms, in terms of intensity and chronicity, by...

  19. Enhanced proteasome degradation extends Caenorhabditis elegans lifespan and alleviates aggregation-related pathologies.

    Science.gov (United States)

    Chondrogianni, Niki; Georgila, Konstantina; Kourtis, Nikos; Tavernarakis, Nektarios; Gonos Efstathios, S

    2014-10-01

    Collapse of proteostasis and accumulation of damaged macromolecules have been recognized as hallmarks of aging and age-related diseases. The proteasome is the major cellular protease responsible for intracellular protein degradation, having an impaired function during aging. We have previously shown that proteasome activation through overexpression of β5 proteasome subunit delays replicative senescence and confers resistance to oxidative stress in primary fibroblasts. Herein, we have investigated the impact of enhanced proteasome function on organismal longevity and aggregation-related pathologies by employing Caenorhabditis elegans as a model system. We have found that overexpression of a core 20S proteasome subunit in wild type worms extends lifespan, healthspan and survival under proteotoxic conditions. The longevity prolonging effect of the proteasome subunit overexpression was found to depend on the FOXO transcription factor DAF-16 and was associated with its elevated transcriptional activity. We have also uncovered a major role of enhanced proteasome activity in aggregation-related pathologies underlying neurodegenerative diseases. Genetic activation of the proteasome minimized the detrimental effect of polyglutamine-induced toxicity mimicking Huntington's disease, whereas knock-down of the proteasome component exaggerated the disease phenotypes. Similar results were obtained by using a C.elegans model of Amyloid beta (Αβ) -induced toxicity mimicking Alzheimer's disease. Collectively, these findings demonstrate that enhanced proteasome function alleviates proteotoxicity and promotes longevity in synergy with other nodes of lifespan regulation in C.elegans. Understanding the mechanism by which preservation of proteostasis via enhancement of proteasome function, decelerates the aging process and alleviates age-related pathologies may assist in the rational design of therapeutic and anti-aging interventions. PMID:26461298

  20. New Insights into the PPAR γ Agonists for the Treatment of Diabetic Nephropathy.

    Science.gov (United States)

    Jia, Zhanjun; Sun, Ying; Yang, Guangrui; Zhang, Aihua; Huang, Songming; Heiney, Kristina Marie; Zhang, Yue

    2014-01-01

    Diabetic nephropathy (DN) is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs), the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor- γ (PPAR γ ), had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPAR γ agonists involving the endogenous PPAR γ ligands and selective PPAR γ modulators (SPPARMs) are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPAR γ agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPAR γ agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPAR γ agonists were fully addressed. PMID:24624137

  1. New Insights into the PPARγ Agonists for the Treatment of Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Zhanjun Jia

    2014-01-01

    Full Text Available Diabetic nephropathy (DN is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs/angiotensin II receptor blockers (ARBs based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs, the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ, had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPARγ agonists involving the endogenous PPARγ ligands and selective PPARγ modulators (SPPARMs are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPARγ agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPARγ agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPARγ agonists were fully addressed.

  2. Regulation of Glial Cell Functions by PPAR-γ Natural and Synthetic Agonists

    Directory of Open Access Journals (Sweden)

    Luisa Minghetti

    2008-04-01

    Full Text Available In the recent years, the peroxisome proliferator-activated receptor-γ (PPAR-γ, a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR-γ agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Δ12,14 prostaglandin J2, and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory drugs have shown anti-inflammatory and protective effects in several experimental models of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR-γ agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes, as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR-γ agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation.

  3. Physiological Responses to Acute Psychological Stress Are Reduced by the PPARγ Agonist Rosiglitazone

    OpenAIRE

    Ryan, Karen K.; Grayson, Bernadette E.; Jones, Kenneth R.; Schneider, Alexander L.; Woods, Stephen C.; Seeley, Randy J.; Herman, James P.; Ulrich-Lai, Yvonne M.

    2012-01-01

    Physiological reactions to psychological stress are positively associated with several important chronic conditions including cardiovascular and neurodegenerative diseases and are linked to increased mortality. As such, the identification of cellular and molecular pathways that act to reduce stress responding may represent important targets for therapeutic intervention. Here we report that acute treatment with the peroxisome-proliferator activated receptor-γ (PPARγ) agonist rosiglitazone (RSG...

  4. Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo.

    OpenAIRE

    FALLON, PADRAIC

    2014-01-01

    OBJECTIVE: Bile acids are important regulators of intestinal physiology, and the nuclear bile acid receptor, farnesoid X receptor (FXR), is emerging as a promising therapeutic target for several intestinal disorders. Here, we investigated a role for FXR in regulating intestinal fluid and electrolyte transport and the potential for FXR agonists in treating diarrhoeal diseases. DESIGN: Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped ...

  5. A synthetic cannabinoid agonist promotes oligodendrogliogenesis during viral encephalitis in rats

    OpenAIRE

    Solbrig, Marylou V.; Fan, Yijun; Hermanowicz, Neal; Morgese, Maria Grazia; Giuffrida, Andrea

    2010-01-01

    Chronic CNS infection by several families of viruses can produce deficits in prefrontal cortex (PFC) and striatal function. Cannabinoid drugs have been long known for their anti-inflammatory properties and their ability to modulate adult neuro and gliogenesis. Therefore, we explored the effects of systemic administration of the cannabinoid agonist WIN55,212-2(WIN) on prefrontal cortex(PFC) and striatal cytogenesis in a viral model of CNS injury and inflammation based on Borna Disease (BD) vir...

  6. Combined Effect of AMPK/PPAR Agonists and Exercise Training in mdx Mice Functional Performance

    OpenAIRE

    Carlos R. Bueno Júnior; Pantaleão, Lucas C; Voltarelli, Vanessa A.; Bozi, Luiz Henrique M.; Brum, Patricia Chakur; Zatz, Mayana

    2012-01-01

    The present investigation was undertaken to test whether exercise training (ET) associated with AMPK/PPAR agonists (EM) would improve skeletal muscle function in mdx mice. These drugs have the potential to improve oxidative metabolism. This is of particular interest because oxidative muscle fibers are less affected in the course of the disease than glycolitic counterparts. Therefore, a cohort of 34 male congenic C57Bl/10J mdx mice included in this study was randomly assigned into four groups:...

  7. A novel potent Fas agonist for selective depletion of tumor cells in hematopoietic transplants

    OpenAIRE

    Nahimana, A; AUBRY, D.; Lagopoulos, L; Greaney, P.; Attinger, A; Demotz, S; Dawson, K. M.; Schapira, M; Tschopp, J; Dupuis, M.; Duchosal, M A

    2011-01-01

    There remains a clear need for effective tumor cell purging in autologous stem cell transplantation (ASCT) where residual malignant cells within the autograft contribute to disease relapse. Here we propose the use of a novel Fas agonist with potent pro-apoptotic activity, termed MegaFasL, as an effective ex-vivo purging agent. MegaFasL selectively kills hematological cancer cells from lymphomas and leukemias and prevents tumor development at concentrations that do not reduce the functional ca...

  8. Subtype selective kainic acid receptor agonists

    DEFF Research Database (Denmark)

    Bunch, Lennart; Krogsgaard-Larsen, Povl

    2009-01-01

    (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors ....... In total, over 100 compounds are described by means of chemical structure and available pharmacological data. With this perspective review, it is our intention to ignite and stimulate inspiration for future design and synthesis of novel subtype selective KA receptor agonists....

  9. Rapamycin-mediated CD36 translational suppression contributes to alleviation of hepatic steatosis.

    Science.gov (United States)

    Wang, Chuan; Yan, Yong; Hu, Lin; Zhao, Lei; Yang, Ping; Moorhead, John F; Varghese, Zac; Chen, Yaxi; Ruan, Xiong Z

    2014-04-25

    Rapamycin, a mammalian target of rapamycin (mTOR)-specific inhibitor, has the effect of anti-lipid deposition on non-alcoholic fatty liver disease (NAFLD), but the mechanisms with which rapamycin alleviates hepatic steatosis are not fully disclosed. CD36 is known to facilitate long-chain fatty acid uptake and contribute to NAFLD progression. Hepatic CD36 expression is closely associated with hepatic steatosis, while mTOR pathway is involved in CD36 translational control. This study was undertaken to investigate whether rapamycin alleviates hepatic steatosis via the inhibition of mTOR pathway-dependent CD36 translation. Human hepatoblastoma HepG2 cells were treated with palmitate and C57BL/6J mice were fed with high fat diet (HFD) to induce hepatic steatosis. Hepatic CD36 protein expression was significantly increased with lipid accumulation in palmitate-treated HepG2 cells or HFD-fed C57BL/6J mice. Rapamycin reduced hepatic steatosis and CD36 protein expression, but it had no influence on CD36 mRNA expression. Rapamycin had no effect on CD36 protein stability, but it significantly decreased CD36 translational efficiency. We further confirmed that rapamycin inhibited the phosphorylation of mTOR and its downstream translational regulators including p70 ribosomal protein S6 kinase (p70S6K), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and eukaryotic initiation factor 4E (eIF4E). This study demonstrates that rapamycin inhibits hepatic CD36 translational efficiency through the mTOR pathway, resulting in reduction of CD36 protein expression and alleviation of hepatic steatosis. PMID:24685479

  10. Parkinson's disease.

    OpenAIRE

    Wolters, E C; Calne, D. B.

    1989-01-01

    In Parkinson's disease there is degeneration of neurons in the substantia nigra, with consequent depletion of the neurotransmitter dopamine. The triad of tremor, rigidity and bradykinesia is the clinical hallmark. Drugs currently used for palliative therapy fall into three categories: anticholinergic agents, dopamine precursors (levodopa combined with extracerebral decarboxylase inhibitors) and artificial dopamine agonists. It has been argued, on theoretical grounds, that some drugs slow the ...

  11. Load alleviation of wind turbines by yaw misalignment

    DEFF Research Database (Denmark)

    Kragh, Knud Abildgaard; Hansen, Morten Hartvig

    2014-01-01

    Vertical wind shear is one of the dominating causes of load variations on the blades of a horizontal axis wind turbine. To alleviate the varying loads, wind turbine control systems have been augmented with sensors and actuators for individual pitch control. However, the loads caused by a vertical...... wind shear can also be affected through yaw misalignment. Recent studies of yaw control have been focused on improving the yaw alignment to increase the power capture at below rated wind speeds. In this study, the potential of alleviating blade load variations induced by the wind shear through yaw...... applied without power loss for wind speeds above rated wind speed. In deterministic inflow, it is shown that the range of the steady-state blade load variations can be reduced by up to 70%. For turbulent inflows, it is shown that the potential blade fatigue load reductions depend on the turbulence level...

  12. The Role of Forests in Poverty Alleviation: Dealing with Multiple Millennium Development Goals

    NARCIS (Netherlands)

    Wiersum, K.F.; Ros-Tonen, Mirjam A.F.

    2005-01-01

    This policy brief summarises the present state of scientific understanding of the potential contribution of tropical forests to poverty alleviation and highlights the implications of this knowledge for forest-based poverty alleviation policies

  13. A Comprehensive Robust Adaptive Controller for Gust Load Alleviation

    OpenAIRE

    Elisa Capello; Giorgio Guglieri; Fulvia Quagliotti

    2014-01-01

    The objective of this paper is the implementation and validation of an adaptive controller for aircraft gust load alleviation. The contribution of this paper is the design of a robust controller that guarantees the reduction of the gust loads, even when the nominal conditions change. Some preliminary results are presented, considering the symmetric aileron deflection as control device. The proposed approach is validated on subsonic transport aircraft for different mass and flight conditions. ...

  14. ANTIANGIOGENESIS STRATEGIES REVISITED: FROM STARVING TUMORS TO ALLEVIATING HYPOXIA

    OpenAIRE

    Jain, Rakesh K.

    2014-01-01

    Ten antiangiogenic drugs targeting VEGF or its receptors are approved for cancer treatment. However, these agents, intended to block tumors’ blood supply, may cause hypoxia, which may fuel tumor progression and treatment resistance. Emerging clinical data suggest that patients whose tumor perfusion or oxygenation increases in response to these agents may actually survive longer. Hence, strategies aimed at alleviating tumor hypoxia while improving perfusion may enhance the outcome of radiother...

  15. A reconceptualization of social value creation as social constraint alleviation

    OpenAIRE

    Sinkovics, Noemi; Rudolf R Sinkovics; Hoque, Samia; Czaban, Laszlo; Sinkovics, Noemi; Sinkovics, Rudolf R; Hoque, Samia; Czaban, Laszlo

    2015-01-01

    Purpose: This paper has two interconnected objectives. The first is to provide a reconceptualisation of social value creation as social constraint alleviation. The second is to respond to the call put forward by Giuliani and Macchi (2014) to produce synergies between bodies of literature exploring the development impact of businesses. The paper focuses on ideas from the global value chain/global production networks (GVC/GPN), business and human rights, corporate social responsibility (CSR), ...

  16. Active control landing gear for ground loads alleviation

    Science.gov (United States)

    Mcgehee, J. R.

    1985-01-01

    An active landing gear has been created by connecting the hydraulic piston in an oleo strut to a hydraulic supply. A controller modulates the pressure in the oleo to achieve the desired dynamic characteristics. Tests on ground rigs (documented by a film) have demonstrated the successful alleviation of induced structural ground loads and the next step will be a flight test using a fighter aircraft.

  17. Factors Influencing Poverty Alleviation amongst Microfinance Adopting Households in Zambia

    Directory of Open Access Journals (Sweden)

    Mavhungu Abel Mafukata

    2016-01-01

    Full Text Available The main objective of this paper is to investigate the factors having the most influence on the alleviation of poverty amongst the households adopting microfinance in Zambia. Ninety nine (n=99 respondents were randomly and purposively selected from amongst 340 microfinance adopters of the so-called Micro Bankers Trust programme operating a microfinance business in the Makululu Compound of Kabwe, Zambia. Socio-demographic primary data were collected through face-to-face interviews based on a semi-structured questionnaire instrument. The data were entered into an excel spreadsheet for analysis. The descriptive data were thereafter exported and fitted to an empirical model. The descriptive results revealed that the majority of the respondents were married, unemployed, fairly educated younger women from larger-sized poor households who drew their household income mainly from microfinance activities. The majority of the respondents thought microfinance had improved their well-being in some crucial areas. The results of the empirical model found that some respondents were indeed alleviated from poverty through microfinance. Conclusion drawn in this paper is that microfinance does alleviate poverty of the poor.

  18. Coronatine alleviates water deficiency stress on winter wheat seedlings.

    Science.gov (United States)

    Li, Xiangwen; Shen, Xuefeng; Li, Jianmin; Eneji, Anthony Egrinya; Li, Zhaohu; Tian, Xiaoli; Duan, Liusheng

    2010-07-01

    With the aim to determine whether coronatine (COR) alleviates drought stress on wheat, two winter wheat (Triticum aestivum L.) cultivars, ChangWu134 (drought-tolerant) and Shan253 (drought-sensitive) were studied under hydroponic conditions. Seedlings at the three-leaf stage were cultured in a Hoagland solution containing COR at 0.1 microM for 24 h, and then exposed to 20% polyethylene glycol 6000 (PEG-6000). Under simulated drought (SD), COR increased the dry weight of shoots and roots of the two cultivars significantly; the root/shoot ratio also increased by 30% for Shan253 and 40% for ChangWu134. Both cultivars treated with COR under SD (0.1COR+PEG) maintained significantly higher relative water content, photosynthesis, transpiration, intercellular concentration of CO(2) and stomatal conductance in leaves than those not treated with PEG. Under drought, COR significantly decreased the relative conductivity and malondialdehyde production, and the loss of 1,1-diphenyl-2-picrylhydrazyl scavenging activity in leaves was significantly alleviated in COR-treated plants. The activity of peroxidase, catalase, glutathione reductase and ascorbate peroxidase were adversely affected by drought. Leaves of plants treated with COR under drought produced less abscisic acid (ABA) than those not treated. Thus, COR might alleviate drought effects on wheat by reducing active oxygen species production, activating antioxidant enzymes and changing the ABA level. PMID:20590992

  19. Environmental stresses can alleviate the average deleterious effect of mutations

    Directory of Open Access Journals (Sweden)

    Leibler Stanislas

    2003-05-01

    Full Text Available Abstract Background Fundamental questions in evolutionary genetics, including the possible advantage of sexual reproduction, depend critically on the effects of deleterious mutations on fitness. Limited existing experimental evidence suggests that, on average, such effects tend to be aggravated under environmental stresses, consistent with the perception that stress diminishes the organism's ability to tolerate deleterious mutations. Here, we ask whether there are also stresses with the opposite influence, under which the organism becomes more tolerant to mutations. Results We developed a technique, based on bioluminescence, which allows accurate automated measurements of bacterial growth rates at very low cell densities. Using this system, we measured growth rates of Escherichia coli mutants under a diverse set of environmental stresses. In contrast to the perception that stress always reduces the organism's ability to tolerate mutations, our measurements identified stresses that do the opposite – that is, despite decreasing wild-type growth, they alleviate, on average, the effect of deleterious mutations. Conclusions Our results show a qualitative difference between various environmental stresses ranging from alleviation to aggravation of the average effect of mutations. We further show how the existence of stresses that are biased towards alleviation of the effects of mutations may imply the existence of average epistatic interactions between mutations. The results thus offer a connection between the two main factors controlling the effects of deleterious mutations: environmental conditions and epistatic interactions.

  20. EFFECTS OF SILICON ON ALLEVIATING ARSENIC TOXICITY IN MAIZE PLANTS

    Directory of Open Access Journals (Sweden)

    Airon José da Silva

    2015-02-01

    Full Text Available Arsenic is a metalloid highly toxic to plants and animals, causing reduced plant growth and various health problems for humans and animals. Silicon, however, has excelled in alleviating stress caused by toxic elements in plants. The aim of this study was to investigate the effects of Si in alleviating As stress in maize plants grown in a nutrient solution and evaluate the potential of the spectral emission parameters and the red fluorescence (Fr and far-red fluorescence (FFr ratio obtained in analysis of chlorophyll fluorescence in determination of this interaction. An experiment was carried out in a nutrient solution containing a toxic rate of As (68 μmol L-1 and six increasing rates of Si (0, 0.25, 0.5, 1.0, 1.5, and 2.0 mmol L-1. Dry matter production and concentrations of As, Si, and photosynthetic pigments were then evaluated. Chlorophyll fluorescence was also measured throughout plant growth. Si has positive effects in alleviating As stress in maize plants, evidenced by the increase in photosynthetic pigments. Silicon application resulted in higher As levels in plant tissue; therefore, using Si for soil phytoremediation may be a promising choice. Chlorophyll fluorescence analysis proved to be a sensitive tool, and it can be successfully used in the study of the ameliorating effects of Si in plant protection, with the Fr/FFr ratio as the variable recommended for identification of temporal changes in plants.

  1. Time and space profiling of NMDA receptor co-agonist functions.

    Science.gov (United States)

    Mothet, Jean-Pierre; Le Bail, Matildé; Billard, Jean-Marie

    2015-10-01

    The N-Methyl D-Aspartic acid (NMDA) receptors (NMDAR) are key tetrameric ionotropic glutamate receptors that transduce glutamatergic signals throughout the central nervous system (CNS) and spinal cord. Although NMDARs are diverse in their subunit composition, subcellular localization, and biophysical and pharmacological properties, their activation always requires the binding of a co-agonist that has long been thought to be glycine. However, intense research over the last decade has challenged this classical model by showing that another amino acid, d-serine, is the preferential co-agonist for a subset of synaptic NMDARs in many areas of the adult brain. Nowadays, a totally new picture of glutamatergic synapses at work is emerging where both glycine and d-serine are involved in a complex interplay to regulate NMDAR functions in the CNS following time and space constraints. The purpose of this review was to highlight the particular role of each co-agonist in modulating NMDAR-dependent activities in healthy and diseased brains. We have herein integrated our most advanced knowledge of how glycine and d-serine may orchestrate synapse dynamics and drive neuronal network activity in a time- and synapse-specific manner and how changes in synaptic availability of these amino acids may contribute to cognitive impairments such as those associated with healthy aging, epilepsy, and schizophrenia. The N-Methyl D-Aspartic acid (NMDA) subtype of glutamate receptors are central to many physiological functions and are linked to brain disorders. Their functions require glutamate and a co-agonist d-serine or glycine. After years of intense research and controversy on the identity of the amino acid that serves as the right co-agonist, we are just entering a new era of consensus where glycine and d-serine are teaming up to regulate the function of different subsets of NMDA receptors and at different synapses during different time windows of brain development. PMID:26088787

  2. Specific immunotherapy plus Clostridium butyricum alleviates ulcerative colitis in patients with food allergy.

    Science.gov (United States)

    Bin Lan; Yang, Fan; Lu, Dong; Lin, Zhenlv

    2016-01-01

    The aberrant T cell activation plays an important role in the pathogenesis of intestinal inflammation, such as ulcerative colitis (UC). C. butyricum (Cb) is a probiotic and has been employed in the treatment of immune diseases. This study tests a hypothesis that specific immunotherapy (SIT) plus oral Cb (an over-the-counter probiotic) alleviates the UC symptoms. In this study, we conducted a randomized, double-blind, clinical study at our hospital. A total of 80 patients with relapsing-remitting ulcerative colitis and high levels of specific IgE antibody was randomly divided into 4 groups, and were treated with SIT or/and Cb, or placebo, respectively for 1 year. The results showed that a food antigen-specific Th2 polarization immune response was observed in UC patients with food allergy (FA). The frequency of regulatory B cells was significantly less in UC patients with FA as compared with healthy subjects. The UC patients with FA were treated with SIT and Cb showed significant amelioration of UC clinical symptoms, reduction of using UC-control medicines, and suppression of the skewed Th2 polarization, which did not occur in those treated with either SIT alone, or Cb alone, or placebo. In conclusion, combination of SIT and Cb efficiently alleviates a fraction of UC patients. PMID:27167186

  3. A Probiotic Preparation Alleviates Atopic Dermatitis-Like Skin Lesions in Murine Models.

    Science.gov (United States)

    Kim, Min-Soo; Kim, Jin-Eung; Yoon, Yeo-Sang; Seo, Jae-Gu; Chung, Myung-Jun; Yum, Do-Young

    2016-04-01

    Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex etiology that encompasses immunologic responses. AD is frequently associated with elevated immunoglobulin (Ig) E levels, and common environmental factors contribute to its pathogenesis. Several recent studies have documented the role of specific lactic acid bacteria in the treatment and prevention of AD in humans and mice. In this study, the efficacy of Duolac ATP, a probiotic preparation, was determined in a mouse model with AD-like skin lesions. Alterations in the cytokine levels and histological staining suggested the alleviation of AD. The in vivo test showed that T helper (Th)2 cytokines, IgE, interleukin (IL)-4, and IL-5, were significantly downregulated, whereas Th1 cytokines, IL-12p40 and interferon (IFN)-γ, were upregulated in all groups of mice treated with Duolac ATP compared to that observed in the group of mice treated with 1-chloro-2,4-dinitrobenzene (DNCB) alone. Moreover, the scratch score decreased in all mice treated with Duolac ATP. Staining of the dorsal area of the mice in each group with hematoxylin and eosin and toluidine blue further confirmed the alleviation of AD in mice orally treated with Duolac ATP. These results suggest that Duolac ATP inhibits the development of AD-like skin lesions in NC/Nga mice by suppressing the Th2 cell response and increasing the Th1 cell response. Thus, Duolac ATP is beneficial and effective for the treatment of AD-like skin lesions. PMID:27123166

  4. A Probiotic Preparation Alleviates Atopic Dermatitis-Like Skin Lesions in Murine Models

    Science.gov (United States)

    Kim, Min-Soo; Kim, Jin-Eung; Yoon, Yeo-Sang; Seo, Jae-Gu; Chung, Myung-Jun; Yum, Do-Young

    2016-01-01

    Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex etiology that encompasses immunologic responses. AD is frequently associated with elevated immunoglobulin (Ig) E levels, and common environmental factors contribute to its pathogenesis. Several recent studies have documented the role of specific lactic acid bacteria in the treatment and prevention of AD in humans and mice. In this study, the efficacy of Duolac ATP, a probiotic preparation, was determined in a mouse model with AD-like skin lesions. Alterations in the cytokine levels and histological staining suggested the alleviation of AD. The in vivo test showed that T helper (Th)2 cytokines, IgE, interleukin (IL)-4, and IL-5, were significantly downregulated, whereas Th1 cytokines, IL-12p40 and interferon (IFN)-γ, were upregulated in all groups of mice treated with Duolac ATP compared to that observed in the group of mice treated with 1-chloro-2,4-dinitrobenzene (DNCB) alone. Moreover, the scratch score decreased in all mice treated with Duolac ATP. Staining of the dorsal area of the mice in each group with hematoxylin and eosin and toluidine blue further confirmed the alleviation of AD in mice orally treated with Duolac ATP. These results suggest that Duolac ATP inhibits the development of AD-like skin lesions in NC/Nga mice by suppressing the Th2 cell response and increasing the Th1 cell response. Thus, Duolac ATP is beneficial and effective for the treatment of AD-like skin lesions. PMID:27123166

  5. Functional potencies of dopamine agonists and antagonists at human dopamine D₂ and D₃ receptors.

    Science.gov (United States)

    Tadori, Yoshihiro; Forbes, Robert A; McQuade, Robert D; Kikuchi, Tetsuro

    2011-09-01

    We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with

  6. Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats

    DEFF Research Database (Denmark)

    Thomsen, Morten Skøtt; El-Sayed, Mona; Mikkelsen, Jens D

    2011-01-01

    The α7 nicotinic acetylcholine receptor (nAChR) is a potential target for the treatment of cognitive deficits in patients with schizophrenia, ADHD and Alzheimer's disease. Here we test the hypothesis that upregulation of α7 nAChR levels underlies the enhanced and sustained procognitive effect...... of agonists and PAMs that may be relevant for clinical development. Importantly, A-582941 and AVL-3288 increase short-term memory 24 hrs after repeated, but not a single, administration, suggesting that repeated administration of both agonists and PAMs may produce sustained effects on cognitive performance...

  7. DISEASES

    DEFF Research Database (Denmark)

    Pletscher-Frankild, Sune; Pallejà, Albert; Tsafou, Kalliopi;

    2015-01-01

    Text mining is a flexible technology that can be applied to numerous different tasks in biology and medicine. We present a system for extracting disease-gene associations from biomedical abstracts. The system consists of a highly efficient dictionary-based tagger for named entity recognition of...... human genes and diseases, which we combine with a scoring scheme that takes into account co-occurrences both within and between sentences. We show that this approach is able to extract half of all manually curated associations with a false positive rate of only 0.16%. Nonetheless, text mining should not...... stand alone, but be combined with other types of evidence. For this reason, we have developed the DISEASES resource, which integrates the results from text mining with manually curated disease-gene associations, cancer mutation data, and genome-wide association studies from existing databases. The...

  8. Unique interaction pattern for a functionally biased ghrelin receptor agonist

    DEFF Research Database (Denmark)

    Sivertsen, Bjørn Behrens; Lang, Manja; Frimurer, Thomas M.;

    2011-01-01

    Based on the conformationally constrained D-Trp-Phe-D-Trp (wFw) core of the prototype inverse agonist [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]substance P, a series of novel, small, peptide-mimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers co...

  9. Highly Potent, Chemically Stable Quorum Sensing Agonists for Vibrio Cholerae

    OpenAIRE

    Perez, Lark J; Karagounis, Theodora K.; Hurley, Amanda; Bassler, Bonnie L.; Semmelhack, Martin F.

    2013-01-01

    In the Vibrio cholerae pathogen, initiation of bacterial quorum sensing pathways serves to suppress virulence. We describe herein a potent and chemically stable small molecule agonist of V. cholerae quorum sensing, which was identified through rational drug design based on the native quorum sensing signal. This novel agonist may serve as a useful lead compound for the control of virulence in V. cholerae.

  10. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

    International Nuclear Information System (INIS)

    Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. Conclusion: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients. - Highlights: • There is no pharmacological agent approved for the treatment of NAFLD. • This study demonstrates that PPAR agonists can reduce fatty acid-induced steatosis. • Some nuclear receptors appear to be potent actors in the control

  11. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

    Energy Technology Data Exchange (ETDEWEB)

    Rogue, Alexandra [Inserm UMR 991, 35043 Rennes Cedex (France); Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex (France); Biologie Servier, Gidy (France); Anthérieu, Sébastien; Vluggens, Aurore [Inserm UMR 991, 35043 Rennes Cedex (France); Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex (France); Umbdenstock, Thierry [Technologie Servier, Orléans (France); Claude, Nancy [Institut de Recherches Servier, Courbevoie (France); Moureyre-Spire, Catherine de la; Weaver, Richard J. [Biologie Servier, Gidy (France); Guillouzo, André, E-mail: Andre.Guillouzo@univ-rennes1.fr [Inserm UMR 991, 35043 Rennes Cedex (France); Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex (France)

    2014-04-01

    Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. Conclusion: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients. - Highlights: • There is no pharmacological agent approved for the treatment of NAFLD. • This study demonstrates that PPAR agonists can reduce fatty acid-induced steatosis. • Some nuclear receptors appear to be potent actors in the control

  12. A peroxisome proliferator-activated receptor-gamma agonist and other constituents from Chromolaena odorata.

    Science.gov (United States)

    Dat, Nguyen Tien; Lee, Kyeong; Hong, Young-Soo; Kim, Young Ho; Minh, Chau Van; Lee, Jung Joon

    2009-06-01

    Peroxisome proliferator-activated receptors (PPARs) are key regulators of lipid and glucose metabolism and have become important therapeutic targets for various diseases. The phytochemical investigation of the chloroform-soluble extract of Chromolaena odorata led to the isolation of a PPAR-gamma agonist, (9 S,13 R)-12-oxo-phytodienoic acid (1), together with 12 other compounds. The structures of chromomoric acid G (2), a new dehydrogenated derivative of 1, and chromolanone (3) were elucidated based on spectroscopic methods. Compound 1 showed a significant effect on PPAR-gamma activation in comparison with rosiglitazone. However, compound 2 was inactive, suggesting that the dehydrogenation of the prostaglandin-like structure in 1 abrogates its PPAR-gamma agonistic activity. PMID:19242902

  13. Drug management of Parkinson's disease.

    OpenAIRE

    Kishore, A.; B. J. Snow

    1996-01-01

    Levodopa remains the cornerstone for managing Parkinson's disease. Physician's preference usually determines the dopamine agonist chosen for the early phases of treatment. The concept of neuro-protection, however, remains unproven. A better understanding of the cause of the disease and treatment-related complications could make managing Parkinson's disease more rewarding.

  14. Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice

    Directory of Open Access Journals (Sweden)

    Jian-Hua Lu

    2015-01-01

    Full Text Available Human and murine lymphocytes express dopamine (DA D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th17/T-regulatory (Treg cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA was prepared by intradermal injection of chicken collagen type II (CII in tail base of DBA/1 mice or Drd2−/− C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL- 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF- β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2−/− CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1−/− CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.

  15. Overlapping binding site for the endogenous agonist, small-molecule agonists, and ago-allosteric modulators on the ghrelin receptor

    DEFF Research Database (Denmark)

    Holst, Birgitte; Frimurer, Thomas M; Mokrosinski, Jacek;

    2008-01-01

    mutational map for agonism but it was not identical with the map for the agonist property of these small-molecule ligands. In molecular models, built over the inactive conformation of rhodopsin, low energy conformations of the nonpeptide agonists could be docked to satisfy many of their mutational hits. It...

  16. Prediction of selective estrogen receptor beta agonist using open data and machine learning approach

    Science.gov (United States)

    Niu, Ai-qin; Xie, Liang-jun; Wang, Hui; Zhu, Bing; Wang, Sheng-qi

    2016-01-01

    Background Estrogen receptors (ERs) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. ERs have been validated as important drug targets for the treatment of various diseases, including breast cancer, ovarian cancer, osteoporosis, and cardiovascular disease. ERs have two subtypes, ER-α and ER-β. Emerging data suggest that the development of subtype-selective ligands that specifically target ER-β could be a more optimal approach to elicit beneficial estrogen-like activities and reduce side effects. Methods Herein, we focused on ER-β and developed its in silico quantitative structure-activity relationship models using machine learning (ML) methods. Results The chemical structures and ER-β bioactivity data were extracted from public chemogenomics databases. Four types of popular fingerprint generation methods including MACCS fingerprint, PubChem fingerprint, 2D atom pairs, and Chemistry Development Kit extended fingerprint were used as descriptors. Four ML methods including Naïve Bayesian classifier, k-nearest neighbor, random forest, and support vector machine were used to train the models. The range of classification accuracies was 77.10% to 88.34%, and the range of area under the ROC (receiver operating characteristic) curve values was 0.8151 to 0.9475, evaluated by the 5-fold cross-validation. Comparison analysis suggests that both the random forest and the support vector machine are superior for the classification of selective ER-β agonists. Chemistry Development Kit extended fingerprints and MACCS fingerprint performed better in structural representation between active and inactive agonists. Conclusion These results demonstrate that combining the fingerprint and ML approaches leads to robust ER-β agonist prediction models, which are potentially applicable to the identification of selective ER-β agonists. PMID:27486309

  17. A Comprehensive Robust Adaptive Controller for Gust Load Alleviation

    Directory of Open Access Journals (Sweden)

    Elisa Capello

    2014-01-01

    Full Text Available The objective of this paper is the implementation and validation of an adaptive controller for aircraft gust load alleviation. The contribution of this paper is the design of a robust controller that guarantees the reduction of the gust loads, even when the nominal conditions change. Some preliminary results are presented, considering the symmetric aileron deflection as control device. The proposed approach is validated on subsonic transport aircraft for different mass and flight conditions. Moreover, if the controller parameters are tuned for a specific gust model, even if the gust frequency changes, no parameter retuning is required.

  18. Restriction alleviation by bacteriophages lambda and lambda reverse.

    OpenAIRE

    Toothman, P

    1981-01-01

    Deletion analysis indicated that the phage lambda restriction alleviation gene(s) ral resides between the cIII and N genes. The Ral+ phenotype was expressed only when lambda ral+ carried a modification such that it was resistant to restriction by the host specificity system. Under these conditions, Ral function protected superinfecting unmodified phages from restriction by EcoK or EcoB but not from restriction by EcoP1. Ral-protected phage DNA was not concomitantly K and B modified, but rathe...

  19. Can housing wealth alleviate poverty among Britain's older population?

    OpenAIRE

    Ruth Hancock

    1998-01-01

    This paper investigates the scope for housing wealth to alleviate poverty among Britain’s older population by modelling the potential effect of equity-release schemes on the net incomes of older homeowners using data from the 1993-94 and 1994-95 Family Expenditure Surveys. We find that, for the older population in general, the potential impact of equity release on poverty is limited by the positive association between homeownership and income in later life. The scope for equity release to enh...

  20. El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB para terapia de enfermedades malignas e infecciones virales crónicas The immunotherapy potential of agonistic anti-CD137 (4-1BB monoclonal antibodies for malignancies and chronic viral diseases

    Directory of Open Access Journals (Sweden)

    C. Alfaro

    2006-04-01

    . Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4 that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start.

  1. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    International Nuclear Information System (INIS)

    Extracellular Ca2+ influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca2+ entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca2+ overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca2+ and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases

  2. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Ruibing [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Lihui [Shandong Normal University, Jinan, Shandong Province 250012 (China); Luo, Zheng; Guo, Xiaolan [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Ming, E-mail: ymylh@163.com [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  3. Puerarin Alleviates Neuropathic Pain by Inhibiting Neuroinflammation in Spinal Cord

    Directory of Open Access Journals (Sweden)

    Ming Liu

    2014-01-01

    Full Text Available Neuropathic pain responds poorly to drug treatments, and partial relief is achieved in only about half of the patients. Puerarin, the main constituent of Puerariae Lobatae Radix, has been used extensively in China to treat hypertension and tumor. The current study examined the effects of puerarin on neuropathic pain using two most commonly used animal models: chronic constriction injury (CCI and diabetic neuropathy. We found that consecutive intrathecal administration of puerarin (4–100 nM for 7 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models puerarin inhibited the activation of microglia and astroglia in the spinal dorsal horn. Puerarin also reduced the upregulated levels of nuclear factor-κB (NF-κB and other proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. In summary, puerarin alleviated CCI- and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal cord. The anti-inflammation effect of puerarin might be related to the suppression of spinal NF-κB activation and/or cytokines upregulation. We conclude that puerarin has a significant effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.

  4. Alleviation of Al Toxicity in Barley by Addition of Calcium

    Institute of Scientific and Technical Information of China (English)

    GUO Tian-rong; CHEN Ying; ZHANG Yan-hua; JIN Ye-fei

    2006-01-01

    The potential mechanism by which Ca alleviates Al toxicity was investigated in barley seedlings. It was found that 100 μM Al-alone treatment inhibited barley plant growth and thereby reduced shoot height and root length, and dry weights of root, shoot and leaf; promoted Al accumulation but inhibited Ca absorption in plant tissues; and induced an increase in the activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) and in the level of lipid peroxidation (MDA content) in leaves. Except for the increase in Ca concentration in plant tissues, treatment with 0.5 mM Ca in the absence of Al had less effect on the above-mentioned parameters, compared with the control. Addition of Ca efficiently reduced Al toxicity, which is reflected by the promotion of plant growth, reduction in Al concentration and MDA content,increase in Ca concentration and in SOD, POD, and CAT activities compared with the Al-alone-treatment; with increase in Ca level (3.0 mM), the ameliorative effect became more dominant. This indicated that the alleviation of aluminum toxicity in barley seedlings with Ca supplementation could be associated with less absorption of Al and the enhancement of the protective ability of the cell because of increased activity of the antioxidative enzyme.

  5. Therapeutic applications of TRAIL receptor agonists in cancer and beyond.

    Science.gov (United States)

    Amarante-Mendes, Gustavo P; Griffith, Thomas S

    2015-11-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. PMID:26343199

  6. PPARα/γ激动剂对糖尿病伴冠心病患者血浆炎症因子的影响%Effects of PPAR α/γ dual agonists on plasma inflammatory cytokine in patients with diabetes complicated with coronary artery disease

    Institute of Scientific and Technical Information of China (English)

    韦金儒; 唐泉

    2012-01-01

    目的 探讨联合应用过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor,PPAR)α/γ激动剂对糖尿病伴冠状动脉粥样硬化性心脏病(冠心病)患者血浆炎症因子的影响.方法 将80例伴有糖尿病的冠心病患者分为马来酸罗格列酮组(n=20)、苯扎贝特组(n=20)、马来酸罗格列酮和苯扎贝特联合组(n=20)、常规治疗组(n=20).治疗后,对所有患者随访12周.治疗前后均对所有患者采血,并用酶联免疫吸附法测定患者血浆C反应蛋白、单核细胞趋化蛋白-1 (monocyte chemotactic protein-1,MCP-1),观察患者空腹血糖、空腹胰岛素、胰岛素抵抗指数、糖化血红蛋白-A1c(HbA1c)、血脂、体质量指数的改变.结果 联合组、马来酸罗格列酮组、苯扎贝特组血浆C反应蛋白、MCP-1、空腹血糖、糖化血红蛋白、胰岛素、总胆固醇、三酰甘油、低密度脂蛋白胆固醇浓度和胰岛素抵抗指数治疗12周后比治疗前明显降低,高密度脂蛋白胆固醇明显升高,差异有统计学意义(P<0.05),且联合组上述指标改善最显著.马来酸罗格列酮组、苯扎贝特组、联合组的单核细胞在脂多糖诱导下分泌MCP-1浓度较治疗前降低,以联合组降低最为显著.C反应蛋白的降低与空腹胰岛素和胰岛素抵抗指数的降低呈正相关(r=0.498,P<0.001和r=0.496,P<0.001),与其他因素的变化无相关性(P>0.05);而MCP-1的变化与糖、脂代谢无相关性(P>0.05);C反应蛋白与MCP-1之间也无明显相关性(P>0.05).结论 联合应用马来酸罗格列酮、苯扎贝特能够降低血浆C反应蛋白和MCP-1浓度,降低血糖和血浆胰岛素浓度,减轻胰岛素抵抗,改善辛伐他汀治疗后残存的高三酰甘油和低高密度脂蛋白胆固醇,效果优于单用马来酸罗格列酮或苯扎贝特.%Objectives To observe the effects of combined peroxisome proliferator-activated receptor (PPAR)ot-agonist and PPAR'y-agonist

  7. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

    Directory of Open Access Journals (Sweden)

    Maharjan Anu S

    2010-11-01

    Full Text Available Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN-α, IFN-γ, interleukin (IL-12, aggregated immunoglobulin G (IgG or serum amyloid P (SAP, factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.

  8. On the Pharmacology of Farnesoid X Receptor Agonists: Give me an “A”, Like in “Acid”

    Directory of Open Access Journals (Sweden)

    Eva Hambruch

    2016-06-01

    Full Text Available The Farnesoid X Receptor (FXR has recently moved into the spotlight through the release of clinical data using Obeticholic Acid, an FXR agonist, that demonstrated effectiveness of this bile acid-like drug in patients with Primary Biliary Cirrhosis and Non-alcoholic Steatohepatitis (NASH. FXR holds the promise to become an attractive drug target for various conditions, from Non-alcoholic Fatty Liver Disease (NAFLD, NASH, liver cirrhosis, portal hypertension and a variety of cholestatic disorders to intestinal diseases including inflammatory bowel disease and bile acid diarrhea. Despite the wide therapeutic potential, surprisingly little is known about the pharmacology, pharmacokinetics and tissue distribution properties of drugs targeting FXR. Are tissue specific FXR agonists preferable for different indications, or might one type of ligand fit all purposes? This review aims to summarize the sparse data which are available on this clinically and pharmacologically relevant topic and provides a mechanistic model for understanding tissue-specific effects in vivo.

  9. Structural Insights into the Activation of Human Relaxin Family Peptide Receptor 1 by Small-Molecule Agonists.

    Science.gov (United States)

    Hu, Xin; Myhr, Courtney; Huang, Zaohua; Xiao, Jingbo; Barnaeva, Elena; Ho, Brian A; Agoulnik, Irina U; Ferrer, Marc; Marugan, Juan J; Southall, Noel; Agoulnik, Alexander I

    2016-03-29

    The GPCR relaxin family peptide receptor 1 (RXFP1) mediates the action of relaxin peptide hormone, including its tissue remodeling and antifibrotic effects. The peptide has a short half-life in plasma, limiting its therapeutic utility. However, small-molecule agonists of human RXFP1 can overcome this limitation and may provide a useful therapeutic approach, especially for chronic diseases such as heart failure and fibrosis. The first small-molecule agonists of RXFP1 were recently identified from a high-throughput screening, using a homogeneous cell-based cAMP assay. Optimization of the hit compounds resulted in a series of highly potent and RXFP1 selective agonists with low cytotoxicity, and excellent in vitro ADME and pharmacokinetic properties. Here, we undertook extensive site-directed mutagenesis studies in combination with computational modeling analysis to probe the molecular basis of the small-molecule binding to RXFP1. The results showed that the agonists bind to an allosteric site of RXFP1 in a manner that closely interacts with the seventh transmembrane domain (TM7) and the third extracellular loop (ECL3). Several residues were determined to play an important role in the agonist binding and receptor activation, including a hydrophobic region at TM7 consisting of W664, F668, and L670. The G659/T660 motif within ECL3 is crucial to the observed species selectivity of the agonists for RXFP1. The receptor binding and activation effects by the small molecule ML290 were compared with the cognate ligand, relaxin, providing valuable insights on the structural basis and molecular mechanism of receptor activation and selectivity for RXFP1. PMID:26866459

  10. Identification of human dopamine D1-like receptor agonist using a cell-based functional assay

    Institute of Scientific and Technical Information of China (English)

    Nan JIANG; Ke-qing OU-YANG; Shao-xi CAI; Ying-he HU; Zhi-liang XU

    2005-01-01

    Aim: To establish a cell-based assay to screen human dopamine D1 and D5 receptor agonists against compounds from a natural product compound library.Methods: Synthetic responsive elements 6×cAMP response elements (CRE) and a mini promoter containing a TATA box were inserted into the pGL3 basic vector to generate the reporter gene construct pCRE/TA/Luci. CHO cells were co-transfected with the reporter gene construct and human D1 or D5 receptor cDNA in mammalian expression vectors. Stable cell lines were established for agonist screening. A natural product compound library from over 300 herbs has been established. The extracts from these herbs were used for human D1 and D5 receptor agonist screenings. Results: A number of extracts were identified that activated both D1 and D5 receptors. One of the herb extracts, SBG492, demonstrated distinct pharmacological characteristics with human D1 and D5 receptors.The EC50 values of SBG492 were 342.7 μg/mL for the D1 receptor and 31.7 μg/mL for the D5 receptor. Conclusion: We have established a cell-based assay for high-throughput drug screening to identify D 1-like receptor agonists from natural products. Several extracts that can active D1-like receptors were discovered.These compounds could be useful tools for studies on the functions of these receptors in the brain and could potentially be developed into therapeutic drugs for the treatment of central nervous system diseases.

  11. Distinct Signaling Cascades Elicited by Different Formyl Peptide Receptor 2 (FPR2 Agonists

    Directory of Open Access Journals (Sweden)

    Fabio Cattaneo

    2013-04-01

    Full Text Available The formyl peptide receptor 2 (FPR2 is a remarkably versatile transmembrane protein belonging to the G-protein coupled receptor (GPCR family. FPR2 is activated by an array of ligands, which include structurally unrelated lipids and peptide/proteins agonists, resulting in different intracellular responses in a ligand-specific fashion. In addition to the anti-inflammatory lipid, lipoxin A4, several other endogenous agonists also bind FPR2, including serum amyloid A, glucocorticoid-induced annexin 1, urokinase and its receptor, suggesting that the activation of FPR2 may result in potent pro- or anti-inflammatory responses. Other endogenous ligands, also present in biological samples, include resolvins, amyloidogenic proteins, such as beta amyloid (Aβ-42 and prion protein (Prp106–126, the neuroprotective peptide, humanin, antibacterial peptides, annexin 1-derived peptides, chemokine variants, the neuropeptides, vasoactive intestinal peptide (VIP and pituitary adenylate cyclase activating polypeptide (PACAP-27, and mitochondrial peptides. Upon activation, intracellular domains of FPR2 mediate signaling to G-proteins, which trigger several agonist-dependent signal transduction pathways, including activation of phospholipase C (PLC, protein kinase C (PKC isoforms, the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt pathway, the mitogen-activated protein kinase (MAPK pathway, p38MAPK, as well as the phosphorylation of cytosolic tyrosine kinases, tyrosine kinase receptor transactivation, phosphorylation and nuclear translocation of regulatory transcriptional factors, release of calcium and production of oxidants. FPR2 is an attractive therapeutic target, because of its involvement in a range of normal physiological processes and pathological diseases. Here, we review and discuss the most significant findings on the intracellular pathways and on the cross-communication between FPR2 and tyrosine kinase receptors triggered by different FPR2

  12. Treatment with a corticotrophin releasing factor 2 receptor agonist modulates skeletal muscle mass and force production in aged and chronically ill animals

    Directory of Open Access Journals (Sweden)

    Ferreira Leonardo F

    2011-01-01

    Full Text Available Abstract Background Muscle weakness is associated with a variety of chronic disorders such as emphysema (EMP and congestive heart failure (CHF as well as aging. Therapies to treat muscle weakness associated with chronic disease or aging are lacking. Corticotrophin releasing factor 2 receptor (CRF2R agonists have been shown to maintain skeletal muscle mass and force production in a variety of acute conditions that lead to skeletal muscle wasting. Hypothesis We hypothesize that treating animals with a CRF2R agonist will maintain skeletal muscle mass and force production in animals with chronic disease and in aged animals. Methods We utilized animal models of aging, CHF and EMP to evaluate the potential of CRF2R agonist treatment to maintain skeletal muscle mass and force production in aged animals and animals with CHF and EMP. Results In aged rats, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater extensor digitorum longus (EDL force production, EDL mass, soleus mass and soleus force production compared to age matched untreated animals. In the hamster EMP model, we demonstrate that treatment with a CRF2R agonist for up to 5 months results in greater EDL force production in EMP hamsters when compared to vehicle treated EMP hamsters and greater EDL mass and force in normal hamsters when compared to vehicle treated normal hamsters. In the rat CHF model, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater EDL and soleus muscle mass and force production in CHF rats and normal rats when compared to the corresponding vehicle treated animals. Conclusions These data demonstrate that the underlying physiological conditions associated with chronic diseases such as CHF and emphysema in addition to aging do not reduce the potential of CRF2R agonists to maintain skeletal muscle mass and force production.

  13. IMIDAZOLINE RECEPTOR AGONISTS: DO WE KNOW EVERYTHING ABOUT THEIR CAPABILITIES?

    Directory of Open Access Journals (Sweden)

    D. V. Nebieridze

    2015-12-01

    Full Text Available The role of selective I1 imidazoline receptor agonists and moxonidine in particular , in modern antihypertensive therapy is discussed. Moxonidine advantages, namely positive effects on insulin resistance, endothelial dysfunction, lipid profile, and plasma fibrinolytic activity are considered.

  14. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    Directory of Open Access Journals (Sweden)

    Akinori Hirashima

    2003-04-01

    Full Text Available The compounds 1-(2,6-diethylphenylimidazolidine-2-thione and 2-(2,6-diethylphenylimidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

  15. Selective 5-HT2C agonists as potential antidepressants.

    Science.gov (United States)

    Leysen, D C

    1999-02-01

    The antidepressants currently used need improvement, especially in terms of efficacy, relapse rate and onset of action. In this review the clinical and experimental data which support the rationale for 5-HT2C agonists in the treatment of depression are listed. Next, the results obtained with the non-selective 5-HT2C agonists on the market and in clinical development are described. Finally, the preclinical data on the more selective 5-HT2C agonists are summarized. These recent preclinical results reveal a greater potency and effect size compared to fluoxetine, good tolerability and no evidence of tolerance development. Selective 5-HT2C agonists might become innovative drugs for the treatment of depression, panic, obsessive-compulsive disorder (OCD), some forms of aggression and eating disorders. PMID:16160946

  16. Development of a radioreceptor assay for β2 adrenergic agonists

    International Nuclear Information System (INIS)

    Several β2 adrenergic agonists are illegally used as growth promoters in meat production. We have developed and evaluated a radioreceptor assay for the multianalyte detection of these compounds. The method is based on a competition for binding with receptors (plasma membranes prepared from bovine teat muscles) between a radioactive tracer (3H-dihydroalprenolol) and β2 agonist residues present in the samples. The method has been validated for three β2 agonists (clenbuterol, mabuterol and cimaterol) in bovine urine samples. The detection limit (mean of ''blank'' values + 3 SEM) in urine was 2.4 ppb clenbuterol. Using this procedure, samples containing at least 5 ppb of clenbuterol, mabuterol or cimaterol could be identified as positive for the presence of β2 agonists. (orig.)

  17. Quantifying Agonist Activity at G Protein-coupled Receptors

    OpenAIRE

    Ehlert, Frederick J.; Suga, Hinako; Griffin, Michael T.

    2011-01-01

    When an agonist activates a population of G protein-coupled receptors (GPCRs), it elicits a signaling pathway that culminates in the response of the cell or tissue. This process can be analyzed at the level of a single receptor, a population of receptors, or a downstream response. Here we describe how to analyze the downstream response to obtain an estimate of the agonist affinity constant for the active state of single receptors.

  18. Agonist Replacement for Stimulant Dependence: A Review of Clinical Research

    OpenAIRE

    Stoops, William W.; Rush, Craig R.

    2013-01-01

    Stimulant use disorders are an unrelenting public health concern worldwide. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. The present paper reviewed clinical data from human laboratory self-administration studies and clinical trials to determine whether agonist replacement therapy is a viable strategy for managing cocaine and/or amphetamine use disorders. The extant literature suggests that ago...

  19. Beta-adrenergic agonists as additive in beef cattle

    OpenAIRE

    Marcelo Vedovatto; Camila Celeste Brandão Ferreira Ítavo; João Artêmio Marin Beltrame; Ricardo Carneiro Brumatti; Gumercindo Loriano Franco

    2014-01-01

    The agonists receptor beta-adrenergic (β-AA) are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine) produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fu...

  20. In silico discovery of novel Retinoic Acid Receptor agonist structures

    OpenAIRE

    Samuels Herbert H; Schapira Matthieu; Raaka Bruce M; Abagyan Ruben

    2001-01-01

    Abstract Background Several Retinoic Acid Receptors (RAR) agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. Results We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived...

  1. Non-pharmacological approaches to alleviate distress in dementia care.

    Science.gov (United States)

    Mitchell, Gary; Agnelli, Joanne

    2015-11-25

    Distress is one of the most common clinical manifestations associated with dementia. Pharmacological intervention may be appropriate in managing distress in some people. However, best practice guidelines advocate non-pharmacological interventions as the preferred first-line treatment. The use of non-pharmacological interventions encourages healthcare professionals to be more person-centred in their approach, while considering the causes of distress. This article provides healthcare professionals with an overview of some of the non-pharmacological approaches that can assist in alleviating distress for people living with dementia including: reminiscence therapy, reality orientation, validation therapy, music therapy, horticultural therapy, doll therapy and pet therapy. It provides a summary of their use in clinical practice and links to the relevant literature. PMID:26602678

  2. Alleviation of acute radiation damages by post-irradiation treatments

    International Nuclear Information System (INIS)

    Radiation induced hematopoietic and gastro-intestinal damages in mice were tried to alleviate experimentally by post-treatment. Combined treatment of OK-432 and aztreonam clearly prevented the radiation induced sepsis and elevated the survival rate in mice; the survival was 80% in the OK-432 plus aztreonam group while it was 55% in the group treated with OK-432 alone and 0% with saline. Irsogladine maleate, an anti-ulcer drug, increased the survival rate of jejunal crypt stem cells with a clear dose-related trend. The D0 for irsogladine maleate was 2.8 Gy although it was 2.3 Gy for saline, These findings suggest that some conventional drugs are effective for radiation induced hematopoietic and gastro-intestinal damages and the possibility that they can be applied for people exposed to radiation accidentally. (author)

  3. Follistatin Alleviates Synovitis and Articular Cartilage Degeneration Induced by Carrageenan

    Science.gov (United States)

    Yamada, Jun; Abula, Kahaer; Inoue, Makiko; Sekiya, Ichiro; Muneta, Takeshi

    2014-01-01

    Activins are proinflammatory cytokines which belong to the TGFβ superfamily. Follistatin is an extracellular decoy receptor for activins. Since both activins and follistatin are expressed in articular cartilage, we hypothesized that activin-follistatin signaling participates in the process of joint inflammation and cartilage degeneration. To test this hypothesis, we examined the effects of follistatin in a carrageenan-induced mouse arthritis model. Synovitis induced by intra-articular injection of carrageenan was significantly alleviated by preinjection with follistatin. Macrophage infiltration into the synovial membrane was significantly reduced in the presence of follistatin. In addition, follistatin inhibited proteoglycan erosion induced by carrageenan in articular cartilage. These data indicate that activin-follistatin signaling is involved in joint inflammation and cartilage homeostasis. Our data suggest that follistatin can be a new therapeutic target for inflammation-induced articular cartilage degeneration. PMID:25574420

  4. Personality and Coping in Peruvian volunteers for poverty alleviation

    Directory of Open Access Journals (Sweden)

    Camila Gastelumendi Gonçalves

    2013-06-01

    Full Text Available This study explores the relationship between coping styles and strategies, and personality styles in a sample of 41 young volunteers of an institution that alleviates poverty in Lima. Peruvian adaptations of COPE and MIPS scales were administered. The results show that volunteers have higher scores on adaptive coping strategies. High scores in some particular personality styles were reported, which allowed to establish a personality profile of this group. According with theoretical framework, most coping strategies correlated with most personality styles, revealing four particular tendencies in these volunteers: they wish to have contact with other people, they usually see positive aspects of situations, they look forward for challenges, and they developed adaptive coping strategies.

  5. Music-reading training alleviates crowding with musical notation.

    Science.gov (United States)

    Wong, Yetta Kwailing; Wong, Alan C-N

    2016-06-01

    Crowding refers to the disrupted recognition of an object by nearby distractors. Prior work has shown that real-world music-reading experts experience reduced crowding specifically for musical stimuli. However, it is unclear whether music-reading training reduced the magnitude of crowding or whether individuals showing less crowding are more likely to learn and excel in music reading later. To examine the first possibility, we tested whether crowding can be alleviated by music-reading training in the laboratory. Intermediate-level music readers completed 8 hr of music-reading training within 2 weeks. Their threshold duration for reading musical notes dropped by 44.1% after training to a level comparable with that of extant expert music readers. Importantly, crowding was reduced with musical stimuli but not with the nonmusical stimuli Landolt Cs. In sum, the reduced crowding for musical stimuli in expert music readers can be explained by music-reading training. PMID:27322085

  6. Should We Use PPAR Agonists to Reduce Cardiovascular Risk?

    Directory of Open Access Journals (Sweden)

    Jennifer G. Robinson

    2008-01-01

    Full Text Available Trials of peroxisome proliferator-activated receptor (PPAR agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR- agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs are PPAR- agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-/ agonists have had unacceptable adverse effects but more selective agents are in development. PPAR- and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.

  7. Characterization of Natural Aryl Hydrocarbon Receptor Agonists from Cassia Seed and Rosemary

    OpenAIRE

    Yoshiaki Amakura; Morio Yoshimura; Masashi Takaoka; Haruka Toda; Tomoaki Tsutsumi; Rieko Matsuda; Reiko Teshima; Masafumi Nakamura; Hiroshi Handa; Takashi Yoshida

    2014-01-01

    Many recent studies have suggested that activation of the aryl hydrocarbon receptor (AhR) reduces immune responses, thus suppressing allergies and autoimmune diseases. In our continuing study on natural AhR agonists in foods, we examined the influence of 37 health food materials on the AhR using a reporter gene assay, and found that aqueous ethanol extracts of cassia seed and rosemary had particularly high AhR activity. To characterize the AhR-activating substances in these samples, the chemi...

  8. Neuroprotective and memory enhancing properties of a dual agonist of the FGF receptor and NCAM

    DEFF Research Database (Denmark)

    Enevoldsen, Maj N; Kochoyan, Artur; Jurgenson, Monika;

    2012-01-01

    subcutaneous administration, enhances long-term memory in normal mice and ameliorates memory deficit in mice with induced brain inflammation. Moreover, Enreptin reduces cognitive impairment and neuronal death induced by Aß25-35 in a rat model of Alzheimer's disease, and reduces the mortality rate and clinical...... NCAM. We demonstrate that this dual specificity agonist induces phosphorylation of FGFR and differentiation and survival of primary neurons in vitro, and that these effects are inhibited by abrogation of both NCAM and FGFR signaling pathways. Furthermore, Enreptin crosses the blood-brain barrier after...

  9. Pyrrolo- and Pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

    OpenAIRE

    V. Kumar; Clark, M J; Traynor, J. R.; Lewis, J W; Husbands, S M

    2014-01-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist...

  10. Assessing the Effects of the New Cooperative Medical Scheme on Alleviating the Health Payment-Induced Poverty in Shaanxi Province, China

    Science.gov (United States)

    Gao, Jianmin; Zhou, Zhongliang; Yan, Jue; Lai, Sha; Xu, Yongjian; Chen, Gang

    2016-01-01

    Background Disease has become one of the key causes of falling into poverty in rural China. The poor households are even more likely to suffer. The New Cooperative Medical Scheme (NCMS) has been implemented to provide rural residents financial protection against health risks. This study aims to assess the effect of the NCMS on alleviating health payment-induced poverty in the Shaanxi Province of China. Methods The data was drawn from the 5th National Health Service Survey of Shaanxi Province, conducted in 2013. In total, 41,037 individuals covered by NCMS were selected. Poverty headcount ratio (HCR), poverty gap and mean positive poverty gap were used for measuring the incidence, depth and intensity of poverty, respectively. The differences on poverty measures pre- and post- insurance reimbursement indicate the effectiveness of alleviating health payment-induced poverty under NCMS. Results For the general insured, 5.81% of households fell below the national poverty line owing to the health payment; this HCR dropped to 4.84% after insurance reimbursement. The poverty HCRs for the insured that had hospitalization in the past year dropped from 7.50% to 2.09% after reimbursement. With the NCMS compensation, the poverty gap declined from 42.90 Yuan to 34.49 Yuan (19.60% decreased) for the general insured and from 57.48 Yuan to 10.01 Yuan (82.59% decreased) for the hospital admission insured. The mean positive poverty gap declined 3.56% and 37.40% for two samples, respectively. Conclusion The NCMS could alleviate the health payment-induced poverty. The effectiveness of alleviating health payment-induced poverty is greater for hospital admission insured than for general insured, mainly because NCMS compensates for serious diseases. Our study suggests that a more comprehensive insurance benefit package design could further improve the effectiveness of poverty alleviation. PMID:27380417

  11. Curcumin Attenuates Beta-Amyloid-Induced Neuroinflammation via Activation of Peroxisome Proliferator-Activated Receptor-Gamma Function in a Rat Model of Alzheimer's Disease.

    Science.gov (United States)

    Liu, Zun-Jing; Li, Zhong-Hao; Liu, Lei; Tang, Wen-Xiong; Wang, Yu; Dong, Ming-Rui; Xiao, Cheng

    2016-01-01

    Neuroinflammation is known to have a pivotal role in the pathogenesis of Alzheimer's disease (AD), and curcumin has been reported to have therapeutical effects on AD because of its anti-inflammatory effects. Curcumin is not only a potent PPARγ agonist, but also has neuroprotective effects on cerebral ischemic injury. However, whether PPARγ activated by curcumin is responsible for the anti-neuroinflammation and neuroprotection on AD remains unclear, and needs to be further investigated. Here, using both APP/PS1 transgenic mice and beta-amyloid-induced neuroinflammation in mixed neuronal/glial cultures, we showed that curcumin significantly alleviated spatial memory deficits in APP/PS1 mice and promoted cholinergic neuronal function in vivo and in vitro. Curcumin also reduced the activation of microglia and astrocytes, as well as cytokine production and inhibited nuclear factor kappa B (NF-κB) signaling pathway, suggesting the beneficial effects of curcumin on AD are attributable to the suppression of neuroinflammation. Attenuation of these beneficial effects occurred when co-administrated with PPARγ antagonist GW9662 or silence of PPARγ gene expression, indicating that PPARγ might be involved in anti-inflammatory effects. Circular dichroism and co-immunoprecipitation analysis showed that curcumin directly bound to PPARγ and increased the transcriptional activity and protein levels of PPARγ. Taking together, these data suggested that PPARγ might be a potential target of curcumin, acting to alleviate neuroinflammation and improve neuronal function in AD. PMID:27594837

  12. Discovery and cardioprotective effects of the first non-Peptide agonists of the G protein-coupled prokineticin receptor-1.

    Directory of Open Access Journals (Sweden)

    Adeline Gasser

    Full Text Available Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI.

  13. Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists.

    Science.gov (United States)

    Kang, Yu Mi; Jung, Chang Hee

    2016-06-01

    Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes. PMID:27118277

  14. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis

    OpenAIRE

    Liu, Yaping; Binz, Jane; Numerick, Mary Jo; Dennis, Steve; Luo, Guizhen; Desai, Bhasha; MacKenzie, Kathleen I.; Mansfield, Traci A.; Kliewer, Steven A.; Goodwin, Bryan; Jones, Stacey A.

    2003-01-01

    Farnesoid X receptor (FXR) is a bile acid–activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestat...

  15. Effect of lesogaberan, a novel GABAB-receptor agonist, on transient lower esophageal sphincter relaxations in male subjects

    OpenAIRE

    Guy E. Boeckxstaens; Rydholm, Hans; Lei, Aaltje; Adler, John; Ruth, Magnus

    2010-01-01

    Abstract Background: Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind gastroesophageal reflux disease (GERD). Aim: To assess the effect of lesogaberan (AZD3355) ? a novel peripherally active GABAB receptor agonist ? on TLESRs. Methods: Twenty-four healthy men were enrolled in this single-blind, placebo-controlled, randomized, single-centre, three-period crossover phase 1 study. Subjects were randomized to receive single oral doses of leso...

  16. Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment

    OpenAIRE

    Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N.; Allen, John A.; Rogan, Sarah C.; Hanson, Bonnie J; Revankar, Chetana; Robers, Matt; Doucette, Chris; Roth, Bryan L.

    2009-01-01

    Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine2B (5-HT2B) receptor agonists. We have shown that activation of 5-HT2B receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscen...

  17. 改革开放以来中国共产党的扶贫实践%CPCˊs Practice of Poverty Alleviation since the Reform and Opening-up

    Institute of Scientific and Technical Information of China (English)

    文建龙

    2016-01-01

    Since the reform and opening up, Chinaˊs poverty alleviation practice can be roughly divided into three stages: system reform, special programs and two-wheel driving to promote poverty alleviation. In the process of deepening the practice of poverty alleviation, its focus has shifted from the simple economic relief type of poverty alleviation to focusing on the productive poverty alleviation, then to focusing on the cultural concept of poverty alleviation, after that, to focusing on the development of the ability to protect the rights of governance based on poverty alleviation. This is a process of treating the "temporary" symptoms to "completely curing the disease". It demonstrates Chinaˊs political civilization progress, and it has helped CPC to accumulate valuable experience on poverty alleviation.%改革开放以来,我国的扶贫实践大致可分为体制改革推动扶贫、专项计划推动扶贫和两轮驱动推动扶贫三个阶段。在扶贫实践不断深化的进程中,扶贫重心发生了转移,由单纯的经济救济式扶贫→侧重生产性扶贫→侧重文化观念性扶贫→侧重发展能力基础上的权利保障治理式扶贫。这是一个从“治标”走向“治本”的过程,彰显了中国的政治文明不断进步,为中国共产党的扶贫实践积累了宝贵的经验。

  18. Activation of chemical biological defense mechanisms and alleviation of in vivo oxidation injury by low dose radiation

    International Nuclear Information System (INIS)

    We clarified that adequate oxygen stress induced by low dose radiation activates not only chemical biological protective function, such as induction of the synthesis of superoxide dismutase (SOD), glutathione peroxidase (GPX) and heat shock protein 70 (HSP70), but also the biomembrane function, such as enhanced membrane fluidity and ATPase activity. It is possible that activation of these mechanisms alleviates in vivo oxidation injuries resulting in alleviation of pathologic condition, such as ferric-nitrilotriacetate (Fe3+-NTA) or CCl4-induced liver damage, 1-methyl-4-phenyl 1,2,3,6-tetrahydro-pyridine (MPTP)-induced brain damage and diabetes mellitus. Namely, in contrast to the toxic effects of high dose irradiation, adequate activation of the functions of the living body by low dose radiation or inhalation of an appropriate amount of radon can contribute to suppressing aging and to preventing or reducing active oxygen species related diseases which are thought to involve peroxidation and have been regarded as the diseases for which radon spring water is an effective treatment. In future, clarification in detail of the mechanisms of these phenomena is required to understand the effects of low dose radiation on the functions of the living body, including adaptive response. (author)

  19. Prediction of selective estrogen receptor beta agonist using open data and machine learning approach

    Directory of Open Access Journals (Sweden)

    Niu AQ

    2016-07-01

    Full Text Available Ai-qin Niu,1 Liang-jun Xie,2 Hui Wang,1 Bing Zhu,1 Sheng-qi Wang3 1Department of Gynecology, the First People’s Hospital of Shangqiu, Shangqiu, Henan, People’s Republic of China; 2Department of Image Diagnoses, the Third Hospital of Jinan, Jinan, Shandong, People’s Republic of China; 3Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China Background: Estrogen receptors (ERs are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. ERs have been validated as important drug targets for the treatment of various diseases, including breast cancer, ovarian cancer, osteoporosis, and cardiovascular disease. ERs have two subtypes, ER-α and ER-β. Emerging data suggest that the development of subtype-selective ligands that specifically target ER-β could be a more optimal approach to elicit beneficial estrogen-like activities and reduce side effects. Methods: Herein, we focused on ER-β and developed its in silico quantitative structure-activity relationship models using machine learning (ML methods. Results: The chemical structures and ER-β bioactivity data were extracted from public chemogenomics databases. Four types of popular fingerprint generation methods including MACCS fingerprint, PubChem fingerprint, 2D atom pairs, and Chemistry Development Kit extended fingerprint were used as descriptors. Four ML methods including Naïve Bayesian classifier, k-nearest neighbor, random forest, and support vector machine were used to train the models. The range of classification accuracies was 77.10% to 88.34%, and the range of area under the ROC (receiver operating characteristic curve values was 0.8151 to 0.9475, evaluated by the 5-fold cross-validation. Comparison analysis suggests that both the random forest and the support vector machine are superior

  20. Epoetin beta pegol alleviates oxidative stress and exacerbation of renal damage from iron deposition, thereby delaying CKD progression in progressive glomerulonephritis rats.

    Science.gov (United States)

    Hirata, Michinori; Tashiro, Yoshihito; Aizawa, Ken; Kawasaki, Ryohei; Shimonaka, Yasushi; Endo, Koichi

    2015-12-01

    The increased deposition of iron in the kidneys that occurs with glomerulopathy hinders the functional and structural recovery of the tubules and promotes progression of chronic kidney disease (CKD). Here, we evaluated whether epoetin beta pegol (continuous erythropoietin receptor activator: CERA), which has a long half-life in blood and strongly suppresses hepcidin-25, exerts renoprotection in a rat model of chronic progressive glomerulonephritis (cGN). cGN rats showed elevated urinary total protein excretion (uTP) and plasma urea nitrogen (UN) from day 14 after the induction of kidney disease (day 0) and finally declined into end-stage kidney disease (ESKD), showing reduced creatinine clearance with glomerulosclerosis, tubular dilation, and tubulointerstitial fibrosis. A single dose of CERA given on day 1, but not on day 16, alleviated increasing uTP and UN, thereby delaying ESKD. In the initial disease phase, CERA significantly suppressed urinary 8-OHdG and liver-type fatty acid-binding protein (L-FABP), a tubular damage marker. CERA also inhibited elevated plasma hepcidin-25 levels and alleviated subsequent iron accumulation in kidneys in association with elevated urinary iron excretion and resulted in alleviation of growth of Ki67-positive tubular and glomerular cells. In addition, at day 28 when the exacerbation of uTP occurs, a significant correlation was observed between iron deposition in the kidney and urinary L-FABP. In our study, CERA mitigated increasing kidney damage, thereby delaying CKD progression in this glomerulonephritis rat model. Alleviation by CERA of the exacerbation of kidney damage could be attributable to mitigation of tubular damage that might occur with lowered iron deposition in tubules. PMID:26634903

  1. Therapeutic applications of synthetic CpG oligodeoxynucleotides as TLR9 agonists for immune modulation.

    Science.gov (United States)

    Jurk, Marion; Vollmer, Jörg

    2007-01-01

    Vertebrate toll-like receptors (TLRs) sense invading pathogens by recognizing bacterial and viral structures and, as a result, activate innate and adaptive immune responses. Ten human functional TLRs have been reported so far; three of these (TLR7, 8, and 9) are expressed in intracellular compartments and respond to single-stranded nucleic acids as natural ligands. The pathogen structure selectively recognized by TLR9 in bacterial or viral DNA was identified to be CpG dinucleotides in specific sequence contexts (CpG motifs). Short phosphorothioate-stabilized oligodeoxynucleotides (ODNs) containing such motifs are used as synthetic TLR9 agonists, and different classes of ODN TLR9 agonists have been identified with distinct immune modulatory profiles. The TLR9-mediated activation of the vertebrate immune system suggests using such TLR9 agonists as effective vaccine adjuvants for infectious disease, and for the treatment of cancer and asthma/allergy. Immune activation by CpG ODNs has been demonstrated to be beneficial in animal models as a vaccine adjuvant and for the treatment of a variety of viral, bacterial, and parasitic diseases. Antitumor activity of CpG ODNs has also been established in numerous mouse models. In clinical vaccine trials in healthy human volunteers or in immunocompromised HIV-infected patients, CpG ODNs strongly enhanced vaccination efficiency. Most encouraging results in the treatment of cancers have come from human phase I and II clinical trials using CpG ODNs as a tumor vaccine adjuvant, monotherapy, or in combination with chemotherapy. Therefore, CpG ODNs represent targeted immune modulatory drugs with a broad range of potential applications. PMID:18020622

  2. Formoterol in the management of chronic obstructive pulmonary disease

    OpenAIRE

    Paschalis Steiropoulos; Argyris Tzouvelekis; Demosthenes Bouros

    2008-01-01

    Paschalis Steiropoulos, Argyris Tzouvelekis, Demosthenes BourosDepartment of Pneumonology, University Hospital of Alexandroupolis, GreeceAbstract: Bronchodilators represent the hallmark of symptomatic treatment of Chronic Obstructive Pulmonary Disease (COPD). There are four categories of bronchodilators: anticholinergics, methylxanthines, short-acting β2-agonists, and long-acting β2-agonists such as formoterol. Significant research has been performed to investigate the effic...

  3. Active gust load alleviation system for flexible aircraft: Mixed feedforward/feedback approach

    DEFF Research Database (Denmark)

    Alam, Mushfiqul; Hromcik, Martin; Hanis, Tomas

    2015-01-01

    Lightweight flexible blended-wing-body (BWB) aircraft concept seems as a highly promising configuration for future high capacity airliners which suffers from reduced stiffness for disturbance loads such as gusts. A robust feedforward gust load alleviation system (GLAS) was developed to alleviate ...

  4. Distinct conformational changes in activated agonist-bound and agonist-free glycine receptor subunits

    DEFF Research Database (Denmark)

    Pless, Stephan Alexander; Lynch, Joseph W

    2009-01-01

    glycine-free or a glycine-bound subunit. Agonist-free subunits were created by incorporating T204A and R65K mutations, which disrupted glycine binding to both (+) and (-) subunit interfaces. In heteromeric receptors comprising wild-type and R65K,T204A,R271C triple-mutant subunits, the fluorescence...... response exhibited a drastically reduced glycine sensitivity relative to the current response. Two conclusions can be drawn from this. First, because the labeled glycine-free subunits were activated by glycine binding to neighboring wild-type subunits, our results provide evidence for a cooperative...... activation mechanism. However, because the fluorescent label on glycine-free subunits does not reflect movements at the channel gate, we conclude that glycine binding also produces a local non-concerted conformational change that is not essential for receptor activation....

  5. Curcumin analog L3 alleviates diabetic atherosclerosis by multiple effects.

    Science.gov (United States)

    Zheng, Bin; Yang, Liu; Wen, Caixia; Huang, Xiuwang; Xu, Chenxia; Lee, Kuan-Han; Xu, Jianhua

    2016-03-15

    L3, an analog of curcumin, is a compound isolated from a traditional Chinese medicine Turmeric. In this paper, we aims to explore the efficacy of L3 on diabetic atherosclerosis and the related mechanism. The effect of L3 was studied on glucose and lipid metabolism, antioxidant status, atherosclerosis-related indexes and pathological changes of main organs in the mice model of diabetes induced by streptozotocin and high-fat diet. The results showed that L3 treatment could meliorate dyslipidemia and hyperglycemia, reduce oxidative stress, enhance the activity of antioxidases, increase the nitric oxide level in plasma and aortic arch, decrease the production of reactive oxygen species in pancreas and lectin-like oxidized low-density lipoprotein receptor-1 expression in aortic arch, and meliorate the fatty and atherosclerotic degeneration in aortic arch, thereby preventing the development of diabetes and its complications. These results suggested that L3 can alleviate the diabetic atherosclerosis by multiple effects. This study provided scientific basis for the further research and clinical application of L3. PMID:26852952

  6. Aeroelastic scaling laws for gust load alleviation control system

    Institute of Scientific and Technical Information of China (English)

    Tang Bo; Wu Zhigang; Yang Chao

    2016-01-01

    Gust load alleviation (GLA) tests are widely conducted to study the effectiveness of the control laws and methods. The physical parameters of models in these tests are aeroelastic scaled, while the scaling of GLA control system is always unreached. This paper concentrates on studying the scaling laws of GLA control system. Through theoretical demonstration, the scaling criterion of a classical PID control system has been come up and a scaling methodology is provided and veri-fied. By adopting the scaling laws in this paper, gust response of the scaled model could be directly related to the full-scale aircraft theoretically under both open-loop and closed-loop conditions. Also, the influences of different scaling choices of an important non-dimensional parameter, the Froude number, have been studied in this paper. Furthermore for practical application, a compen-sating method is given when the theoretical scaled actuators or sensors cannot be obtained. Also, the scaling laws of some non-linear elements in control system such as the rate and amplitude sat-urations in actuator have been studied and examined by a numerical simulation.

  7. Probucol alleviates atherosclerosis and improves high density lipoprotein function

    Directory of Open Access Journals (Sweden)

    Zhong Jian-Kai

    2011-11-01

    Full Text Available Abstract Background Probucol is a unique hypolipidemic agent that decreases high density lipoprotein cholesterol (HDL-C. However, it is not definite that whether probucol hinders the progression of atherosclerosis by improving HDL function. Methods Eighteen New Zealand White rabbits were randomly divided into the control, atherosclerosis and probucol groups. Control group were fed a regular diet; the atherosclerosis group received a high fat diet, and the probucol group received the high fat diet plus probucol. Hepatocytes and peritoneal macrophages were isolated for [3H] labeled cholesterol efflux rates and expression of ABCA1 and SR-B1 at gene and protein levels; venous blood was collected for serum paraoxonase 1, myeloperoxidase activity and lipid analysis. Aorta were prepared for morphologic and immunohistochemical analysis after 12 weeks. Results Compared to the atherosclerosis group, the paraoxonase 1 activity, cholesterol efflux rates, expression of ABCA1 and SR-BI in hepatocytes and peritoneal macrophages, and the level of ABCA1 and SR-BI in aortic lesions were remarkably improved in the probucol group, But the serum HDL cholesterol concentration, myeloperoxidase activity, the IMT and the percentage plaque area of aorta were significantly decreased. Conclusion Probucol alleviated atherosclerosis by improving HDL function. The mechanisms include accelerating the process of reverse cholesterol transport, improving the anti-inflammatory and anti-oxidant functions.

  8. Effectiveness of Zakah Targeting in Alleviating Poverty in Indonesia

    Directory of Open Access Journals (Sweden)

    Rahmatina A Kasri

    2016-07-01

    Full Text Available Zakah is a unique Islamic institution targeted to eight groups of recipients with the aim to redistribute income, reduce poverty and achieve social welfare. However, the impacts and effectiveness of zakah targeting in reducing poverty is rarely measured. This is the main objective of the study. To achieve it, a survey was conducted to collect primary data from zakah recipients in Greater Jakarta Indonesia. The data were subsequently analysed by using descriptive and poverty index analyses. The main results suggest that the incidence, depth and severity of poverty amongst the recipients have decreased due to the contributions from zakah organizations. There are also indications that zakah has been distributed to the most disadvantaged people such as the uneducated and unemployed. The findings provide empirical evidence regarding positive contribution and effectiveness of zakah targeting in reducing poverty in Indonesia. Some policy implications of the findings are also highlighted to enrich discourses on the role of zakah in alleviating poverty in Muslim societies.DOI: 10.15408/aiq.v8i2.3005

  9. Aeroelastic scaling laws for gust load alleviation control system

    Directory of Open Access Journals (Sweden)

    Tang Bo

    2016-02-01

    Full Text Available Gust load alleviation (GLA tests are widely conducted to study the effectiveness of the control laws and methods. The physical parameters of models in these tests are aeroelastic scaled, while the scaling of GLA control system is always unreached. This paper concentrates on studying the scaling laws of GLA control system. Through theoretical demonstration, the scaling criterion of a classical PID control system has been come up and a scaling methodology is provided and verified. By adopting the scaling laws in this paper, gust response of the scaled model could be directly related to the full-scale aircraft theoretically under both open-loop and closed-loop conditions. Also, the influences of different scaling choices of an important non-dimensional parameter, the Froude number, have been studied in this paper. Furthermore for practical application, a compensating method is given when the theoretical scaled actuators or sensors cannot be obtained. Also, the scaling laws of some non-linear elements in control system such as the rate and amplitude saturations in actuator have been studied and examined by a numerical simulation.

  10. 扶贫研究概述%On Poverty Alleviation

    Institute of Scientific and Technical Information of China (English)

    肖立新

    2011-01-01

    贫困是一个伴随着人类生存和发展的历史性问题;同时,贫困也是一个存在于发达国家和发展中国家的世界性问题。2011年起,我国对农村低收入人口全面实施扶贫政策,实行新的扶贫标准,新标准提高到人均1500元,扶贫对象覆盖9000万人左右,标志着我国扶贫开发进入一个新阶段。但这也意味着我国扶贫工作的长期性、艰巨性。为此,作者对贫困、扶贫的国内外研究现状进行梳理,以期为相关的研究和扶贫实践提供理论借鉴和实践借鉴。%Poverty is a historical problem that accompanied by survival and development of humankind.Meanwhile,poverty is also a world-wide problem that exists in developed and developing countries.Since 2011,China has carried out policies of poverty alleviation on

  11. Indacaterol: a new once daily long-acting beta2 adrenoceptor agonist

    Directory of Open Access Journals (Sweden)

    Kai M Beeh

    2009-06-01

    Full Text Available Kai M Beeh, Jutta BeierInsaf Respiratory Research Institute, Wiesbaden, GermanyIntroduction: Indacaterol is a novel once daily long-acting beta agonist (LABA developed for the treatment of chronic obstructive pulmonary disease (COPD and asthma.Aims: This review summarizes preclinical and clinical data of indacaterol, including all data generated during the phase II trial program, and further discusses the outlook and potential of the drug in the future treatment of COPD and asthma.Evidence review: Clinical studies suggest that indacaterol produces rapid and sustained bronchodilation in COPD patients and asthmatics of different severities. Until now, clinical studies of up to 28 days’ duration have been published that have confirmed the suitability of indacaterol for once daily dosing, along with a favorable overall safety and tolerability profile. Outcomes summary: Indacaterol monotherapy has potential in COPD, where antiinflammatory treatment is not fully established and issues about a potential risk of LABA use causing excess mortality have not been raised. In addition, indacaterol represents an option for future combination therapies in both asthma and COPD. However, more data are required, particularly in COPD, to fully assess the therapeutic potential of indacaterol in improving symptoms, quality of life, exacerbation rates, disease progression, exercise capacity, and hyperinflation. The currently ongoing phase III clinical trial program will add knowledge in respect to many long-term efficacy outcomes and gather further safety and tolerability data in both asthma and COPD. Keywords: indacaterol, long-acting beta agonist, asthma, COPD

  12. Nutmeg oil alleviates chronic inflammatory pain through inhibition of COX-2 expression and substance P release in vivo

    Science.gov (United States)

    Zhang, Wei Kevin; Tao, Shan-Shan; Li, Ting-Ting; Li, Yu-Sang; Li, Xiao-Jun; Tang, He-Bin; Cong, Ren-Huai; Ma, Fang-Li; Wan, Chu-Jun

    2016-01-01

    Background Chronic pain, or sometimes referred to as persistent pain, reduces the life quality of patients who are suffering from chronic diseases such as inflammatory diseases, cancer and diabetes. Hence, herbal medicines draw many attentions and have been shown effective in the treatment or relief of pain. Methods and Results Here in this study, we used the CFA-injected rats as a sustainable pain model to test the anti-inflammatory and analgesic effect of nutmeg oil, a spice flavor additive to beverages and baked goods produced from the seed of Myristica fragrans tree. Conclusions We have demonstrated that nutmeg oil could potentially alleviate the CFA-injection induced joint swelling, mechanical allodynia and heat hyperanalgesia of rats through inhibition of COX-2 expression and blood substance P level, which made it possible for nutmeg oil to be a potential chronic pain reliever. PMID:27121041

  13. Heart Valve Disease among Patients with Hyperprolactinaemia

    DEFF Research Database (Denmark)

    Steffensen, Charlotte; Maegbaek, Merete Lund; Laurberg, Peter;

    2012-01-01

    Increased risk of heart valve disease during treatment with certain dopamine agonists, such as cabergoline, has been observed in patients with Parkinson's disease. The same compound is used to treat hyperprolactinemia, but it is unknown whether this also associates with heart valve disease....

  14. Neurotransmitter replacement therapy in Alzheimer's disease.

    OpenAIRE

    Mohr, E; Mendis, T; Rusk, I N; Grimes, J. D.

    1994-01-01

    The relative success of symptomatic attenuation of motor dysfunction in Parkinson's disease with dopaminomimetics has spurred interest in neurotransmitter replacement therapy for treating Alzheimer's disease. While cholinergic dysfunction has been linked to various clinical parameters in Alzheimer's disease, cholinergic replacement, including precursor therapy, administration of direct-acting agonists and inhibition of enzymatic degradation has had only very modest success. The inhibition of ...

  15. Alpha-2 agonists as pain therapy in horses.

    Science.gov (United States)

    Valverde, Alexander

    2010-12-01

    Alpha-2 agonists, such as xylazine, clonidine, romifidine, detomidine, medetomidine, and dexmedetomidine, are potent analgesic drugs that also induce physiologic and behavioral changes, such as hypertension, bradycardia, atrioventricular block, excessive sedation and ataxia, all of which can potentially limit their systemic use as analgesics in some clinical cases. The use of medetomidine and dexmetomidine has been introduced for equine anesthesia/analgesia, and although not approved in this species, their increased specificity for alpha-2 receptors may offer some potential advantages over the traditional alpha-2 agonists. Similarly, other routes of administration and benefits of alpha-2 agonists are recognized in the human and laboratory animal literature, which may prove useful in the equine patient if validated in the near future. This review presents this relevant information. PMID:21056297

  16. Principles of agonist recognition in Cys-loop receptors

    Directory of Open Access Journals (Sweden)

    Timothy eLynagh

    2014-04-01

    Full Text Available Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine and GABA. After the term chemoreceptor emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands.

  17. In silico discovery of novel Retinoic Acid Receptor agonist structures

    Directory of Open Access Journals (Sweden)

    Samuels Herbert H

    2001-06-01

    Full Text Available Abstract Background Several Retinoic Acid Receptors (RAR agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. Results We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually to the structure of the receptor with the Internal Coordinates Mechanics (ICM program. Thirty ligand candidates were tested in vitro. Conclusions Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

  18. Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor.

    Directory of Open Access Journals (Sweden)

    Ying Shi

    Full Text Available The histamine H3 receptor (H3R has been recognized as a promising target for the treatment of various central and peripheral nervous system diseases. In this study, a non-imidazole compound, ZEL-H16, was identified as a novel histamine H3 receptor agonist. ZEL-H16 was found to bind to human H3R with a Ki value of approximately 2.07 nM and 4.36 nM to rat H3R. Further characterization indicated that ZEL-H16 behaved as a partial agonist on the inhibition of forskolin-stimulated cAMP accumulation (the efficacy was 60% of that of histamine and activation of ERK1/2 signaling (the efficacy was 50% of that of histamine at H3 receptors, but acted as a full agonist just like histamin in the guinea-pig ileum contraction assay. These effects were blocked by pertussis toxin and H3 receptor specific antagonist thioperamide. ZEL-H16 showed no agonist or antagonist activities at the cloned human histamine H1, H2, and H4 receptors and other biogenic amine GPCRs in the CRE-driven reporter assay. Furthermore, our present data demonstrated that treatment of ZEL-H16 resulted in intensive H3 receptor internalization and delayed recycling to the cell surface as compared to that of control with treatment of histamine. Thus, ZEL-H16 is a novel and potent nonimidazole agonist of H3R, which might serve as a pharmacological tool for future investigations or as possible therapeutic agent of H3R.

  19. Identification of PPARgamma partial agonists of natural origin (II: in silico prediction in natural extracts with known antidiabetic activity.

    Directory of Open Access Journals (Sweden)

    Laura Guasch

    Full Text Available BACKGROUND: Natural extracts have played an important role in the prevention and treatment of diseases and are important sources for drug discovery. However, to be effectively used in these processes, natural extracts must be characterized through the identification of their active compounds and their modes of action. METHODOLOGY/PRINCIPAL FINDINGS: From an initial set of 29,779 natural products that are annotated with their natural source and using a previously developed virtual screening procedure (carefully validated experimentally, we have predicted as potential peroxisome proliferators-activated receptor gamma (PPARγ partial agonists 12 molecules from 11 extracts known to have antidiabetic activity. Six of these molecules are similar to molecules with described antidiabetic activity but whose mechanism of action is unknown. Therefore, it is plausible that these 12 molecules could be the bioactive molecules responsible, at least in part, for the antidiabetic activity of the extracts containing them. In addition, we have also identified as potential PPARγ partial agonists 10 molecules from 16 plants with undescribed antidiabetic activity but that are related (i.e., they are from the same genus to plants with known antidiabetic properties. None of the 22 molecules that we predict as PPARγ partial agonists show chemical similarity with a group of 211 known PPARγ partial agonists obtained from the literature. CONCLUSIONS/SIGNIFICANCE: Our results provide a new hypothesis about the active molecules of natural extracts with antidiabetic properties and their mode of action. We also suggest plants with undescribed antidiabetic activity that may contain PPARγ partial agonists. These plants represent a new source of potential antidiabetic extracts. Consequently, our work opens the door to the discovery of new antidiabetic extracts and molecules that can be of use, for instance, in the design of new antidiabetic drugs or functional foods focused

  20. Inhibition of the mitochondrial unfolded protein response by acetylcholine alleviated hypoxia/reoxygenation-induced apoptosis of endothelial cells.

    Science.gov (United States)

    Xu, Man; Bi, Xueyuan; He, Xi; Yu, Xiaojiang; Zhao, Ming; Zang, Weijin

    2016-05-18

    The mitochondrial unfolded protein response (UPR(mt)) is involved in numerous diseases that have the common feature of mitochondrial dysfunction. However, its pathophysiological relevance in the context of hypoxia/reoxygenation (H/R) in endothelial cells remains elusive. Previous studies have demonstrated that acetylcholine (ACh) protects against cardiomyocyte injury by suppressing generation of mitochondrial reactive oxygen species (mtROS). This study aimed to explore the role of UPR(mt) in endothelial cells during H/R and to clarify the beneficial effects of ACh. Our results demonstrated that H/R triggered UPR(mt) in endothelial cells, as evidenced by the elevation of heat shock protein 60 and LON protease 1 protein levels, and resulted in release of mitochondrial pro-apoptotic proteins, including cytochrome C, Omi/high temperature requirement protein A 2 and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low PI, from the mitochondria to cytosol. ACh administration markedly decreased UPR(mt) by inhibiting mtROS and alleviating the mitonuclear protein imbalance. Consequently, ACh alleviated the release of pro-apoptotic proteins and restored mitochondrial ultrastructure and function, thereby reducing the number of terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL)-positive cells. Intriguingly, 4-diphenylacetoxy-N-methylpiperidine methiodide, a type-3 muscarinic ACh receptor (M3AChR) inhibitor, abolished the ACh-elicited attenuation of UPR(mt) and TUNEL positive cells, indicating that the salutary effects of ACh were likely mediated by M3AChR in endothelial cells. In conclusion, our studies demonstrated that UPR(mt) might be essential for triggering the mitochondrion-associated apoptotic pathway during H/R. ACh markedly suppressed UPR(mt) by inhibiting mtROS and alleviating the mitonuclear protein imbalance, presumably through M3AChR. PMID:27111378

  1. Synthesis of Selective A3 and M1 Receptor Agonists

    OpenAIRE

    Snee, Stephen

    2011-01-01

    Detailed within this thesis is the synthesis of three A1 agonists which were designed by Muscagen using computational studies. The agonists are derived from condensation of the modified adenosine: (4S,6R)-6-(6-chloro-9H-purin-9-yl)-N,2,2-trimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide with novel heterocyclic primary amines.The amines 5-(aminomethyl)-N,N-diethyl-7-methyloxazolo[4,5-b]pyridin-2-amine, 5-(1-aminoethyl)-N,N,7-trimethyloxazolo[4,5-b]pyridin-2-amine and 5-(1-aminoethyl)-N,...

  2. Adenosine A1 receptor agonists inhibit trigeminovascular nociceptive transmission

    DEFF Research Database (Denmark)

    Goadsby, P J; Hoskin, K L; Storer, R J;

    2002-01-01

    There is a considerable literature to suggest that adenosine A1 receptor agonists may have anti-nociceptive effects, and we sought to explore the role of adenosine A1 receptors in a model of trigeminovascular nociceptive transmission. Cats were anaesthetized (alpha-chloralose 60 mg/kg, intraperit......There is a considerable literature to suggest that adenosine A1 receptor agonists may have anti-nociceptive effects, and we sought to explore the role of adenosine A1 receptors in a model of trigeminovascular nociceptive transmission. Cats were anaesthetized (alpha-chloralose 60 mg...

  3. Nephrogenic Systemic Fibrosis Symptoms Alleviated by Renal Transplantation

    DEFF Research Database (Denmark)

    Bangsgaard, Nannie; Hansen, J. M.; Marckmann, P.; Skov, L.

    2011-01-01

    Nephrogenic systemic fibrosis (NSF) is a rare, serious, and life-threatening disease of patients with severe renal impairment. Gadolinium-containing contrast agents have been shown to be the crucial trigger. There is no proven medical cure for the disease, and symptomatic treatment options are...

  4. Stratification requirements for seed dormancy alleviation in a wetland weed.

    Directory of Open Access Journals (Sweden)

    Louis G Boddy

    Full Text Available Echinochloaoryzicola(syn.E. phyllopogon is an exotic weed of California rice paddies that has evolved resistance to multiple herbicides. Elimination of seedlingsthroughcertain weed control methods can limit the spread of this weed, but is contingent on accurate predictions of germination and emergence timing, which are influenced by seed dormancy levels.In summer annuals, dormancy can often be relieved through stratification, a period of prolonged exposure to cold and moist conditions.We used population-based threshold models to quantify the effects of stratification on seed germination of four E. Oryzicola populations at a range of water potential (Ψ and oxygen levels. We also determined how stratification temperatures, moisture levels and durations contributed to dormancy release. Stratification released dormancy by decreasing base Ψ and hydrotimerequired for germination and by eliminating any germination sensitivity to oxygen. Stratification also increased average germination rates (GR, which were used as a proxy for relative dormancy levels. Alternating temperatures nearly doubled GR in all populations, indicating that seeds could be partially dormant despite achieving high final germination percentages. Stratification at Ψ = 0 MPa increased GR compared to stratification at lower water potentials, demonstrating that Ψ contributed to regulating dormancy release. Maximum GR occurred after 2-4 weeks of stratification at 0 MPa; GR were often more rapid for herbicide-resistant than for herbicide-susceptible seeds, implying greater dormancy in the latter. Manipulation of field conditions to promote dormancy alleviation of E. oryzicola seeds might improve the rate and uniformity of germination for seed bank depletion through seedling weed control. Our results suggest field soil saturation in winter would contribute towards E. oryzicola dormancy release and decrease the time to seedling emergence.

  5. Towards a virtual observatory for ecosystem services and poverty alleviation

    Science.gov (United States)

    Buytaert, W.; Baez, S.; Cuesta, F.; Veliz Rosas, C.

    2010-12-01

    Over the last decades, near real-time environmental observation, technical advances in computer power and cyber-infrastructure, and the development of environmental software algorithms have increased dramatically. The integration of these evolutions, which is commonly referred to as the establishment of a virtual observatory, is one of the major challenges of the next decade for environmental sciences. Worldwide, many coordinated activities are ongoing to make this integration a reality. However, far less attention is paid to the question of how these developments can benefit environmental services management in a poverty alleviation context. Such projects are typically faced with issues of large predictive uncertainties, limited resources, limited local scientific capacity. At the same time, the complexity of the socio-economic contexts requires a very strong bottom-up oriented and interdisciplinary approach to environmental data collection and processing. In this study, we present three natural resources management cases in the Andes and the Amazon basin, and investigate how "virtual observatory" technology can improve ecosystem management. Each of these case studies present scientific challenges in terms of model coupling, real-time data assimilation and visualisation for management purposes. The first project deals with water resources management in the Peruvian Andes. Using a rainfall-runoff model, novel visualisations are used to give farmers insight in the water production and regulation capacity of their catchments, which can then be linked to land management practices such as conservation agriculture, wetland protection and grazing density control. In a project in the Amazonian floodplains, optimal allocation of the nesting availability and quality of the giant freshwater turtle are determined using a combined hydraulic model and weather forecasts. Finally, in the rainforest of the Yasuní Biosphere Reserve, Ecuador, biodiversity models are used to

  6. Biomass energy: Employment generation and its contribution to poverty alleviation

    International Nuclear Information System (INIS)

    Studies were undertaken in Malawi from 1995 to 1997 and 2007 to 2008 to estimate the supply and demand of household energy. Because little is known about the supply chain for biomass, surveys were carried out for urban areas on its production, transport and trade as well as sustainable supply. Also, because biomass is used by all people for a multitude of purposes, a complete picture was made of regional and urban biomass supply and demand. The results indicated that biomass is not only the principal energy, accounting for 89 percent of demand, but also the main traded energy in the two time periods accounting for 56-59 percent of commercial demand. Petroleum products supplied 26-27 percent, electricity 8-12 percent and coal 6-10 percent. The market value of traded woodfuel was US$ 48.8 million and US$ 81.0 million in 1996 and 2008 respectively, about 3.5 percent of gross domestic product (GDP). The study found that in 1996 and 2008 respectively, the equivalent of 93,500 and 133,000 full-time people was employed in the biomass supply chain, approximately 2 percent of the potential workforce. In contrast, about 3400 and 4600 people were employed in the supply chain of other fuels in these years. If the Malawi findings are applied to the current estimated wood energy consumption in sub-Saharan Africa, then approximately 13 million people could be employed in commercial biomass energy; this highlights its importance as a means to assist with sustainable development and poverty alleviation. (author)

  7. Building synergies between climate change mitigation and energy poverty alleviation

    International Nuclear Information System (INIS)

    Even though energy poverty alleviation and climate change mitigation are inextricably linked policy goals, they have remained as relatively disconnected fields of research inquiry and policy development. Acknowledging this gap, this paper explores the mainstream academic and policy literatures to provide a taxonomy of interactions and identify synergies and trade-offs between them. The most important trade-off identified is the potential increase in energy poverty levels as a result of strong climate change action if the internalisation of the external costs of carbon emissions is not offset by efficiency gains. The most significant synergy was found in deep energy efficiency in buildings. The paper argues that neither of the two problems – deep reductions in GHG emissions by mid-century, and energy poverty eradication – is likely to be solved fully on their own merit, while joining the two policy goals may provide a very solid case for deep efficiency improvements. Thus, the paper calls for a strong integration of these two policy goals (plus other key related benefits like energy security or employment), in order to provide sufficient policy motivation to mobilise a wide-scale implementation of deep energy efficiency standards. - Highlights: ► A taxonomy of interactions between climate change and energy poverty is offered. ► Energy poverty levels may increase as a result of strong climate change action. ► However, strong synergies are offered by deep improvements of energy efficiency. ► Access to modern energy carriers is a key requirement in developing countries. ► Sufficiently solving both problems requires the integration of policy goals.

  8. INTRATHYMIC INOCULATION OF LIVER SPECIFIC ANTIGEN ALLEVIATES LIVER TRANSPLANT REJECTION

    Institute of Scientific and Technical Information of China (English)

    贾长库; 郑树森; 朱有法

    2004-01-01

    Objective To study the effects of liver specific antigen (LSA) on liver allotransplantation rejection. Methods Orthotopic liver transplantation was performed in this study. Group Ⅰ: syngeneic control (Wistar-to-Wistar); Group Ⅱ: acute rejection (SD-to-Wistar). Group Ⅲ: thymic inoculation of SD rat LSA day 7 before transplantation. The observation of general condition and survival time, rejection grades and the NF-κB activity of splenocytes were used to analyze severity of acute rejection and immune state of animals in different groups. Results The general condition of group Ⅰ was fair post transplantation with no sign of rejection. All recipients of group Ⅱ died within days 9 to 13 post transplantation with median survival time of 10.7 ±1.37 days. As for group Ⅲ, 5 out of 6 recipients survived for a long period with remarkably better general condition than that of group Ⅱ. Its rejection grades were significantly lower than group Ⅱ (P< 0.05).NF-κB activity was only detected in group Ⅰ between days 5 and 7 after transplantation, whereas high activity of NF-κB was detected at all points in group Ⅱ and low NF-κB activity was detected in group Ⅲ which was significantly lower than that of group Ⅱ (P < 0.05). Conclusions LSA is an important transplantation antigen directly involved in the immunorejection of liver transplantation. Intrathymic inoculation of LSA can alleviate the rejection of liver allotransplantation,grafts survive for a period of time thereby, allowing a novel way to liver transplantation immunotolerance.

  9. Cellular Recycling of Proteins in Seed Dormancy Alleviation and Germination.

    Science.gov (United States)

    Oracz, Krystyna; Stawska, Marlena

    2016-01-01

    Each step of the seed-to-seed cycle of plant development including seed germination is characterized by a specific set of proteins. The continual renewal and/or replacement of these biomolecules are crucial for optimal plant adaptation. As proteins are the main effectors inside the cells, their levels need to be tightly regulated. This is partially achieved by specific proteolytic pathways via multicatalytic protease complexes defined as 20S and 26S proteasomes. In plants, the 20S proteasome is responsible for degradation of carbonylated proteins, while the 26S being a part of ubiquitin-proteasome pathway is known to be involved in proteolysis of phytohormone signaling regulators. On the other hand, the role of translational control of plant development is also well-documented, especially in the context of pollen tube growth and light signaling. Despite the current progress that has been made in seed biology, the sequence of cellular events that determine if the seed can germinate or not are still far from complete understanding. The role and mechanisms of regulation of proteome composition during processes occurring in the plant's photosynthetic tissues have been well-characterized since many years, but in non-photosynthetic seeds it has emerged as a tempting research task only since the last decade. This review discusses the recent discoveries providing insights into the role of protein turnover in seed dormancy alleviation, and germination, with a focus on the control of translation and proteasomal proteolysis. The presented novel data of translatome profiling in seeds highlighted that post-transcriptional regulation of germination results from a timely regulated initiation of translation. In addition, the importance of 26S proteasome in the degradation of regulatory elements of cellular signaling and that of the 20S complex in proteolysis of specific carbonylated proteins in hormonal- and light-dependent processes occurring in seeds is discussed. Based on the

  10. Strawberry consumption alleviates doxorubicin-induced toxicity by suppressing oxidative stress.

    Science.gov (United States)

    Giampieri, Francesca; Alvarez-Suarez, Jose M; Gasparrini, Massimiliano; Forbes-Hernandez, Tamara Y; Afrin, Sadia; Bompadre, Stefano; Rubini, Corrado; Zizzi, Antonio; Astolfi, Paola; Santos-Buelga, Celestino; González-Paramás, Ana M; Quiles, Josè L; Mezzetti, Bruno; Battino, Maurizio

    2016-08-01

    Doxorubicin (Dox), one of the most used chemotherapeutic agents, is known to generate oxidative stress and block DNA synthesis, which result in severe dose-limiting toxicity. A strategy to protect against Dox toxic effects could be to use dietary antioxidants of which fruits and vegetable are a rich source. In this context, strawberry consumption is associated with the maintenance of good health and the prevention of several diseases, thanks to the antioxidant capacities of its bioactive compounds. The aim of the present study was to evaluate the protective effects of strawberry consumption against oxidative stress induced by Dox in rats. Animals were fed with strawberry enriched diet (15% of the total calories) for two months and Dox (10 mg/kg; i.p.) was injected at the end of the experimental period. Strawberry consumption significantly inhibited ROS production and oxidative damage biomarkers accumulation in plasma and liver tissue and alleviated histopathological changes in rat livers treated with Dox. The reduction of antioxidant enzyme activities was significantly mitigated after strawberry consumption. In addition, strawberry enriched diet ameliorated liver mitochondrial antioxidant levels and functionality. In conclusion, strawberry intake protects against Dox-induced toxicity, at plasma, liver and mitochondrial levels thanks to its high contents of bioactive compounds. PMID:27286747

  11. Antioxidant properties of the mung bean flavonoids on alleviating heat stress.

    Directory of Open Access Journals (Sweden)

    Dongdong Cao

    Full Text Available BACKGROUND: It is a widespread belief in Asian countries that mung bean soup (MBS may afford a protective effect against heat stress. Lack of evidence supports MBS conferring a benefit in addition to water. RESULTS: Here we show that vitexin and isovitexin are the major antioxidant components in mungbean (more than 96% of them existing in the bean seed coat, and both of them could be absorbed via gavage into rat plasma. In the plasma of rats fed with mungbean coat extract before or after exposure to heat stress, the levels of malonaldehyde and activities of lactate dehydrogenase and nitric oxide synthase were remarkably reduced; the levels of total antioxidant capacity and glutathione (a quantitative assessment of oxidative stress were significantly enhanced. CONCLUSIONS: Our results demonstrate that MBS can play additional roles to prevent heat stress injury. Characterization of the mechanisms underlying mungbean beneficial effects should help in the design of diet therapy strategies to alleviate heat stress, as well as provide reference for searching natural medicines against oxidative stress induced diseases.

  12. Running Exercise Alleviates Pain and Promotes Cell Proliferation in a Rat Model of Intervertebral Disc Degeneration

    Directory of Open Access Journals (Sweden)

    Shuo Luan

    2015-01-01

    Full Text Available Chronic low back pain accompanied by intervertebral disk degeneration is a common musculoskeletal disorder. Physical exercise, which is clinically recommended by international guidelines, has proven to be effective for degenerative disc disease (DDD patients. However, the mechanism underlying the analgesic effects of physical exercise on DDD remains largely unclear. The results of the present study showed that mechanical withdrawal thresholds of bilateral hindpaw were significantly decreased beginning on day three after intradiscal complete Freund’s adjuvant (CFA injection and daily running exercise remarkably reduced allodynia in the CFA exercise group beginning at day 28 compared to the spontaneous recovery group (controls. The hindpaw withdrawal thresholds of the exercise group returned nearly to baseline at the end of experiment, but severe pain persisted in the control group. Histological examinations performed on day 70 revealed that running exercise restored the degenerative discs and increased the cell densities of the annulus fibrosus (AF and nucleus pulposus (NP. Furthermore, immunofluorescence labeling revealed significantly higher numbers of 5-bromo-2-deoxyuridine (BrdU-positive cells in the exercise group on days 28, 42, 56 and 70, which indicated more rapid proliferation compared to the control at the corresponding time points. Taken together, these results suggest that running exercise might alleviate the mechanical allodynia induced by intradiscal CFA injection via disc repair and cell proliferation, which provides new evidence for future clinical use.

  13. Two cases of radiotherapy-induced oral mucositis alleviated with hange-shashin-to

    International Nuclear Information System (INIS)

    It has been reported that concurrent chemoradiotherapy (CCRT) can result in a superior treatment response and survival outcome compared with radiotherapy alone in patients with squamous cell carcinoma of the head and neck, and it has become the standard of care for locally advanced disease and organ preservation. However, the major limitation to radiotherapy or CCRT is locoregional treatment-related toxicities, particularly oral mucositis (OM). We experienced two cases of pain-uncontrolled OM in which the Traditional Oriental Medicine Hange-shashin-to (TJ-14) was effective. A 44-year-old man with nasopharyngeal carcinoma and neck metastases underwent CCRT and suffered from OM of grade 3 according to the Common Terminology Criteria for Adverse Effects (CTCAE). His pain was uncontrolled with a variety of analgesics, so we prescribed TJ-14 for him as a gargle. Even during CCRT, the pain significantly diminished and OM was improved to grade 1. TJ-14 contributed to completion of CCRT and improvement of the patient's nutrition status. A 67-year-old man with unknown primary and neck metastases underwent neck dissection and adjuvant radiotherapy. During adjuvant radiotherapy, he had OM of grade 3 and was unable to eat, so he was hospitalized and was started to have TJ-14. Although his OM remained grade 3 during the therapy, his pain was alleviated, leading to completion of the treatment. TJ-14 can be an effective supportive therapy for OM caused by radiotherapy. (author)

  14. Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Ho, Peggy P; Steinman, Lawrence

    2016-02-01

    Bile acids are ligands for the nuclear hormone receptor, farnesoid X receptor (FXR). The bile acid-FXR interaction regulates bile acid synthesis, transport, and cholesterol metabolism. Recently, bile acid-FXR regulation has been reported to play an integral role in both hepatic and intestinal inflammation, and in atherosclerosis. In this study, we found that FXR knockout mice had more disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Obeticholic acid (6α-ethyl-chenodeoxycholic acid, 6-ECDCA), a synthetic FXR agonist, is an orally available drug that is currently in clinical trials for the treatment of inflammatory diseases such as alcoholic hepatitis, nonalcoholic steatohepatitis, and primary biliary cirrhosis. When we treated mice exhibiting established EAE with 6-ECDCA, or the natural FXR ligand chenodeoxycholic acid (CDCA), clinical disease was ameliorated by (i) suppressing lymphocyte activation and proinflammatory cytokine production; (ii) reducing CD4(+) T cells and CD19(+) B cell populations and their expression of negative checkpoint regulators programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and B and T lymphocyte attenuator (BTLA); (iii) increasing CD8(+) T cells and PD1, PDl-1, and BTLA expression; and (iv) reducing VLA-4 expression in both the T- and B-cell populations. Moreover, adoptive transfer of 6-ECDCA- or CDCA-treated donor cells failed to transfer disease in naive recipients. Thus, we show that FXR functions as a negative regulator in neuroinflammation and we highlight that FXR agonists represent a potential previously unidentified therapy for MS. PMID:26811456

  15. Recurrence after robotic myomectomy: is it associated with use of GnRH agonist?

    Science.gov (United States)

    Sangha, Roopina; Katukuri, Vivek; Palmer, Matthew; Khangura, Raminder Kaur

    2016-09-01

    Gonadotropin-releasing hormone (GnRH) agonist therapy is used before myomectomy to decrease the size of the fibroids, but its association with fibroid recurrence postoperatively remains unsettled. We undertook a retrospective study of robotic-assisted myomectomy (RM) patients at our academic medical center to determine symptomatic recurrence and reoperation rates in those who did versus did not receive preoperative GnRH therapy. Only patients, who had their index myomectomy at least 2 years prior to the chart review, were included in this study. Of 118 RM patients identified between January 2005 and December 2009, 17 patients (14.4 %) had symptomatic recurrence as early as 5 months to as late as 30 months postoperatively. The symptomatic recurrence group had significantly higher preoperative GnRH use (35 vs 9 % non-recurrence; p = 0.009). A total of 7.6 % of all patients underwent reoperation. GnRH agonist use was significantly higher in the reoperation group (56 vs 9 % no reoperation; p = 0.002). Cavity entry during the initial surgery was also more frequent in the reoperation group (56 vs 20 %; p = 0.030), whereas the presence of multiple fibroids, size of the largest leiomyoma, and uterine volume were not statistically different between groups. Our study is among the earliest to report RM reoperation rates in patients receiving preoperative GnRH therapy, showing that the role of GnRH agonist therapy to shrink myomas may not be beneficial when measured against risk of disease recurrence. PMID:27072151

  16. The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor.

    Directory of Open Access Journals (Sweden)

    Edmond F O'Donnell

    Full Text Available BACKGROUND: The aryl hydrocarbon receptor (AhR is a ligand-activated transcription factor that mediates the toxicity and biological activity of dioxins and related chemicals. The AhR influences a variety of processes involved in cellular growth and differentiation, and recent studies have suggested that the AhR is a potential target for immune-mediated diseases. METHODOLOGY/PRINCIPAL FINDINGS: During a screen for molecules that activate the AhR, leflunomide, an immunomodulatory drug presently used in the clinic for the treatment of rheumatoid arthritis, was identified as an AhR agonist. We aimed to determine whether any biological activity of leflunomide could be attributed to a previously unappreciated interaction with the AhR. The currently established mechanism of action of leflunomide involves its metabolism to A771726, possibly by cytochrome P450 enzymes, followed by inhibition of de novo pyrimidine biosynthesis by A771726. Our results demonstrate that leflunomide, but not its metabolite A771726, caused nuclear translocation of AhR into the nucleus and increased expression of AhR-responsive reporter genes and endogenous AhR target genes in an AhR-dependent manner. In silico Molecular Docking studies employing AhR ligand binding domain revealed favorable binding energy for leflunomide, but not for A771726. Further, leflunomide, but not A771726, inhibited in vivo epimorphic regeneration in a zebrafish model of tissue regeneration in an AhR-dependent manner. However, suppression of lymphocyte proliferation by leflunomide or A771726 was not dependent on AhR. CONCLUSIONS: These data reveal that leflunomide, an anti-inflammatory drug, is an agonist of the AhR. Our findings link AhR activation by leflunomide to inhibition of fin regeneration in zebrafish. Identification of alternative AhR agonists is a critical step in evaluating the AhR as a therapeutic target for the treatment of immune disorders.

  17. The Approaches of Islamic and Conventional Microfinancing for Poverty Alleviation and Sustainable Livelihood

    Directory of Open Access Journals (Sweden)

    Abul Bashar Bhuiyan

    2012-01-01

    Full Text Available Poverty is the main illness for sustainable livelihood because it destroyed human basic rights for surviving with minimum opportunities especially political, social stability and economic processes, literature and environment. The aims of this study are to discuss about existing approaches of poverty alleviation and sustainable livelihood. The study found throughout the discussion of the theoretical sources i.e., participatory approaches have determined as a good way of poverty alleviation and sustainable livelihood especially zakat based Islamic mode of financing and Qard-al-Hasan on the basis of spiritual values as an alternative model for poverty alleviation and ensuring sustainable livelihood."

  18. Can Aidi injection alleviate the toxicity and improve the clinical efficacy of radiotherapy in lung cancer?

    Science.gov (United States)

    Xiao, Zheng; Liang, Rui; Wang, Cheng-qiong; Xu, Shaofeng; Li, Nana; He, Yuejuan; Tang, Fushan; Chen, Ling; Ma, Hu

    2016-01-01

    Abstract Background/Introduction: Aidi injection plus radiotherapy is widely used for lung cancer in China. Can Aidi injection alleviate the toxicity and improve the clinical efficacy of radiotherapy in lung cancer? Has Aidi injection the attenuation and synergistic efficacy to radiotherapy? There is lack of strong evidence to prove it. Objectives: To reveal its real attenuation and synergistic efficacy to radiotherapy and provide sufficient evidence for adjuvant chemotherapy strategies to lung cancer, we systematically evaluated all related studies. Data Sources: We collected all studies about Aidi injection plus radiotherapy for lung cancer in Medline, Embase, Web of Science, China national knowledge infrastructure database (CNKI), Chinese scientific journals full-text database (VIP), Wanfang database, China biological medicine database (CBM) (established to June 2015), and Cochrane Central Register of Controlled Trials (June 2015), evaluated their quality according to the Cochrane evaluation handbook of randomized controlled trials (5.1.0), extracted data following the PICO principles and synthesized the data by Meta analysis. Results: Sixteen randomized controlled trials (RCTs) with 1192 lung cancer patients were included, with general methodological quality in most trials. The merged relative risk (RR) values and their 95% CI of meta-analysis for objective response rate (ORR), disease control rate (DCR), and quality of life (QOL) were as follows: 1.54, (1.39,1.70), 1.10 (1.02, 1.19), and 2.13 (1.68, 2.68). The merged RR values and their 95% CI of meta-analysis for myelosuppression and neutropenia, radiation pneumonitis, and radiation esophagitis were as follows: 0.51 (0.38, 0.69), 0.53 (0.42, 0.65), 0.52 (0.41, 0.67), and 0.52 (0.40, 0.68). All were statistically significant. The possibility of publication bias was small which objectively reported the results. Conclusions: The evidence available indicates that Aidi injection plus radiotherapy can significantly

  19. Dopamine Receptors and Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Shin Hisahara

    2011-01-01

    Full Text Available Parkinson's disease (PD is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS. In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist.

  20. A high affinity kidney targeting by chitobionic acid-conjugated polysorbitol gene transporter alleviates unilateral ureteral obstruction in rats.

    Science.gov (United States)

    Islam, Mohammad Ariful; Kim, Sanghwa; Firdous, Jannatul; Lee, Ah-Young; Hong, Seong-Ho; Seo, Min Kyeong; Park, Tae-Eun; Yun, Cheol-Heui; Choi, Yun-Jaie; Chae, Chanhee; Cho, Chong-Su; Cho, Myung-Haing

    2016-09-01

    Aside from kidney transplantation - a procedure which is exceedingly dependent on donor-match and availability leading to excessive costs - there are currently no permanent treatments available which reverse kidney injury and failure. However, kidney-specific targeted gene therapy has outstanding potential to treat kidney-related dysfunction. Herein we report a novel kidney-specific targeted gene delivery system developed through the conjugation of chitobionic acid (CBA) to a polysorbitol gene transporter (PSGT) synthesized from sorbitol diacrylate and low molecular weight polyethylenimine (PEI) carrying hepatocyte growth factor (HGF) gene to alleviate unilateral ureteral obstruction (UUO) in rats. CBA-PSGT performed exceptionally well for targeted delivery of HGF to kidney tissues compared to its non-targeted counterparts (P type I and II), blood urea nitrogen (BUN), creatinine, and the expressions of ICAM-1, TIMP-1 and α-SMA which play a critical role in obstructive kidney functions. Therefore, CBA-PSGT should be further investigated because of its potential to alleviate UUO and kidney-related diseases using high affinity kidney targeting. PMID:27318934

  1. Short-term intratracheal use of PEG-modified IL-2 and glucocorticoid persistently alleviates asthma in a mouse model

    Science.gov (United States)

    Wu, Kefei; Ma, Jiexian; Bai, Weiya; Cui, Xiaoxian; Han, Tao; Wang, Shiyuan; Xie, Youhua; Xie, Yanhui

    2016-01-01

    Regulatory T (Treg) cells play an important role in allergic airway diseases, and upregulation of Treg cells is a potential therapeutic strategy for asthma. In this study, we show that short-term intratracheal use of IL-2 combined with glucocorticoid alleviates antigen-induced airway inflammation and reduces airway hyperresponsiveness by expanding antigen-nonspecific Treg cells, with a decrease in T helper 2 (Th2) cells and Th2-associated cytokines. We also designed a long-acting polyethylene glycol (PEG)-modified IL-2 and demonstrated that the optimal dosage form is IL-2(PEG) plus budesonide, which can upregulate Treg cells and ameliorate asthma at a lower dose. The therapeutic effect was faster than treatment with dexamethasone and was effective at a low dose suitable for humans that could last for at least 6 weeks. This study unveils a new therapeutic regimen and suggests that such endogenous Treg therapy could be a useful tool to persistently alleviate asthma. PMID:27527926

  2. Neonatal Bacillus Calmette-Guérin vaccination alleviates lipopolysaccharide-induced neurobehavioral impairments and neuroinflammation in adult mice.

    Science.gov (United States)

    Yang, Junhua; Qi, Fangfang; Yao, Zhibin

    2016-08-01

    The Bacillus Calmette-Guérin (BCG) vaccine is routinely administered to human neonates worldwide. BCG has recently been identified as a neuroprotective immune mediator in several neuropathological conditions, exerting neuroprotection in a mouse model of Parkinson's disease and slowing the progression of clinically isolated syndrome in patients with multiple sclerosis. The immune system is significantly involved in brain development, and several types of neonatal immune activations exert influences on the brain and behavior following a secondary immune challenge in adulthood. However, whether the neonatal BCG vaccination affects the brain in adulthood remains to be elucidated. In the present study, newborn C57BL/6 mice were injected subcutaneously with BCG (105 colony forming units) or phosphate‑buffered saline (PBS). A total of 12 weeks later, the mice were injected intraperitoneally with 330 µg/kg lipopolysaccharide (LPS) or PBS. The present study reported that the neonatal BCG vaccination alleviated sickness, anxiety and depression‑like behavior, lessened the impairments in hippocampal cell proliferation and downregulated the proinflammatory responses in the serum and brain that were induced by the adult LPS challenge. However, BCG vaccination alone had no evident influence on the brain and behavior in adulthood. In conclusion, the neonatal BCG vaccination alleviated the neurobehavioral impairments and neuroinflammation induced by LPS exposure in adult mice, suggesting a potential neuroprotective role of the neonatal BCG vaccination in adulthood. PMID:27357155

  3. Short-term intratracheal use of PEG-modified IL-2 and glucocorticoid persistently alleviates asthma in a mouse model.

    Science.gov (United States)

    Wu, Kefei; Ma, Jiexian; Bai, Weiya; Cui, Xiaoxian; Han, Tao; Wang, Shiyuan; Xie, Youhua; Xie, Yanhui

    2016-01-01

    Regulatory T (Treg) cells play an important role in allergic airway diseases, and upregulation of Treg cells is a potential therapeutic strategy for asthma. In this study, we show that short-term intratracheal use of IL-2 combined with glucocorticoid alleviates antigen-induced airway inflammation and reduces airway hyperresponsiveness by expanding antigen-nonspecific Treg cells, with a decrease in T helper 2 (Th2) cells and Th2-associated cytokines. We also designed a long-acting polyethylene glycol (PEG)-modified IL-2 and demonstrated that the optimal dosage form is IL-2(PEG) plus budesonide, which can upregulate Treg cells and ameliorate asthma at a lower dose. The therapeutic effect was faster than treatment with dexamethasone and was effective at a low dose suitable for humans that could last for at least 6 weeks. This study unveils a new therapeutic regimen and suggests that such endogenous Treg therapy could be a useful tool to persistently alleviate asthma. PMID:27527926

  4. Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands

    DEFF Research Database (Denmark)

    Herth, Matthias M; Petersen, Ida Nymann; Hansen, Hanne Demant;

    2016-01-01

    INTRODUCTION: The serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins...... developed and validated the first 5-HT2AR agonist PET tracer, [(11)C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an (18)F-labeled 5-HT2AR agonist PET-ligand. METHODS AND RESULTS: Three fluorine containing derivatives of Cimbi-36 were synthesized and found...... characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [(18)F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist....

  5. Duration of drug action of dopamine D2 agonists in mice with 6-hydroxydopamine-induced lesions.

    Science.gov (United States)

    Tsuchioka, Akihiro; Oana, Fumiki; Suzuki, Takayuki; Yamauchi, Yuji; Ijiro, Tomoyuki; Kaidoh, Kouichi; Hiratochi, Masahiro

    2015-12-16

    Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans. PMID:26559726

  6. Innovations in agonist maintenance treatment of opioid-dependent patients

    NARCIS (Netherlands)

    C. Haasen; W. van den Brink

    2006-01-01

    Purpose of review To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. Recent findings The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid depe

  7. Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Due-Hansen, Maria E; Urban, Christian;

    2012-01-01

    FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic...

  8. N-methyl-D-aspartic acid receptor agonists

    DEFF Research Database (Denmark)

    Madsen, U; Frydenvang, Karla Andrea; Ebert, B;

    1996-01-01

    (R,S)-2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid [(R,S)-AMAA, 4] is a potent and selective agonist at the N-methyl-D-aspartic acid (NMDA) subtype of excitatory amino acid receptors. Using the Ugi "four-component condensation" method, the two diastereomers (2R)- and (2S)-2-[3-(benzylox...

  9. Glucagon-like peptide 1 receptor agonist (GLP-1 RA)

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter;

    2015-01-01

    AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim was to...

  10. Synthetic RORγt Agonists Enhance Protective Immunity.

    Science.gov (United States)

    Chang, Mi Ra; Dharmarajan, Venkatasubramanian; Doebelin, Christelle; Garcia-Ordonez, Ruben D; Novick, Scott J; Kuruvilla, Dana S; Kamenecka, Theodore M; Griffin, Patrick R

    2016-04-15

    The T cell specific RORγ isoform RORγt has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and TC17 cells, cells that have demonstrated antitumor efficacy. RORγt controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of RORγt have been shown to increase the basal activity of RORγt enhancing TH17 cell proliferation. Here, we show that activation of RORγt using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, a mechanism that should enhance antitumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment; thus such a molecule would provide a unique approach for the treatment of cancer. PMID:26785144

  11. Pharmacophore-driven identification of PPARγ agonists from natural sources

    DEFF Research Database (Denmark)

    Petersen, R. K.; Christensen, Kathrine Bisgaard; Assimopoulou, A. N.;

    2011-01-01

    medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios...

  12. Cell-penetrable mouse forkhead box protein 3 alleviates experimental arthritis in mice by up-regulating regulatory T cells.

    Science.gov (United States)

    Liu, Xia; Ji, Baoju; Sun, Mengyi; Wu, Weijiang; Huang, Lili; Sun, Aihua; Zong, Yangyong; Xia, Sheng; Shi, Liyun; Qian, Hui; Xu, Wenrong; Shao, Qixiang

    2015-07-01

    Regulatory T cells (T(regs)) have potential applications in clinical disease therapy, such as autoimmune diseases and transplant rejection. However, their numbers are limited. Forkhead box protein 3 (FoxP3) is a key transcription factor that controls T(reg) development and function. Here, we generated a cell-permeable fusion protein, protein transduction domain (PTD)-conjugated mouse FoxP3 protein (PTD-mFoxP3), and evaluated whether PTD-mFoxp3 can alleviate rheumatoid arthritis (RA) in the collagen-induced arthritis (CIA) mouse model. As expected, PTD-mFoxP3 was transduced into cells effectively, and inhibited T cell activation and attenuated the cell proliferation. It decreased interleukin (IL) 2 and interferon (IFN)-γ expression, and increased IL-10 expression in activated CD4(+)CD25(-) T cells. PTD-mFoxP3-transduced CD4(+)CD25(-) T cells attenuated proliferation of activated CD4(+)CD25(-) T cells. In addition, PTD-mFoxP3 blocked the Th17 differentiation programme in vitro and down-regulated IL-17 production from T cells by modulating induction and levels of retinoid-related orphan receptor gamma t (RORγt). Intra-articular delivery of PTD-mFoxP3 delayed disease incidence remarkably and alleviated autoimmune symptoms of CIA mice. Moreover, protective effects of PTD-mFoxP3 were associated with regulating the balance of T helper type 17 (Th17) and T(regs). These results suggest that PTD-mFoxP3 may be a candidate for RA therapy. PMID:25809415

  13. Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy.

    Science.gov (United States)

    Nelson, Michael D; Rosenberry, Ryan; Barresi, Rita; Tsimerinov, Evgeny I; Rader, Florian; Tang, Xiu; Mason, O'Neil; Schwartz, Avery; Stabler, Thomas; Shidban, Sarah; Mobaligh, Neigena; Hogan, Shomari; Elashoff, Robert; Allen, Jason D; Victor, Ronald G

    2015-12-01

    Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOSμ), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein α-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSμ-derived nitric oxide (NO) attenuates α-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSμ, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo-controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease. PMID:26437761

  14. Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment.

    Science.gov (United States)

    Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N; Allen, John A; Rogan, Sarah C; Hanson, Bonnie J; Revankar, Chetana; Robers, Matt; Doucette, Chris; Roth, Bryan L

    2009-10-01

    Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine(2B) (5-HT(2B)) receptor agonists. We have shown that activation of 5-HT(2B) receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT(2B) receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT(2B) receptor agonists (hits); 14 of these had previously been identified as 5-HT(2B) receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT(2B) receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC(50) data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT(2B) receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease. PMID:19570945

  15. Blended Buffet-Load-Alleviation System for Fighter Airplane

    Science.gov (United States)

    Moses, Robert W.

    2005-01-01

    The capability of modern fighter airplanes to sustain flight at high angles of attack and/or moderate angles of sideslip often results in immersion of part of such an airplane in unsteady, separated, vortical flow emanating from its forebody or wings. The flows from these surfaces become turbulent and separated during flight under these conditions. These flows contain significant levels of energy over a frequency band coincident with that of low-order structural vibration modes of wings, fins, and control surfaces. The unsteady pressures applied to these lifting surfaces as a result of the turbulent flows are commonly denoted buffet loads, and the resulting vibrations of the affected structures are known as buffeting. Prolonged exposure to buffet loads has resulted in fatigue of structures on several airplanes. Damage to airplanes caused by buffeting has led to redesigns of airplane structures and increased support costs for the United States Air Force and Navy as well as the armed forces of other countries. Time spent inspecting, repairing, and replacing structures adversely affects availability of aircraft for missions. A blend of rudder-control and piezoelectric- actuator engineering concepts was selected as a basis for the design of a vertical-tail buffet-load-alleviation system for the F/A-18 airplane. In this system, the rudder actuator is used to control the response of the first tail vibrational mode (bending at a frequency near 15 Hz), while directional patch piezoelectric actuators are used to control the second tail vibrational mode (tip torsion at a frequency near 45 Hz). This blend of two types of actuator utilizes the most effective features of each. An analytical model of the aeroservoelastic behavior of the airplane equipped with this system was validated by good agreement with measured results from a full-scale ground test, flight-test measurement of buffet response, and an in-flight commanded rudder frequency sweep. The overall performance of the

  16. CB2 receptor agonists protect human dopaminergic neurons against damage from HIV-1 gp120.

    Directory of Open Access Journals (Sweden)

    Shuxian Hu

    Full Text Available Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Recent work suggests that the nigrostriatal dopaminergic area is a critical brain region for the neuronal dysfunction and death seen in HAND and that human dopaminergic neurons have a particular sensitivity to gp120-induced damage, manifested as reduced function (decreased dopamine uptake, morphological changes, and reduced viability. Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes. Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model, which contains dopaminergic neurons, microglia, and astrocytes, we were able to show that the CB1/CB2 agonist WIN55,212-2 blunts gp120-induced neuronal damage as measured by dopamine transporter function, apoptosis and lipid peroxidation; these actions were mediated principally by the CB2 receptor. Adding supplementary human microglia to our cultures enhances gp120-induced damage; WIN55,212-2 is able to alleviate this enhanced damage. Additionally, WIN55,212-2 inhibits gp120-induced superoxide production by purified human microglial cells, inhibits migration of human microglia towards supernatants generated from gp120-stimulated human mesencephalic neuronal/glial cultures and reduces chemokine and cytokine production from the human mesencephalic neuronal/glial cultures. These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from

  17. β-Adrenoreceptor agonists in the management of pain associated with renal colic: a systematic review

    OpenAIRE

    Tabner, Andrew John; Johnson, Graham David; Fakis, Apostolos; Surtees, Jane; Lennon, Robert Iain

    2016-01-01

    Objectives To determine whether β-adrenoreceptor agonists are effective analgesics for patients with renal colic through a systematic review of the literature. Setting Adult emergency departments or acute assessment units. Participants Human participants with proven or suspected renal colic. Interventions β-adrenoreceptor agonists. Outcome measures Primary: level of pain at 30 min following administration of the β-agonist. Secondary: level of pain at various time points following β-agonist ad...

  18. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    Science.gov (United States)

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  19. Use Of Dynamic Distortion To Predict And Alleviate Loss Of Control Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Improvements to aviation safety will be made by the development and validation of means to alleviate, alert, and inhibit loss of control associated with unfavorable...

  20. Predictive Gust Load Alleviation Control Using Leading Edge Stagnation Point Sensor Project

    Data.gov (United States)

    National Aeronautics and Space Administration — ZONA Technology, Inc proposes an R&D effort to develop a Gust Load Alleviation (GLA) control system using a novel Leading Edge Stagnation Point (LESP) sensor...

  1. Alleviation of Severe Restless Legs Syndrome (RLS) Symptoms by Cigarette Smoking

    OpenAIRE

    Oksenberg, Arie

    2010-01-01

    Cigarette smoking is in general considered an aggravating factor for restless legs syndrome (RLS). The author presents a case in which cigarette smoking has produced for many years a consistent and effective alleviation of RLS symptoms.

  2. Seed storage-mediated dormancy alleviation in Fabaceae from campo rupestre

    Directory of Open Access Journals (Sweden)

    Naïla Nativel

    2015-09-01

    Full Text Available ABSTRACTWe studied the effects of seed storage on germination and dormancy alleviation in three species of Fabaceae endemic to campo rupestrein southeastern Brazil. Fresh seeds of Collaea cipoensis, Mimosa maguirei and Mimosa foliolosawere set to germinate and germination of seeds after four, five and 13 years of storage was tested. Seed viability was maintained for all species after the full storage period. Seed storage significantly increased germination percentage and decreased germination time for C. cipoensisand M. foliolosa, suggesting the alleviation of physical dormancy with storage. However, we did not find evidence of dormancy alleviation in M. maguirei since stored seeds showed a decrease in germination in comparison to that of fresh seeds. Our data indicate species-specific storage-mediated dormancy alleviation, which will have important implications for restoration of campo rupestre.

  3. Use Of Dynamic Distortion To Predict And Alleviate Loss Of Control Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The intent of this project is to develop and validate means to alert, constrain and thereby alleviate loss of control (LOC) associated with unfavorable...

  4. Alleviating the Entrance to Serious Games by Exploring the Use of Commonly Available Tools

    OpenAIRE

    Van Rosmalen, Peter; Klemke, Roland; WESTERA, Wim

    2011-01-01

    Van Rosmalen, P., Klemke, R., & Westera, W. (2011, 20-21 October). Alleviating the Entrance to Serious Games by Exploring the Use of Commonly Available Tools. Presentation at 5th European Conference on Games Based Learning, Athens, Greece.

  5. Combining GLP-1 receptor agonists with insulin

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Vilsbøll, T

    2013-01-01

    , compared with insulin, the antihyperglycaemic efficacy of GLP-1RAs is limited. The combination of a GLP-1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic......-dependent manner, thus conferring glycaemic control with a low incidence of hypoglycaemia. GLP-1RAs also promote weight loss, and have beneficial effects on markers of β cell function, lipid levels, blood pressure and cardiovascular risk markers. However, the durability of their effectiveness is unknown and......Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among...

  6. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

    Science.gov (United States)

    Pertwee, Roger G

    2012-12-01

    Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'. PMID:23108552

  7. Pharmacophore Pattern Identification of Tachykinin Receptor Selective Peptide Agonists: Implications in Receptor Selectivity

    Directory of Open Access Journals (Sweden)

    Anjali Dike

    2007-01-01

    Full Text Available The mammalian tachykinin (TK peptides and their three Neurokinin (NK1, NK2 and NK3 receptors represent an effector system with wide-ranging actions on neuronal, airway smooth muscle, mucosal, endothelial, immune, inflammatory and remodeling cell function. Recent clinical and preclinical data suggests the pathophysiological role of TKs in various diseases including asthma, emesis and depression. The TK-NK receptor interactions and overlapping functions mediated by each NK receptor indicate added therapeutic benefit of using multiple NK receptor blockade. In the absence of structural data on neurokinin receptors, the membrane-induced structure of tachykinins play an important role as a first step towards understanding structure-activity relationship. A comparison of the conformational features of different NK1, NK2 and NK3 receptor agonists highlights several features which might be responsible for determining selectivity for the particular receptor subtype. An attempt has been made to correlate the observed conformational differences to the binding ability and biological activity of various NK1, NK2 and NK3 receptor agonists. The membrane bound conformations of tachykinins have been used as a starting point, leading to useful pharmacophore patterns that can be used for identifying lead structures with novel scaffolds.

  8. Synthesis, Activity, and Docking Study of Novel Phenylthiazole-Carboxamido Acid Derivatives as FFA2 Agonists.

    Science.gov (United States)

    Ma, Liang; Wang, Taijin; Shi, Min; Fu, Ping; Pei, Heying; Ye, Haoyu

    2016-07-01

    Free fatty acid receptor 2 (FFA2), also known as GPR43, is activated by short-chain fatty acids (SCFAs) that are mainly produced by the gut microbiota through the fermentation of undigested carbohydrates and dietary fibers. FFA2 currently appears to be a potential target in the management of obesity, diabetes, inflammatory diseases, and cancer. In the study, a series of novel phenylthiazole-carboxamido acid derivatives has been synthesized and evaluated as potential orthosteric FFA2 ligands for the study of structure-activity relationships. Compound 6e was found to exhibit the twofold potent agonistic activity in the stable hFFA2-transfected CHO-K1 cells (EC50 = 23.1 μm) as that of positive control propionate (EC50 = 43.3 μm). We also reported the results of mutagenesis studies based on the crystal structure of hFFA1 bound to TAK-875 at 2.3 Å resolution to identify important residues for orthosteric agonist 6e inducing FFA2 activation. PMID:26808470

  9. Trial of Zolpidem, Eszopiclone, and Other GABA Agonists in a Patient with Progressive Supranuclear Palsy

    Directory of Open Access Journals (Sweden)

    Andrew Young Chang

    2014-01-01

    Full Text Available Progressive supranuclear palsy (PSP is a progressive, debilitating neurodegenerative disease of the Parkinson-plus family of syndromes. Unfortunately, there are no pharmacologic treatments for this condition, as most sufferers of the classic variant respond poorly to Parkinson medications such as levodopa. Zolpidem, a gamma aminobutyric acid (GABA agonist specific to the α-1 receptor subtype, has been reported to show improvements in symptoms of PSP patients, including motor dysfunction, dysarthria, and ocular disturbances. We observed a 73-year-old woman with a six-year history of PSP, who, upon administration of a single 12.5 mg dose of sustained-release zolpidem, exhibited marked enhancements in speech, facial expressions, and fine motor skills for five hours. These results were reproduced upon subsequent clinic visits. In an effort to find a sustainable medication that maximized these beneficial effects while minimizing side effects and addressing some of her comorbid neuropsychological conditions, a trial of five other GABA receptor agonists was performed with the patient’s consent, while she and her caregivers were blinded to the specific medications. She and her caretakers subsequently reported improvements, especially visual, while on eszopiclone, and, to a lesser degree, temazepam and flurazepam.

  10. Spatial analysis and source profiling of beta-agonists and sulfonamides in Langat River basin, Malaysia.

    Science.gov (United States)

    Sakai, Nobumitsu; Yusof, Roslan Mohd; Sapar, Marni; Yoneda, Minoru; Mohd, Mustafa Ali

    2016-04-01

    Beta-agonists and sulfonamides are widely used for treating both humans and livestock for bronchial and cardiac problems, infectious disease and even as growth promoters. There are concerns about their potential environmental impacts, such as producing drug resistance in bacteria. This study focused on their spatial distribution in surface water and the identification of pollution sources in the Langat River basin, which is one of the most urbanized watersheds in Malaysia. Fourteen beta-agonists and 12 sulfonamides were quantitatively analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A geographic information system (GIS) was used to visualize catchment areas of the sampling points, and source profiling was conducted to identify the pollution sources based on a correlation between a daily pollutant load of the detected contaminant and an estimated density of human or livestock population in the catchment areas. As a result, 6 compounds (salbutamol, sulfadiazine, sulfapyridine, sulfamethazine, sulfadimethoxine and sulfamethoxazole) were widely detected in mid catchment areas towards estuary. The source profiling indicated that the pollution sources of salbutamol and sulfamethoxazole were from sewage, while sulfadiazine was from effluents of cattle, goat and sheep farms. Thus, this combination method of quantitative and spatial analysis clarified the spatial distribution of these drugs and assisted for identifying the pollution sources. PMID:26799806

  11. Pan-PPAR Agonist, Bezafibrate, Restores Angiogenesis in Hindlimb Ischemia in Normal and Diabetic Rats

    Directory of Open Access Journals (Sweden)

    M. Khazaei

    2012-01-01

    Full Text Available Introduction. The aim of this study was to investigate the effect of bezafibrate as a pan-PPAR agonist on angiogenesis and serum nitrite, the main metabolite of nitric oxide (NO, vascular endothelial growth factor (VEGF and VEGF receptor-2 (VEGFR-2 concentrations in hindlimb ischemia model of normal and type I diabetic rats. Methods. 28 male Wistar rats were divided into control and diabetic groups. Then, all rats underwent unilateral hindlimb ischemia. After recovery, they were randomly assigned to one of the following experimental groups: (1 control; (2 control + bezafibrate (400 mg/kg/day; (3 diabetic; (4 diabetic + beztafibrate. After three weeks, blood samples were taken and capillary density was evaluated in the gasterocnemius muscle of ischemic limb. Results. Bezafibrate increased capillary density and capillary/fiber ratio in ischemic leg of diabetic and control rats (<0.05. Serum VEGF and VEGFR-2 concentrations did not alter after bezafibrate administration, however, serum nitrite concentration was significantly higher in bezafibrate-treated groups than non-treated groups (<0.05. Discussion. It seems that bezafibrate, as a pan PPAR agonist, restores angiogenesis in hindlimb ischemic diabetic animals and is useful for prevention and/or treatment of peripheral artery disease in diabetic subjects.

  12. Poverty Alleviation through Sustainable Tourism Development in Nepal: Marketing Strategy Point of View

    OpenAIRE

    Kafle, Jagannath

    2011-01-01

    This research has been conducted through desk study as well as by field visit and collected the opinion of Finnish tour operators who have been operating tour in Nepal. It has aimed to study the role and importance of sustainable tourism marketing in alleviating poverty in Nepal. The research has been taken three major objectives. They are: to evaluate Nepal’s current tourism marketing strategy and to what extend it takes poverty alleviation through tourism into account; to evaluate whether t...

  13. Are beta2-agonists responsible for increased mortality in heart failure?

    LENUS (Irish Health Repository)

    Bermingham, Margaret

    2012-02-01

    AIMS: Previous large-scale, retrospective studies have shown increased mortality in heart failure (HF) patients using beta2-agonists (B2As). We further examined the relationship between B2A use and mortality in a well-characterized population by adjusting for natriuretic peptide levels as a measure of HF severity. METHODS AND RESULTS: This was a retrospective cohort study of patients attending an HF Disease Management Programme with mean follow-up of 2.9 +\\/- 2.4 years. Chart review confirmed B2A use, dose and duration of use, and documented pulmonary function evaluation. The primary endpoint was the effect of B2A use compared with no B2A use on mortality using unadjusted and adjusted Kaplan-Meier survival curves. Data were available for 1294 patients (age 70.6 +\\/- 11.5 years) of whom 64% were male and 22.2% were taking B2As. beta2-Agonist users were older, more likely to be male, to have smoked, to have chronic obstructive pulmonary disease (COPD) and asthma, and less likely to take beta-blockers. Multivariable associates of mortality included: B-type natriuretic peptide (BNP), coronary artery disease, age, and beta-blocker use. Unadjusted mortality rates for B2A users were found to be significantly higher than non-B2A users [hazard ratio (HR) 1.304, 95% confidence interval (CI) 1.030-1.652, P= 0.028]. However, when adjusted for age, sex, medication, co-morbidity, smoking, COPD, and BNP differences, overall mortality rates were similar [HR 1.043, 95% CI (0.771-1.412), P= 0.783]. CONCLUSION: Unlike previous reports, this retrospective evaluation of B2A therapy in HF patients shows no relationship with long-term mortality when adjusted for population differences including BNP. Large, prospective studies are required to define the risk\\/benefit ratio of B2As in patients with heart failure.

  14. Chromium supplementation alleviates risk factors associated with the metabolic syndrome

    Science.gov (United States)

    Metabolic syndrome has been applied to a clustering of risk factors of diabetes and cardiovascular diseases including elevated blood lipids, elevated glucose, elevated blood pressure, proinflammatory state including increased C-reactive protein and TNF-alpha, and prothrombotic state including anomal...

  15. Illegal use of beta-adrenergic agonists: European Community.

    Science.gov (United States)

    Kuiper, H A; Noordam, M Y; van Dooren-Flipsen, M M; Schilt, R; Roos, A H

    1998-01-01

    The use of veterinary medicinal products within the European Community is governed by a series of directives and regulations that describe the requirements for safety, quality, and efficacy of these products. Veterinary therapeutic use of beta-agonists has only been approved in the case of clenbuterol for bronchodilatation in horses and calves and for tocolysis in cows. No beta-agonists have been permitted in the European Community for growth-promoting purposes in farm animals. Surveillance for the presence of residues of veterinary agents in food-producing animals and meat is regulated by the Directive 86/469/EEC containing specific guidelines for sampling procedures on farms and in slaughterhouses. The level and frequency of sampling is dependent on the category of compounds and animal species. When positive samples have been identified (above certain action levels), sampling intensity is increased. Results of monitoring programs in EU member states during 1992 and 1993 for the occurrence of residues of beta-agonists in food-producing animals vary substantially with respect to the percentages of positive samples, ranging from 0 to 7%. The variability is partly explained by differences in sampling strategies, detection methods, and action levels applied. Identification of the proper matrices for sampling and detection of beta-agonists is important. In the case of clenbuterol, hair and choroid retinal tissue are appropriate tissues because clenbuterol accumulates in these matrices. A clear decrease in the use of clenbuterol in cattle has been observed in The Netherlands, Germany, Northern Ireland, and Spanish Basque Country over the last 3 yr. This is partly due to intensified surveillance activities at farms and slaughterhouses by governmental agencies and production sector organizations. There are data on human intoxication following consumption of liver or meat from cattle treated with beta-agonists. At the concentrations of clenbuterol measured in contaminated

  16. Interactions of dopamine agonists with brain D1 receptors labeled by 3H-antagonists. Evidence for the presence of high and low affinity agonist-binding states

    International Nuclear Information System (INIS)

    The interactions of dopaminergic agonists and antagonists with 3H-antagonist labeled D1 dopamine receptors of rat striatum have been characterized. [3H]Flupentixol has been found to selectively label D1 dopamine receptors when its binding to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone. Antagonist/3H-antagonist competition curves are of uniformly steep slope (nH . 1.0) suggesting the presence of a single D1 dopamine receptor. Agonist/3H-antagonist competition curves are extremely shallow (nH less than or equal to 0.5) for agonists of high relative efficacy, suggesting the presence of heterogeneous populations of agonist-binding states of the D1 dopamine receptor. Computer-modeling techniques were used to estimate affinities and relative site densities for these heterogeneous binding states. This analysis indicates that the ratio of agonist affinities for low and high affinity agonist-binding states is correlated with agonist relative efficacies in activating adenylate cyclase in membrane homogenates. Under the assay conditions employed, the addition of saturating concentrations of guanine nucleotides reduced, but did not abolish, the relative density of high affinity agonist-binding sites. These binding data can, at least in part, be explained by postulating two states of the D1 dopamine receptor, inducible by agonists but not by antagonists and modulated by guanine nucleotides

  17. Knocking on FXR's door: the "hammerhead"-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities.

    Science.gov (United States)

    Gege, Christian; Kinzel, Olaf; Steeneck, Christoph; Schulz, Andreas; Kremoser, Claus

    2014-01-01

    The Farnesoid X Receptor (FXR) was recently validated in clinical studies using the bile acid analogue Obeticholic Acid (OCA) as an attractive drug target for liver diseases such as Primary Biliary Cirrhosis (PBC) or Non-alcoholic Steatohepatitis (NASH). OCA, however, turned out to induce cholesterol- related side effects upon prolonged treatment and it shows bile acid like pharmacokinetics. The quest for synthetic non-steroidal FXR agonists with general drug likeliness and improved pharmacokinetic and - dynamic properties has started more than a decade ago: The first non-steroidal and selective FXR agonist with decent submicromolar potency, GW4064, was patented in 1998 and published in 2000. Since then, many pharmaceutical companies have taken GW4064 as a structural template for their efforts in identifying novel patentable FXR agonists with the GW-derived trisubstituted isoxazole general structure. However, so far only one compound out of these different series has made it into the early stages of clinical development: The Px-102/Px-104 from Phenex is currently tested in a phase IIa study in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). In this review we try to summarize from the patent and scientific literature the attempts to improve the GW4064 structure into different directions. Furthermore, we suggest directions for further improvements of this special class of synthetic FXR agonists which all display the typical "hammerhead"-conformation in the FXR ligand binding pocket that provides the basis for their impressive in vitro and in vivo potencies. PMID:25388536

  18. Total Androgen Blockade Versus a Luteinizing Hormone-Releasing Hormone Agonist Alone in Men With High-Risk Prostate Cancer Treated With Radiotherapy

    International Nuclear Information System (INIS)

    Purpose: To assess whether short-course total androgen blockade vs. a luteinizing hormone-releasing hormone (LHRH) agonist alone affects the risk of prostate cancer-specific mortality (PCSM) in men with localized but high-risk disease treated with radiotherapy. Methods and Materials: The study cohort comprised 628 men with T1-T4, N0, M0 prostate cancer with high-risk disease (prostate-specific antigen level >20 ng/mL, Gleason score ≥8, or clinical category ≥T3) treated with 45 Gy of external beam radiotherapy followed by a brachytherapy boost in addition to receiving a median of 4.3 (interquartile range [IQR], 3.6-6.4) months of hormonal blockade with an LHRH agonist plus an antiandrogen or monotherapy with an LHRH agonist. Fine and Gray's multivariable regression analysis was used to determine whether combination androgen suppression therapy (AST) vs. monotherapy affected the risk of PCSM, adjusting for treatment year, duration of AST, age, and known prognostic factors. Results: After a median follow-up of 4.9 (IQR, 3.5-6.5) years, men receiving combination AST had a lower risk of PCSM than those treated with monotherapy (adjusted hazard ratio [AHR], 0.18; 95% confidence interval [CI], 0.04-0.90; p = 0.04). An increasing prostate-specific antigen level (AHR, 2.70; 95% CI, 1.64-4.45; p < 0.001) and clinical category T3/4 disease (AHR, 29.6; 95% CI, 2.88-303.5; p = 0.004) were also associated with an increased risk of PCSM. Conclusions: In men with localized but high-risk prostate cancer treated with external beam radiotherapy and brachytherapy, short-course AST with an LHRH agonist plus an antiandrogen is associated with a decreased risk of PCSM when compared with monotherapy with an LHRH agonist.

  19. Novel Small Molecule Agonist of TGR5 Possesses Anti-Diabetic Effects but Causes Gallbladder Filling in Mice.

    Directory of Open Access Journals (Sweden)

    Daniel A Briere

    Full Text Available Activation of TGR5 via bile acids or bile acid analogs leads to the release of glucagon-like peptide-1 (GLP-1 from intestine, increases energy expenditure in brown adipose tissue, and increases gallbladder filling with bile. Here, we present compound 18, a non-bile acid agonist of TGR5 that demonstrates robust GLP-1 secretion in a mouse enteroendocrine cell line yet weak GLP-1 secretion in a human enteroendocrine cell line. Acute administration of compound 18 to mice increased GLP-1 and peptide YY (PYY secretion, leading to a lowering of the glucose excursion in an oral glucose tolerance test (OGTT, while chronic administration led to weight loss. In addition, compound 18 showed a dose-dependent increase in gallbladder filling. Lastly, compound 18 failed to show similar pharmacological effects on GLP-1, PYY, and gallbladder filling in Tgr5 knockout mice. Together, these results demonstrate that compound 18 is a mouse-selective TGR5 agonist that induces GLP-1 and PYY secretion, and lowers the glucose excursion in an OGTT, but only at doses that simultaneously induce gallbladder filling. Overall, these data highlight the benefits and potential risks of using TGR5 agonists to treat diabetes and metabolic diseases.

  20. Pain alleviation in Unani medicine – A conceptual analysis

    Directory of Open Access Journals (Sweden)

    Mirza Ghufran Baig

    2014-12-01

    Full Text Available The objective of medical science mainly comprises of prevention and treatment of diseases in order to maintain health. Unani system of medicine also focuses on the same objectives Hifzane Sehat (preservation of health and Ilajul Amarz (restoration of health with glorifying history of serving humanity since Hippocratic era. Pain is a clinical feature of several diseases and commonest manifestation which tends to bring the patient to physician. Pain makes sufferer as well as doctor aware to protect the body from disease for preservation or restoration of health and maintain homeostasis which accomplishes both the goal. It has certain characteristics, location, course which provides important diagnostic hints. It is prime responsibility of the physician's to relieve pain efficiently. Influences of sustained or chronic pain have varying degrees of physical dysfunction, personality changes, depression, anxiety, social isolation, may also affect the patient’s quality of life. At present therapeutic alternatives is being preferred over conventional medicine. This review article is aimed to highlight the concept of pain in Unani system of medicine, its management and correlation with modern theories. The article may also serve the objective of providing well being or to improve quality of life of the sufferer.

  1. PPAR GAMMA AGONISTS: AN EFFECTIVE STRATEGY FOR CANCER TREATMENT

    Directory of Open Access Journals (Sweden)

    Divya G.S

    2013-10-01

    Full Text Available PPAR-γ regulates cellular differentiation, development and metabolism. They play these essential roles by functioning as transcription factors regulating the expression of genes. The PPARs mainly are of three types α, β and γ. The PPAR-γ expressed in three forms γ1, γ2 and γ3 present in different tissues. When PPAR binds its ligand, transcription of target gene is increased or decreased. Tzds were able to induce cell differentiation and apoptosis or inhibit cell proliferation both in vitro and in vivo. However, widespread use of thiazolidinediones (TZDs, the clinically used synthetic PPAR gamma agonists, has been limited by adverse effects. So in this review we are suggesting some new molecules other than thiazolidine diones which can act as potential anticancer agents, after explaining the mechanism of action of PPAR-γ agonists as anticancer agents especially thiazolidinediones.

  2. Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1.

    Science.gov (United States)

    Xiao, Jingbo; Huang, Zaohua; Chen, Catherine Z; Agoulnik, Irina U; Southall, Noel; Hu, Xin; Jones, Raisa E; Ferrer, Marc; Zheng, Wei; Agoulnik, Alexander I; Marugan, Juan J

    2013-01-01

    The anti-fibrotic, vasodilatory and pro-angiogenic therapeutic properties of recombinant relaxin peptide hormone have been investigated in several diseases, and recent clinical trial data has shown benefit in treating acute heart failure. However, the remodelling capacity of these peptide hormones is difficult to study in chronic settings because of their short half-life and the need for intravenous administration. Here we present the first small-molecule series of human relaxin/insulin-like family peptide receptor 1 agonists. These molecules display similar efficacy as the natural hormone in several functional assays. Mutagenesis studies indicate that the small molecules activate relaxin receptor through an allosteric site. These compounds have excellent physical and in vivo pharmacokinetic properties to support further investigation of relaxin biology and animal efficacy studies of the therapeutic benefits of relaxin/insulin-like family peptide receptor 1 activation. PMID:23764525

  3. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    OpenAIRE

    Hayley Patricia Ellis; Kathreena Mary Kurian

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common primary intrinsic central nervous system tumor and has an extremely poor overall survival with only 10% patients being alive after 5 years. There has been interesting preliminary evidence suggesting that diabetic patients receiving peroxisome proliferator-activated receptor gamma (PPARγ) agonists, a group of anti-diabetic, thiazolidinedione drugs, have an increased median survival for glioblastoma. Although thiazolidinediones are effective oral...

  4. In Vitro Evaluation of TLR4 Agonist Activity: Formulation Effects

    OpenAIRE

    Misquith, Ayesha; Millie Fung, H. W.; Dowling, Quinton M.; Guderian, Jeffrey A.; Vedvick, Thomas S.; Fox, Christopher B.

    2013-01-01

    Effective in vitro evaluation of vaccine adjuvants would allow higher throughput screening compared to in vivo studies. However, vaccine adjuvants comprise a wide range of structures and formulations ranging from soluble TLR agonists to complex lipid-based formulations. The effects of formulation parameters on in vitro bioactivity assays and the correlations with in vivo adjuvant activity is not well understood. In the present work, we employ the Limulus amebocyte lysate assay and a human mac...

  5. Alternation of Agonists and Antagonists During Turtle Hindlimb Motor Rhythms

    OpenAIRE

    Stein, Paul S.G.

    2010-01-01

    In a variety of vertebrates, including turtle, many classical and contemporary studies of spinal cord neuronal networks generating rhythmic motor behaviors emphasize a Reciprocal Model with alternation of agonists and antagonists, alternation of excitatory and inhibitory postsynaptic potentials, and reciprocal inhibition. Some studies of spinal cord neuronal networks, including those in turtle during scratch motor rhythms, describe a Balanced Model with concurrent excitatory and inhibitory po...

  6. Melatonin agonists for treatment of sleep and depressive disorders

    OpenAIRE

    Pandi-Perumal, Seithikurippu R.; Brown, Gregory M.; Daniel P. Cardinali; Venkataramanujan Srinivasan

    2011-01-01

    Melatonin the hormone secreted by the pineal gland has been effective in improving sleep both in normal sleepers and insomniacs and has been used successfully in treating sleep and circadian rhythm sleep disorders. The lack of consistency in the reports published by the authors is attributed to the differential bioavailabilty and short half-life of melatonin. Sleep disturbances are also prominent features of depressive disorders. To overcome this problem, melatonergic agonists with sleep prom...

  7. Discriminative learning occasioned by the administration of a dopamine agonist

    OpenAIRE

    Keller, Sabine; Delius, Juan

    2001-01-01

    Rationale: The repeated administration of psychostimulants usually brings about a progressive increment of the behavioral responses that they induce. We examined to what extent this sensitization is due to an associative learning process. Objectives: The dopamine agonist apomorphine elicits stereotyped pecking in pigeons, a response that increases with successive intramuscular injections. We tested whether this sensitized pecking would be discriminatively directed at environmental stimuli tha...

  8. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K. (GSKPA)

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  9. Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1.

    Science.gov (United States)

    Aliouane, Lucie; Chao, Sovy; Brizuela, Leyre; Pfund, Emmanuel; Cuvillier, Olivier; Jean, Ludovic; Renard, Pierre-Yves; Lequeux, Thierry

    2014-09-01

    The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported. PMID:25047939

  10. Phentolamine--an unexpected agonist in the rabbit.

    OpenAIRE

    Angus, J. A.; Lew, M. J.

    1984-01-01

    Phentolamine (0.1-10 microM) caused an anomalous rightward shift of the relationship between the number of electrical field pulses and tachycardia in the rabbit isolated right atrium. Phentolamine was apparently acting as a presynaptic agonist on sympathetic nerve endings to inhibit transmitter release. The effect was prevented by benextramine treatment and antagonized 10 fold by yohimbine (1 microM) but not by prazosin (0.1 microM). In ganglion-blocked (mecamylamine) conscious or anaesthetiz...

  11. Beta-adrenergic agonists as additive in beef cattle

    Directory of Open Access Journals (Sweden)

    Marcelo Vedovatto

    2014-10-01

    Full Text Available The agonists receptor beta-adrenergic (β-AA are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fully understood, these may cause morphological and physiological changes such as increased blood flow decrease in plasma insulin, decreased lipogenesis, and muscle hypertrophy mainly in type II fibers. We also observed changes in motility and secretions grastointestinal tract, beyond the direct influence on the rumen bacteria, altering the digestibility of the diet. The β-AA agonists released in some countries for use in beef cattle are ractopamine hydrochloride and zilpaterol hydrochloride. According to literature data, the inclusion of these additives in the diet of feedlot cattle has been associated with an increase infeed efficiency with the increase in daily weight gain and with equal or lower feed intake. Carcass characteristics improvement was verified in carcass weight, and increased loin eye area, but with the possibility to decrease the subcutaneous fat thickness and marbling. Reviews in sensory panel of meat from animals consuming β-AA agonists showed decreased tenderness and juiciness. Thus β-AA improve performance and carcass characteristics, but more studies are needed to confirm whether they have negative influence on the organoleptic characteristics of the meat.

  12. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    Science.gov (United States)

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  13. Suppression of atherosclerosis by synthetic REV-ERB agonist

    Energy Technology Data Exchange (ETDEWEB)

    Sitaula, Sadichha [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Billon, Cyrielle [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States); Kamenecka, Theodore M.; Solt, Laura A. [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Burris, Thomas P., E-mail: burristp@slu.edu [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States)

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  14. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Hayley Patricia Ellis

    2014-03-01

    Full Text Available Glioblastoma Multiforme (GBM is the most common primary intrinsic CNS tumour and has an extremely poor overall survival, despite advances in neurosurgery, chemotherapy and radiation therapy. There has been interesting preliminary evidence suggesting that patients receiving the group of anti-diabetic drugs known as PPARγ (Peroxisome proliferator-activated receptor gamma agonists have a lower incidence of glioma. The nuclear hormone receptor PPARγ has been found to be expressed in high grade gliomas, and its activation has been shown to have several antineoplastic effects on human and rat glioma cell lines, and in some instances an additional protective increase in antioxidant enzymes has been observed in normal astrocytes. At present, no clinical trials are underway with regards to treating glioma patients using PPARγ agonists, as Pioglitazone and Rosiglitazone are only FDA-approved for use in treatment of type-2 diabetes. This review presents the case for evaluating the potential of PPARγ agonists as novel adjuvants in the treatment of high grade glioma. We introduce the PPARγ pathway, PPARγ gene and its products and examine recent research in glioblastoma.

  15. Suppression of atherosclerosis by synthetic REV-ERB agonist

    International Nuclear Information System (INIS)

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization

  16. Dopamine agonist activity of EMD 23,448

    Energy Technology Data Exchange (ETDEWEB)

    Martin, G.E.; Pettibone, D.J. (Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania (USA). Dept. of Pharmacology)

    1985-01-01

    EMD 23,448 was examined in tests of dopaminergic function and was found to be an atypical dopamine (DA) agonist. EMD 23,448 was a weak or inactive DA agonist when examined in tests of normal postsynaptic DA receptor function: production of stereotypy in the rat (ED/sub 50/ greater than sign 5.0 mg/kg.i.p.); production of emesis in beagles (minimum effective dose = 81..mu..g/kg i.v.); and, enhanced locomotor activity of the mouse (no excitation in doses <=50 mg/i.p.). Moreover, EMD 23,448 was relatively weak in competing for (/sup 3/H)-apomorphine binding to rat striatal membranes (Ki, 205 nM). On the other hand, this indolyl-3-butylamine did activate supersensitive postsynaptic DA receptors. Specifically, it elicited contralateral turning in rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra (ED/sub 50/ value = 0.9 mg/kg) and did elicit stereotypy in rats given chronic daily haloperidol treatments. EMD 23,448 also exerted pharmacological effects in tests designed to measure activation of dopamine autoreceptors. It inhibited the ..gamma..-butyrolactone-induced increase in striatal dopa levels (ED/sub 50/ = 1 mg/kg i.p.) and produced a dose-related fall in the locomotor activity of the mouse. The results are discussed and contrasted with data derived for apomorphine and the putatively selective autoreceptor agonist (+-)-3-PPP.

  17. Rational design of humanized dual-agonist antibodies.

    Science.gov (United States)

    Zhang, Yong; Liu, Yan; Wang, Ying; Schultz, Peter G; Wang, Feng

    2015-01-14

    The ultralong heavy chain complementarity determining region 3 (CDR3H) of bovine antibody BLV1H12 folds into a novel "stalk-knob" structural motif and has been exploited to generate novel agonist antibodies through replacement of the "knob" domain with cytokines and growth factors. By translating this unique "stalk-knob" architecture to the humanized antibody trastuzumab (referred to hereafter by its trade name, Herceptin, Genentech USA), we have developed a versatile approach to the generation of human antibody agonists. Human erythropoietin (hEPO) or granulocyte colony-stimulating factor (hGCSF) was independently fused into CDR3H, CDR2H, or CDR3L of Herceptin using an engineered "stalk" motif. The fusion proteins express in mammalian cells in good yields and have similar in vitro biological activities compared to hEPO and hGCSF. On the basis of these results we then generated a bi-functional Herceptin-CDR fusion protein in which both hEPO and hGCSF were grafted into the heavy- and light-chain CDR3 loops, respectively. This bi-functional antibody fusion exhibited potent EPO and GCSF agonist activities. This work demonstrates the versatility of the CDR-fusion strategy for generating functional human antibody chimeras and provides a novel approach to the development of multi-functional antibody-based therapeutics. PMID:25494484

  18. CXCR2 agonists in ADPKD liver cyst fluids promote cell proliferation

    Science.gov (United States)

    Amura, Claudia; Brodsky, Kelley; Gitomer, Berenice; McFann, Kim; Lazennec, Gwendal; Nichols, Matthew T.; Jani, Alkesh; Schrier, Robert W.; Brian Doctor, R.

    2008-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a highly prevalent genetic disease that results in cyst formation in kidney and liver. Cytokines and growth factors secreted by the cyst lining epithelia are positioned to initiate autocrine/paracrine signaling and promote cyst growth. Comparative analyses of human kidney and liver cyst fluids revealed disparate cytokine/growth factor profiles. CXCR2 agonists, including interleukin-8 (IL-8), epithelial neutrophil activating peptide (ENA78), growth related oncogne alpha (GROα), are potent proliferative agents that were found at high levels in liver but not kidney cyst fluids. Liver cysts are lined by epithelial cells derived from the intrahepatic bile duct (i.e. cholangiocytes). In polarized pkd2(WS25/−) mouse liver cyst epithelial monolayers, CXCR2 agonists were released both apically and basally, indicating they may act both on the endothelial and epithelial cells within or lining the cyst wall. IL-8 and human liver cyst fluid induced cell proliferation of HMEC-1 cells, a human microvascular endothelial cell line, and Mz-ChA1 cells, a human cholangiocyte cell model. IL-8 expression can be regulated by specific stresses. Hypoxia and mechanical stretch, two likely stressors acting on the liver cyst epithelia, significantly increased IL-8 secretion and promoter activity. AP-1, c/EBP and NFκB were required but not sufficient to drive the stress-induced increase in IL-8 transcription. An upstream element between −272 and −1,481 bp allowed for the stress-induced increase in IL-8 transcription. These studies support the hypothesis that CXCR2 signaling promotes ADPKD liver cyst growth. PMID:18199703

  19. Comparative Evaluation of Partial α2 -Adrenoceptor Agonist and Pure α2 -Adrenoceptor Antagonist on the Behavioural Symptoms of Withdrawal after Chronic Alcohol Administration in Mice.

    Science.gov (United States)

    Arora, Shivani; Vohora, Divya

    2016-08-01

    As an addictive drug, alcohol produces withdrawal symptoms if discontinued abruptly after chronic use. Clonidine (CLN), a partial α2 -adrenergic agonist, and mirtazapine (MRT), an antagonist of α2 -adrenoceptor, both clinically aid alcohol withdrawal. Considering different mechanisms of action of the two drugs, this study was designed to see how far these two mechanistically different drugs differ in their ability to decrease the severity of ethanol withdrawal syndrome. The effect of CLN and MRT on ethanol withdrawal-induced anxiety, depression and memory impairment was analysed using EPM, FST and PAR tests, respectively. Animals received distilled water, ethanol and/or either of the drugs (CLN and MRT) in different doses. Relapse to alcohol use was analysed by CPP test. Animals received ethanol as a conditioning drug and distilled water, CLN or MRT as test drug. CLN and MRT both alleviated anxiety in a dose-dependent manner. MRT (4 mg/kg) was more effective than CLN (0.1 mg/kg) in ameliorating the anxiogenic effect of alcohol withdrawal. However, CLN treatment increased depression. It significantly decreased swimming time and increased immobility time, whereas MRT treatment decreased immobility time and increased climbing and swimming time during abstinence. The effect was dose dependent for both drugs. The results of PAR test show that CLN treatment worsens working memory. Significant increase in SDE and TSZ and decrease in SDL were observed in CLN-treated animals. MRT treatment, on the other hand, improved working memory at both doses. Further, both CLN and MRT alleviated craving. A significant decrease in time spent in the ethanol-paired chamber was seen. MRT treatment at both doses showed better effect than CLN in preventing the development of preference in CPP test. These findings indicate a potential therapeutic use and better profile of mirtazapine over clonidine in improving memory, as well as in alleviating depression, anxiety and craving associated

  20. Endogenous retroviruses are associated with autoimmune diseases

    DEFF Research Database (Denmark)

    Nexø, Bjørn A; Jensen, Sara B; Hansen, Bettina;

    2016-01-01

    transmission is called vertical. Viral variants of importance for development of disease must be more frequent among diseased persons than among healthy individuals. Multiple sclerosis, diabetes and rheumatoid arthritis are all associated with sets of endogenouos retroviruses but not the same sets. If a virus...... grows and this contributes to disease, one should be able to alleviate disease with antiretroviral drugs. We call for clinical trials to elucidate this issue....

  1. Neuroprotection of pramipexole in UPS impairment induced animal model of Parkinson's disease.

    Science.gov (United States)

    Li, Chao; Guo, Yuan; Xie, Wenjie; Li, Xingang; Janokovic, Joseph; Le, Weidong

    2010-10-01

    Pramipexole (PPX), a dopamine (DA) receptor D3 preferring agonist, has been used as monotherapy or adjunct therapy to treat Parkinson's disease (PD) for many years. Several in vitro and in vivo studies in neurotoxin-induced DA neuron injury models have reported that PPX may possess neuroprotective properties. The present study is to evaluate the neuroprotection of PPX in a sustained DA neuron degeneration model of PD induced by ubiquitin-proteasome system (UPS) impairment. Adult C57BL/6 mice were treated with PPX (low dose 0.1 mg/kg or high dose 0.5 mg/kg, i.p, twice a day) started 7 days before, and continued after microinjection of proteasome inhibitor lactacystin in the medial forebrain bundle for a total 4 weeks. Animal behavior observation, and pathological and biochemical assays were conducted to determine the neuroprotective effects of PPX. We report here that PPX treatment significantly improves rotarod performance, attenuates DA neuron loss and striatal DA reduction, and alleviates proteasomal inhibition and microglial activation in the substantia nigra of lactacystin-lesioned mice. PPX can increase the levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor and induce an activation of autophagy. Furthermore, pretreatment with D3 receptor antagonist U99194 can significantly block the PPX-mediated neuroprotection. These results suggest that multiple molecular pathways may be attributed to the neuroprotective effects of PPX in the UPS impairment model of PD. PMID:20635141

  2. Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain.

    Science.gov (United States)

    Guillemyn, Karel; Starnowska, Joanna; Lagard, Camille; Dyniewicz, Jolanta; Rojewska, Ewelina; Mika, Joanna; Chung, Nga N; Utard, Valérie; Kosson, Piotr; Lipkowski, Andrzej W; Chevillard, Lucie; Arranz-Gibert, Pol; Teixidó, Meritxell; Megarbane, Bruno; Tourwé, Dirk; Simonin, Frédéric; Przewlocka, Barbara; Schiller, Peter W; Ballet, Steven

    2016-04-28

    Herein, the opioid pharmacophore H-Dmt-d-Arg-Aba-β-Ala-NH2 (7) was linked to peptide ligands for the nociceptin receptor. Combination of 7 and NOP ligands (e.g., H-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) led to binding affinities in the low nanomolar domain. In vitro, the hybrids behaved as agonists at the opioid receptors and antagonists at the nociceptin receptor. Intravenous administration of hybrid 13a (H-Dmt-d-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) to mice resulted in potent and long lasting antinociception in the tail-flick test, indicating that 13a was able to permeate the BBB. This was further supported by a cell-based BBB model. All hybrids alleviated allodynia and hyperalgesia in neuropathic pain models. Especially with respect to hyperalgesia, they showed to be more effective than the parent compounds. Hybrid 13a did not result in significant respiratory depression, in contrast to an equipotent analgesic dose of morphine. These hybrids hence represent a promising avenue toward analgesics for the dual treatment of acute and neuropathic pain. PMID:27035422

  3. Pinpointing brainstem mechanisms responsible for autonomic dysfunction in Rett syndrome: therapeutic perspectives for 5-HT1A agonists.

    Science.gov (United States)

    Abdala, Ana P; Bissonnette, John M; Newman-Tancredi, Adrian

    2014-01-01

    Rett syndrome is a neurological disorder caused by loss of function of methyl-CpG-binding protein 2 (MeCP2). Reduced function of this ubiquitous transcriptional regulator has a devastating effect on the central nervous system. One of the most severe and life-threatening presentations of this syndrome is brainstem dysfunction, which results in autonomic disturbances such as breathing deficits, typified by episodes of breathing cessation intercalated with episodes of hyperventilation or irregular breathing. Defects in numerous neurotransmitter systems have been observed in Rett syndrome both in animal models and patients. Here we dedicate special attention to serotonin due to its role in promoting regular breathing, increasing vagal tone, regulating mood, alleviating Parkinsonian-like symptoms and potential for therapeutic translation. A promising new symptomatic strategy currently focuses on regulation of serotonergic function using highly selective serotonin type 1A (5-HT1A) "biased agonists." We address this newly emerging therapy for respiratory brainstem dysfunction and challenges for translation with a holistic perspective of Rett syndrome, considering potential mood and motor effects. PMID:24910619

  4. Economic contribution of participatory agroforestry program to poverty alleviation: a case from Sal forests, Bangladesh

    Institute of Scientific and Technical Information of China (English)

    K.K.Islam; Marjanke Hoogstra; M.O.Ullah; Noriko Sato

    2012-01-01

    In the Forest Department of Bangladesh,a Participatory Agroforestry Program (PAP) was initiated at a denuded Sal forests area to protect the forest resources and to alleviate poverty amongst the local poor population.We explored whether the PAP reduced poverty and what factors might be responsible for poverty alleviation.We used three poverty measurement methods:the Head Count Index,the Poverty Gap Index and the Foster-Greer-Thorbecke index to determine the extent poverty reduction.We used a linear regression model to determine the possible differences among factors in poverty reduction.Data were collected through semi-structured questionnaires and face to face interviews within the study area.PAP proved effective at poverty alleviation,considerably improving the local situation.The linear regression model showed that PAP output explained the income differences in poverty reduction. Participants identified bureaucracy and illegal money demands by forest department officials,an uncontrolled market system,and underdeveloped road infrastructure as the main obstacles to reduction of poverty.Overall,PAP is quite successful in alleviating poverty.So this program might be of interest at other degraded forest areas as a tool to alleviate poverty.

  5. Current therapy for Parkinson's disease

    OpenAIRE

    A. V. Obukhova

    2014-01-01

    The main goal of therapy for Parkinson's disease (PD) is to correct dopamine deficiency in the nigrostriatal system. Levodopa preparations and dopamine receptor agonists (DRAs) that are prescribed with regards to patient age and disease severity are mainly used now. Notwithstanding the fact that levodopa preparations are the gold standard of therapy, their long-term use gives rise to complications as motor fluctuations and drug-induced dyskinesias. The currently available DRAs are the drugs o...

  6. Dopamine Receptors and Parkinson's Disease

    OpenAIRE

    Shin Hisahara; Shun Shimohama

    2011-01-01

    Parkinson's disease (PD) is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa) significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first ...

  7. Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors

    OpenAIRE

    Watson, J.; Brough, S.; Coldwell, M C; Gager, T; Ho, M; Hunter, A. J.; Jerman, J; Middlemiss, D. N.; Riley, G J; Brown, A M

    1998-01-01

    Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5-HT1 and 5-HT2 receptors in native tissue and/or human cloned receptors.Xanomeline had affinity for muscarinic receptors in rat cortical membranes where the ratio of the displacement affinity of [3H]-Quinuclidi...

  8. Indacaterol er en én gang dagligt inhaleret β 2-agonist til behandling af kronisk obstruktiv lungesygdom

    DEFF Research Database (Denmark)

    Ulrik, Charlotte Suppli

    2010-01-01

    The aim of pharmacological treatment of COPD is best possible disease control. Bronchodilators are accepted as the mainstay of COPD therapy. This short review focuses on the available data on indacaterol - a new once-daily beta2-agonist. The analysed studies show that indacaterol has clinically i...... important effects on quality of life, dyspnoea, level of FEV1, hyperinflation, and exacerbation rate in patients with COPD. Indacaterol is therefore in the near future expected to be an important part of maintenance therapy for patients with COPD....

  9. The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation.

    Science.gov (United States)

    Larsson, Olivia J; Manson, Martijn L; Starkhammar, Magnus; Fuchs, Barbara; Adner, Mikael; Kumlien Georén, Susanna; Cardell, Lars-Olaf

    2016-06-01

    Toll-like receptor (TLR) 7 agonists are known to reduce allergic airway inflammation. Their recently reported ability to rapidly relax airways has further increased their interest in the treatment of pulmonary disease. However, the mechanisms behind this effect are not fully understood. The present study, therefore, aimed to determine whether airway smooth muscle (ASM)-dependent mechanisms could be identified. TLR7 agonists were added to guinea pig airways following precontraction with carbachol in vitro or histamine in vivo. Pharmacological inhibitors were used to dissect conventional pathways of bronchodilation; tetrodotoxin was used or bilateral vagotomy was performed to assess neuronal involvement. Human ASM cells (HASMCs) were employed to determine the effect of TLR7 agonists on intracellular Ca(2+) ([Ca(2+)]i) mobilization. The well-established TLR7 agonist imiquimod rapidly relaxed precontracted airways in vitro and in vivo. This relaxation was demonstrated to be independent of nitric oxide, carbon monoxide, and cAMP signaling, as well as neuronal activity. A limited role for prostanoids could be detected. Imiquimod induced [Ca(2+)]i release from endoplasmic reticulum stores in HASMCs, inhibiting histamine-induced [Ca(2+)]i The TLR7 antagonist IRS661 failed to inhibit relaxation, and the structurally dissimilar agonist CL264 did not relax airways or inhibit [Ca(2+)]i This study shows that imiquimod acts directly on ASM to induce bronchorelaxation, via a TLR7-independent release of [Ca(2+)]i The effect is paralleled by other bronchorelaxant compounds, like chloroquine, which, like imiquimod, but unlike CL264, contains the chemical structure quinoline. Compounds with quinoline moieties may be of interest in the development of multifunctional drugs to treat pulmonary disease. PMID:27084847

  10. The role of forestry development in China in alleviating greenhouse effects

    Energy Technology Data Exchange (ETDEWEB)

    Liu Hong

    1996-12-31

    Forestry development in China has gained great achievements and made great progress in realizing sustainable forest management and alleviating global climate change. The main measures to mitigate greenhouse effects through the means of forestry development include afforestation to increase the forested area, fuel wood forest development, management improvement, wise utilization, international cooperation, investment increase, forest related scientific research, strengthening the forest law enforcement system. Climate change as well as how to alleviate the greenhouse effects is a hot topic at present. This paper describes the achievements of China`s forestry development and its role to alleviate the greenhouse effects, and puts forward the measures to mitigate greenhouse effects through the means of forestry development.

  11. Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yanyan; Gao, Chao; Shi, Yanru; Tang, Yuhan; Liu, Liang; Xiong, Ting; Du, Min [Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Ministry of Education Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Xing, Mingyou [Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Liu, Liegang [Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Ministry of Education Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Yao, Ping, E-mail: yaoping@mails.tjmu.edu.cn [Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Ministry of Education Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China)

    2013-11-15

    Stress-inducible protein heme oxygenase-1(HO-1) is well-appreciative to counteract oxidative damage and inflammatory stress involving the pathogenesis of alcoholic liver diseases (ALD). The potential role and signaling pathways of HO-1 metabolite carbon monoxide (CO), however, still remained unclear. To explore the precise mechanisms, ethanol-dosed adult male Balb/c mice (5.0 g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100 mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8 mg/kg for mice or 20 μmol/L for hepatocytes), as well as other pharmacological reagents. Our data showed that CO released from HO-1 induction by quercetin prevented ethanol-derived oxidative injury, which was abolished by CO scavenger hemoglobin. The protection was mimicked by CORM-2 with the attenuation of GSH depletion, SOD inactivation, MDA overproduction, and the leakage of AST, ALT or LDH in serum and culture medium induced by ethanol. Moreover, CORM-2 injection or incubation stimulated p38 phosphorylation and suppressed abnormal Tnfa and IL-6, accompanying the alleviation of redox imbalance induced by ethanol and aggravated by inflammatory factors. The protective role of CORM-2 was abolished by SB203580 (p38 inhibitor) but not by PD98059 (ERK inhibitor) or SP600125 (JNK inhibitor). Thus, HO-1 released CO prevented ethanol-elicited hepatic oxidative damage and inflammatory stress through activating p38 MAPK pathway, suggesting a potential therapeutic role of gaseous signal molecule on ALD induced by naturally occurring phytochemicals. - Highlights: • CO alleviated ethanol-derived liver oxidative and inflammatory stress in mice. • CO eased ethanol and inflammatory factor-induced oxidative damage in hepatocytes. • The p38 MAPK is a key signaling mechanism for the protective function of CO in ALD.

  12. Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway

    International Nuclear Information System (INIS)

    Stress-inducible protein heme oxygenase-1(HO-1) is well-appreciative to counteract oxidative damage and inflammatory stress involving the pathogenesis of alcoholic liver diseases (ALD). The potential role and signaling pathways of HO-1 metabolite carbon monoxide (CO), however, still remained unclear. To explore the precise mechanisms, ethanol-dosed adult male Balb/c mice (5.0 g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100 mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8 mg/kg for mice or 20 μmol/L for hepatocytes), as well as other pharmacological reagents. Our data showed that CO released from HO-1 induction by quercetin prevented ethanol-derived oxidative injury, which was abolished by CO scavenger hemoglobin. The protection was mimicked by CORM-2 with the attenuation of GSH depletion, SOD inactivation, MDA overproduction, and the leakage of AST, ALT or LDH in serum and culture medium induced by ethanol. Moreover, CORM-2 injection or incubation stimulated p38 phosphorylation and suppressed abnormal Tnfa and IL-6, accompanying the alleviation of redox imbalance induced by ethanol and aggravated by inflammatory factors. The protective role of CORM-2 was abolished by SB203580 (p38 inhibitor) but not by PD98059 (ERK inhibitor) or SP600125 (JNK inhibitor). Thus, HO-1 released CO prevented ethanol-elicited hepatic oxidative damage and inflammatory stress through activating p38 MAPK pathway, suggesting a potential therapeutic role of gaseous signal molecule on ALD induced by naturally occurring phytochemicals. - Highlights: • CO alleviated ethanol-derived liver oxidative and inflammatory stress in mice. • CO eased ethanol and inflammatory factor-induced oxidative damage in hepatocytes. • The p38 MAPK is a key signaling mechanism for the protective function of CO in ALD

  13. Andrographolide alleviates imiquimod-induced psoriasis in mice via inducing autophagic proteolysis of MyD88.

    Science.gov (United States)

    Shao, Fenli; Tan, Tao; Tan, Yang; Sun, Yang; Wu, Xingxin; Xu, Qiang

    2016-09-01

    Psoriasis is a chronic inflammatory skin disease with excessive activation of toll-like receptors (TLRs), which play important roles in developing psoriasis. Targeting TLR signaling remains a challenge for treating psoriasis. Here, we found that andrographolide (Andro), a small-molecule natural product, alleviated imiquimod- but not interleukin 23 (IL-23)-induced psoriasis in mice with reducing expressions of IL-23 and IL-1β in the skin. The improvement in imiquimod-induced psoriasis by Andro was not observed in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) knockout mice. Furthermore, Andro inhibited mRNA expressions of IL-23, IL-6 and IL-1β but not CD80 and CD86 in bone-marrow derived dendritic cells (BMDCs) treated with lipopolysaccharide (LPS) in a MAP1LC3B-dependent manner. In addition, Andro inhibited imiquimod-induced mRNA expressions of IL-23, IL-6, IL-1β, CD80 and CD86 in BMDCs from mice. Interestingly, Andro induced a degradation of myeloid differentiation factor 88 (MyD88) and blocked the recruitment of TNF receptor-associated factor 6 (TRAF6) to MyD88 upon LPS stimulation in BMDCs from mice. Blockade of autophagic proteolysis using NH4Cl or MAP1LC3B(-/-) BMDCs abolished the Andro-induced MyD88 degradation. In conclusion, Andro controls activation of MyD88-dependent cytokines and alleviates psoriasis in mice via inducing autophagic proteolysis of MyD88, which could be a novel strategy to treat psoriasis. PMID:27265145

  14. Do Economic Reforms Alleviate Subjective Well-Being Losses of Economic Crises?

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    2014-01-01

    Major economic crises tend to be followed by crises in subjective well-being. Following the financial and debt crises, politicians and social scientists have engaged in heated discussions of ways to alleviate such losses. In particular, should governments intervene more or less? This paper explores...... whether liberalizing economic institutions, a type of reform favoured by some economists, is likely to alleviate such loses. Estimating the effects of crises across European states 1975–2011 suggest that countries with relatively easy market regulations suffered smaller well-being losses....

  15. Halting angiogenesis by non-viral somatic gene therapy alleviates psoriasis and murine psoriasiform skin lesions

    DEFF Research Database (Denmark)

    Zibert, John Robert; Wallbrecht, Katrin; Schön, Margarete;

    2011-01-01

    epidermal expression of human TGF-ß1, we have demonstrated that antiangiogenic non-viral somatic gene therapy reduces the cutaneous microvasculature and alleviates chronic inflammatory skin disorders. Transient muscular expression of the recombinant disintegrin domain (RDD) of metargidin (also known as ADAM...... in all models. Thus, non-viral antiangiogenic gene therapy can alleviate psoriasis and may do so in other angiogenesis-related inflammatory skin disorders.......-15) by in vivo electroporation reduced cutaneous angiogenesis and vascularization in all 3 models. As demonstrated using red fluorescent protein-coupled RDD, the treatment resulted in muscular expression of the gene product and its deposition within the cutaneous hyperangiogenic connective tissue...

  16. Alleviating Energy Poverty through innovation: The case of Jyotigram Yojana (rural lighting scheme) of Gujarat

    Energy Technology Data Exchange (ETDEWEB)

    Mishra, Pramod Kumar

    2010-09-15

    Access to electricity is important for alleviation energy poverty in rural areas of developing countries. In spite of rural electrification schemes people in numerous villages do not have access to electricity because of inadequate and erratic power supply. The Jyotigram Yojana (Rural Lighting Scheme) of Gujarat in India transformed the rural electricity distribution scenario creating immense opportunities for socio-economic development. It shows how vision and political will can transcend the boundaries of technical and financial expertise and systemic rigidities, and facilitate successful adoption of simple but innovative approaches for alleviation of energy poverty and bringing about socio-economic development.

  17. Alleviating Effect of Phenol Compounds on Cucumber Fusarium Wilt and Mechanism

    Institute of Scientific and Technical Information of China (English)

    YUAN Fei; ZHANG Chun-lan; SHEN Qi-rong

    2003-01-01

    The amount of phenol compounds in the soil increased after adding organic material into the soil. It was found that p-hydroxybenzoic acid, p-coumaric acid and frulic acid alleviated Fusarium wilt of cucumber, the alleviating effect of p-hydroxybenzoic acid was the best, followed by p-coumaric acid and frulic acid. The total amount of bacterial, actinomyces and fungus in high phenol compounds treatment decreased than that of control treatment, while the microorganisms' amount in low phenol compounds treatment increased. Phenol compounds inhibit the growth of pathogen.

  18. Processed coffee alleviates DSS-induced colitis in mice

    Directory of Open Access Journals (Sweden)

    Bernd L. Fiebich

    2013-05-01

    Full Text Available ABSTRACTBackground: Coffee is one of the most widely consumed beverages in the world and it has been demonstrated that it has important therapeutic activities not only because of its caffeine content but also owing to the presence of other biologically active small molecules such as chlorogenic acid, trigonelline and cyclopentadiones. However, chlorogenic acid is degraded into catechol, pyrogallol and hydroxyhydroquinone, which are thought to induce irritation of the gastric mucosa. To reduce the content of irritant compounds processing methods have been developed prior to roasting the coffee beans.Objectives: The aim of this study was to study the anti-inflammatory and gastro-protective effects of processed coffee (Idee-Kaffee on in LPS-treated human primary monocytes and in a murine model of colon inflammation (IBD model.Results: In this study we have analyzed the effects on inflammatory events in cultured cells and in mice drinking a commercially available processed coffee. The processed coffee inhibited lipopolysaccharide (LPS-induced proinflammatory cytokines such as interleukin (IL-1, tumor necrosis factor (TNF, IL-6 and IL-8, and other inflammatory mediators such as prostaglandin (PGE2 and 8-isoprostane in cultured human primary monocytes. Oral administration of dissolved processed coffee, i.e., in its usual beverage form, improved greatly the adverse macroscopic and histological features of dextran sodium sulfate (DSS-induced colitis in mice in a dose-dependent manner. Processed coffee not only largely prevented DSS-induced colitis but also dramatically suppressed in vivo NF-B and STAT3 activities through inhibition of IB and STAT3 phosphorylation. Furthermore, this solubleFunctional Foods in Health and Disease 2013; 3(5:133-145coffee bean extract reduced the expression of proinflammatory cytokines TNF, IL-11, and IL-6 and the expression of cyclooxygenase (COX-2 in colonic tissues.Conclusions: This work identified

  19. Intracolonical administration of protease-activated receptor-2 agonists produced visceral hyperalgesia by up-regulating serotonin in the colon of rats.

    Science.gov (United States)

    Li, Zhi; Zhang, Xiao-Jun; Xu, Hong-xi; Sung, Joseph J Y; Bian, Zhao-xiang

    2009-03-15

    This study aimed to investigate the underlying mechanism of protease-activated receptor-2 (PAR-2) agonist-induced visceral hyperalgesia. Male Sprague-Dawley rat pups were submitted to colonic injection of PAR-2 agonist for 6 consecutive days. The visceral sensitivity to colorectal distention was evaluated by electromyography. The enterochromaffin (EC) cell number, 5-HT content and tryrptophan hydroxylase (TPH) protein expression were detected with immunohistochemistry, fluorescent measurement and Western blot analysis. PAR-2 agonist induced a significant increase of visceral nociceptive response to colorectal distention and a series of neurochemical changes in rat colon, including proliferation of EC cells, increased 5-HT content and enhanced TPH expression. Expression of PAR-2 in EC cells was reported for the first time. Further, selective 5-HT(3) receptor antagonist alosteron significantly inhibited PAR-2-induced visceral hyperalgesia. The enhanced 5-HT signaling is likely responsible for the visceral hyperalgesia induced by PAR-2 agonist. Interruption of this pathway is a possible target for the treatment of visceral hyperalgesia in gastrointestinal diseases. PMID:19374846

  20. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats

    Directory of Open Access Journals (Sweden)

    Lili eGao

    2015-10-01

    Full Text Available Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA, a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition and activation of tansforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.

  1. Decreased Dengue Replication and an Increased Anti-viral Humoral Response with the use of Combined Toll-Like Receptor 3 and 7/8 Agonists in Macaques

    OpenAIRE

    SARIOL, Carlos A.; Martínez, Melween I.; Rivera, Francheska; Rodríguez, Idia Vanessa; Pantoja, Petraleigh; Abel, Kristina; Arana, Teresa; Giavedoni, Luis; Hodara, Vida; White, Laura J.; Angleró, Yesseinia I.; Montaner, Luis J.; KRAISELBURD, EDMUNDO N.

    2011-01-01

    Background Pathogenic versus protective outcomes to Dengue virus (DENV) infection are associated with innate immune function. This study aimed to determine the role of increased TLR3- and TLR7/8-mediated innate signaling after Dengue infection of rhesus macaques in vivo to evaluate its impact on disease and anti-DENV immune responses. Methodology/Principal Findings TLR3 and TLR7/8 agonists (emulsified in Montanide) were administered subcutaneously to rhesus macaques at 48 hours and 7 days aft...

  2. Functional Characterization of the Semisynthetic Bile Acid Derivative INT-767, a Dual Farnesoid X Receptor and TGR5 AgonistS⃞

    OpenAIRE

    Rizzo, Giovanni; Passeri, Daniela; Franco, Francesca; Ciaccioli, Gianmario; Donadio, Loredana; Rizzo, Giorgia; Orlandi, Stefano; Sadeghpour, Bahman; Wang, Xiaoxin X.; Jiang, Tao; Levi, Moshe; Pruzanski, Mark; Adorini, Luciano

    2010-01-01

    Two dedicated receptors for bile acids (BAs) have been identified, the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, which represent attractive targets for the treatment of metabolic and chronic liver diseases. Previous work characterized 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (INT-747), a potent and selective FXR agonist, as well as ...

  3. The effect of polymorphisms of beta2 adrenoceptors on response to long-acting beta2 agonists in Iranian asthmatic patients.

    OpenAIRE

    Fatemeh Soleimani; Fanak Fahimi; Parisa Adimi Naghan; Seyed Alireza Nadji; Saeid Morowati; Nima Naderi; Mohammad Reza Masjedi

    2013-01-01

    The results of many studies suggested possible relationship between polymorphism at codons 16 and 27 and development of tolerance to beta-2 adrenoceptor agonist responses as well as disease severity in asthmatic patients. This study was designed to evaluate the effect of polymorphism of beta2 adrenoceptors on response to salmeterol and fluticasone (as inhaled Seretide).Sixty-four patients with either mild or moderate-severe asthma were evaluated in this study. A four-week therapy with Seretid...

  4. Discovery of potent and selective agonists for the free fatty acid receptor 1 (FFA(1)/GPR40), a potential target for the treatment of type II diabetes.

    Science.gov (United States)

    Christiansen, Elisabeth; Urban, Christian; Merten, Nicole; Liebscher, Kathrin; Karlsen, Kasper K; Hamacher, Alexandra; Spinrath, Andreas; Bond, Andrew D; Drewke, Christel; Ullrich, Susanne; Kassack, Matthias U; Kostenis, Evi; Ulven, Trond

    2008-11-27

    A series of 4-phenethynyldihydrocinnamic acid agonists of the free fatty acid receptor 1 (FFA(1)) has been discovered and explored. The preferred compound 20 (TUG-424, EC(50) = 32 nM) significantly increased glucose-stimulated insulin secretion at 100 nM and may serve to explore the role of FFA(1) in metabolic diseases such as diabetes or obesity. PMID:18947221

  5. Antinociceptive properties of selective MT(2) melatonin receptor partial agonists.

    Science.gov (United States)

    López-Canul, Martha; Comai, Stefano; Domínguez-López, Sergio; Granados-Soto, Vinicio; Gobbi, Gabriella

    2015-10-01

    Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5-40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT2 partial agonists were blocked by the pre-treatment with the MT2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT2 melatonin receptor may be a novel target for analgesic drug development. PMID:26162699

  6. Agonist binding to high-affinity dopamine sites

    Energy Technology Data Exchange (ETDEWEB)

    Tedesco, J.L.

    1985-01-01

    The authors have characterized the dopamine D/sub 3/ site and its binding requirements. The dopamine D/sub 3/ site in calf caudate crude homogenate has a site density of 214-230 fmoles/mg. protein by both /sup 3/H-apomorphine (/sup 3/H-AOP) and /sup 3/H-dopamine (/sup 3/H-DA) Scatchard analysis of specific binding (SB). Stereospecific subsets of /sup 3/H-APO and /sup 3/H-DA sites were defined by the use of agonist and antagonist enantiomer-pairs as a rigorous test for D/sub 3/ site heterogeneity. IC/sub 50/ values for both /sup 3/H-APO and /sup 3/H-DA SB sites were assessed for 55 agonist ligands and an excellent correlation was obtained. The authors conclude that both /sup 3/H-ligands label the same D/sub 3/ site. The D/sub 3/ site affinities of 105 dopamine-agonist ligands, in particular 2-aminotetralins,, aporphines and flexible dopamine analogues were measured. Low D/sub 3/-site affinities of N-quaternary analogues confirm the need for a lone pair. Subadditivity of substituents' effects in semi-flexible DA analogues confirms their postulate that sidechain conformation is the critical determinant of affinity. They conclude that there are at least two high-affinity ligand conformations of the DA sidechain pharmacophore. These binding requirements are presented as two interface-Geometry tetrahedral models of the double H-bond interface between the D/sub 3/ site and the ideal ligand.

  7. Ramelteon: A melatonin receptor agonist for the treatment of insomnia

    Directory of Open Access Journals (Sweden)

    Devi V

    2008-01-01

    Full Text Available Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for the treatment of insomnia characterized by difficulty in sleep onset. It is a nonscheduled drug since it lacks the potential for abuse and does not interact with neurotransmitter receptors most associated with these phenomena. Although the effects of ramelteon use> 5 weeks are unknown, the available data confirms its safety and efficacy for short-term use. Clinical use and future research should uncover more information about ramelteon′s properties.

  8. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    Science.gov (United States)

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight. PMID:26198605

  9. Principles of agonist recognition in Cys-loop receptors

    DEFF Research Database (Denmark)

    Lynagh, Timothy Peter; Pless, Stephan Alexander

    2014-01-01

    diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to......Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term "chemoreceptor" emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning...

  10. AG-4:A NICOTINIC AGONIST ENDOWED WITH ANTIAMNESIC PROPERTIES

    OpenAIRE

    Ghelardini, C; Galeotti, N; Di Cesare Mannelli, L.; S. Dei; F. GUALTIERI; Bartolini, A.

    2000-01-01

    The effect of the nicotinic agonist AG-4 on memory processes was evaluated in the mouse passive avoidance test. AG-4 (100 mg per mouse icv) prevented amnesia induced by scopolamine (1.5 mg kg–1 ip), mecamylamine (20 mg kg–1 ip), and dihydro-b-erythroidine (10 mg per mouse icv). In the same experimental conditions, AG-4 (100 mg per mouse icv) also prevented baclofen (2 mg kg–1 ip), clonidine (0.125 mg kg–1 ip), and diphenhydramine (20 mg kg–1 ip) amnesia in mice. AG-4 exerted an an...

  11. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    Science.gov (United States)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  12. Alleviating effects of morin against experimentally-induced diabetic osteopenia

    Directory of Open Access Journals (Sweden)

    Abuohashish Hatem M

    2013-02-01

    Full Text Available Abstract Background Plant flavonoids are emerging as potent therapeutic drugs effective against a wide range of aging diseases particularly bone metabolic disorders. Morin (3,5,7,20,40-pentahydroxyflavone, a member of flavonols, is an important bioactive compound by interacting with nucleic acids, enzymes and protein. The present study was designed to investigate the putative beneficial effect of morin on diabetic osteopenia in rats. Methods Streptozotocin (STZ-induced diabetic model was used by considering 300 mg/dl fasting glucose level as diabetic. Morin (15 and 30 mg/kg was treated for five consecutive weeks to diabetic rats. Serum levels of glucose, insulin, deoxypyridinoline cross links (DPD, osteocalcin (OC, bone specific alkaline phosphatase (BALP, telopeptides of collagen type I (CTX, interleukin 1 beta (IL-1β, interleukin 6 (IL-6, tumor necrosis factor alpha (TNF-α, thiobarbituric acid reactive substance (TBARS and reduced glutathione (GSH were estimated. Femoral bones were taken for micro CT scan to measure trabecular bone mineral density (BMD and other morphometric parameters. Results Significant bone loss was documented as the level of bone turnover parameters including DPD, OC, BALP and CTX were increased in serum of diabetic rats. Morin treatment significantly attenuated these elevated levels. Bone micro-CT scan of diabetic rats showed a significant impairment in trabecular bone microarchitecture, density and other morphometric parameters. These impairments were significantly ameliorated by morin administration. Serum levels of glucose, TBARS, IL-1β, IL-6 and TNF-α were significantly elevated, while the level of insulin and GSH was decreased in diabetic rats. These serum changes in diabetic rats were bring back to normal values after 5 weeks morin treatment. Conclusion These findings revealed the protective effect of morin against diabetic induced osteopenia. We believed that this effect is through its both the anti

  13. Riboflavin alleviates cardiac failure in Type I diabetic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Xue Zhao

    2011-09-01

    Full Text Available Heart failure (HF is a common and serious comorbidity of diabetes. Oxidative stress has been associated with the pathogenesis of chronic diabetic complications including cardiomyopathy. The ability of antioxidants to inhibit injury has raised the possibility of new therapeutic treatment for diabetic heart diseases. Riboflavin constitutes an essential nutrient for humans and animals and it is an important food additive. Riboflavin, a precursor of flavin mononucleotide (FMN and flavin adenine dinucleotide (FAD, enhances the oxidative folding and subsequent secretion of proteins. The objective of this study was to investigate the cardioprotective effect of riboflavin in diabetic rats. Diabetes was induced in 30 rats by a single injection of streptozotocin (STZ (70 mg /kg. Riboflavin (20 mg/kg was orally administered to animals immediately after induction of diabetes and was continued for eight weeks. Rats were examined for diabetic cardiomyopathy by left ventricular (LV remadynamic function. Myocardial oxidative stress was assessed by measuring the activity of superoxide dismutase (SOD, the level of malondialdehyde (MDA as well as heme oxygenase-1 (HO-1 protein level. Myocardial connective tissue growth factor (CTGF level was measured by Western blot in all rats at the end of the study. In the untreated diabetic rats, left ventricular systolic pressure (LVSP rate of pressure rose (+dp/dt, and rate of pressure decay (−dp/dt were depressed while left ventricular enddiastolic pressure (LVEDP was increased, which indicated the reduced left ventricular contractility and slowing of left ventricular relaxation. The level of SOD decreased, CTGF and HO-1 protein expression and MDA content rose. Riboflavin treatment significantly improved left ventricular systolic and diastolic function in diabetic rats, there were persistent increases in significant activation of SOD and the level of HO-1 protein, and a decrease in the level of CTGF. These results suggest

  14. Biochemical and pharmacological studies on pramipexole, a potent and selective dopamine D2 receptor agonist.

    Science.gov (United States)

    Mierau, J; Schingnitz, G

    1992-05-14

    Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole- dihydrochloride) was tested for its agonistic activity at pre- and postsynaptic dopamine (DA) receptors. L-Dihydroxyphenylalanine (L-dopa) accumulation in the rat striatum and limbic system and the alpha-methyltyrosine-induced reduction of DA were inhibited. Both effects were fully antagonized by haloperidol but not by the selective DA D1 receptor antagonist SCH 23390. Pramipexole decreased the levels of DA metabolites dose dependently, whereas striatal DA levels remained unchanged. In mice, pramipexole (0.001-1 mg/kg s.c.) reduced exploratory locomotor activity. In rats with unilateral striatal lesions, only weak ipsilateral rotation was produced by pramipexole at the highest dose. However, in rats with unilateral lesions of the medial forebrain bundle, pramipexole potently induced contralateral circling (ED50 0.026 mg/kg s.c.). In the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model, pramipexole also had potent stimulatory effects. Finally, in haloperidol-sensitized monkeys, the substance did not elicit dyskinesia/dystonia when given alone, but rather inhibited those symptoms which had been induced by haloperidol (ED50 0.116 mg/kg i.m.). It is concluded that pramipexole has therapeutic potential for schizophrenic patients, as a result of its autoreceptor agonistic effects and its weak effects at normosensitive postsynaptic DA receptors. Furthermore, its potent stimulatory effects in DA-depleted animals suggest a possible use in the treatment of Parkinson's disease. PMID:1356788

  15. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury

    Energy Technology Data Exchange (ETDEWEB)

    Goto, Hiromasa [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Nomiyama, Takashi, E-mail: tnomiyama@fukuoka-u.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Mita, Tomoya; Yasunari, Eisuke; Azuma, Kosuke; Komiya, Koji; Arakawa, Masayuki; Jin, Wen Long; Kanazawa, Akio [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Sportology Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Fujitani, Yoshio; Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Sportology Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan)

    2011-02-04

    Research highlights: {yields} Exendin-4 reduces neointimal formation after vascular injury in a mouse model. {yields} Exendin-4 dose not alter metabolic parameters in non-diabetic, non-obese mouse model. {yields} Exendin-4 reduces PDGF-induced cell proliferation in cultured SMCs. {yields} Exendin-4 may reduces neointimal formation after vascular injury at least in part through its direct action on SMCs. -- Abstract: Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4 weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10 nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.

  16. Coexpressed RIG-I agonist enhances humoral immune response to influenza virus DNA vaccine.

    Science.gov (United States)

    Luke, Jeremy M; Simon, Gregory G; Söderholm, Jonas; Errett, John S; August, J Thomas; Gale, Michael; Hodgson, Clague P; Williams, James A

    2011-02-01

    Increasing levels of plasmid vector-mediated activation of innate immune signaling pathways is an approach to improve DNA vaccine-induced adaptive immunity for infectious disease and cancer applications. Retinoic acid-inducible gene I (RIG-I) is a critical cytoplasmic double-stranded RNA (dsRNA) pattern receptor required for innate immune activation in response to viral infection. Activation of RIG-I leads to type I interferon (IFN) and inflammatory cytokine production through interferon promoter stimulator 1 (IPS-1)-mediated activation of interferon regulatory factor 3 (IRF3) and NF-κB signaling. DNA vaccines coexpressing antigen and an expressed RNA (eRNA) RIG-I agonist were made, and the effect of RIG-I activation on antigen-specific immune responses to the encoded antigen was determined. Plasmid vector backbones expressing various RIG-I ligands from RNA polymerase III promoters were screened in a cell culture assay for RIG-I agonist activity, and optimized, potent RIG-I ligands were developed. One of these, eRNA41H, combines (i) eRNA11a, an immunostimulatory dsRNA expressed by convergent transcription, with (ii) adenovirus VA RNAI. eRNA41H was integrated into the backbone of DNA vaccine vectors expressing H5N1 influenza virus hemagglutinin (HA). The resultant eRNA vectors potently induced type 1 IFN production in cell culture through RIG-I activation and combined high-level HA antigen expression with RNA-mediated type I IFN activation in a single plasmid vector. The eRNA vectors induced increased HA-specific serum antibody binding avidity after naked DNA intramuscular prime and boost delivery in mice. This demonstrates that DNA vaccine potency may be augmented by the incorporation of RIG-I-activating immunostimulatory RNA into the vector backbone. PMID:21106745

  17. Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing.

    Science.gov (United States)

    Modi, Meera E; Majchrzak, Mark J; Fonseca, Kari R; Doran, Angela; Osgood, Sarah; Vanase-Frawley, Michelle; Feyfant, Eric; McInnes, Heather; Darvari, Ramin; Buhl, Derek L; Kablaoui, Natasha M

    2016-08-01

    Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non-brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response. PMID:27217590

  18. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    Energy Technology Data Exchange (ETDEWEB)

    Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  19. beta-Adrenoceptor agonists enhance 5-hydroxytryptamine-mediated behavioural responses.

    OpenAIRE

    Cowen, P. J.; Grahame-Smith, D.G.; Green, A R; Heal, D. J.

    1982-01-01

    The beta-adrenoceptor agonists, salbutamol, terbutaline and clenbuterol, were investigated for their effect on 5-hydroxytryptamine-mediated (5-HT) hyperactivity. 2 The lipophilic beta-adrenoceptor agonist, clenbuterol (5 mg/kg) enhanced the behaviours induced by quipazine (25 mg/kg), including headweaving, forepaw treading and hind-limb abduction and thus increased automated activity recording. Clenbuterol (5 mg/kg) also enhanced the hyperactivity syndrome produced by the 5-HT agonist, 5-meth...

  20. Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.

    Science.gov (United States)

    Sheppeck, James E; Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Nirschl, David; Doweyko, Arthur M; Sack, Jack S; Corbett, Martin J; Malley, Mary F; Gougoutas, Jack Z; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Dodd, John H; Nadler, Steven G; Somerville, John E; Barrish, Joel C

    2013-10-01

    Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. PMID:23953070

  1. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa-Moriyama, Maiko, E-mail: hase-mai@m3.kufm.kagoshima-u.ac.jp [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas

  2. Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

    International Nuclear Information System (INIS)

    In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-[125I]iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants

  3. Dopamine agonist-induced substance addiction: the next piece of the puzzle.

    Science.gov (United States)

    Evans, Andrew

    2011-02-01

    Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor "off" periods. The recent recognition of a range of "behavioural addictions" that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions. PMID:20980151

  4. Sustained wash-resistant receptor activation responses of GPR119 agonists.

    Science.gov (United States)

    Hothersall, J Daniel; Bussey, Charlotte E; Brown, Alastair J; Scott, James S; Dale, Ian; Rawlins, Philip

    2015-09-01

    G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses. PMID:26101059

  5. Galanin transgenic mice with elevated circulating galanin levels alleviate demyelination in a cuprizone-induced MS mouse model.

    Directory of Open Access Journals (Sweden)

    Lin Zhang

    Full Text Available Multiple Sclerosis (MS is a demyelinating autoimmune disease of the central nervous system (CNS with a presumed autoimmune etiology. Approved treatments for MS are immunoregulatory and are able to reduce the inflammatory components of the disease. However, these treatments do not suppress progressive clinical disability. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination are likely to improve long-term outcomes and reduce the rate of axonal damage. Galanin (GAL is a bioactive neuropeptide that is widely distributed throughout the nervous system and has diverse neuromodulatory effects. In this study, using the cuprizone (CPZ demyelination model of MS, we demonstrate that GAL has pronounced neuroprotective effects with respect to demyelination and remyelination. Using our GAL transgenic mouse (GAL-Tg, we identified a novel attenuation of OLs against CPZ induced demyelination, which was exerted independently of progenitor cells. Alleviation of myelin breakdown in the GAL-Tg mice was observed to be significant. Furthermore, we observed changes in the expression of the GAL receptor GalR1 during the demyelination and remyelination processes. Our data strongly indicate that GAL has the capacity to influence the outcome of primary insults that directly target OLs, as opposed to cases where immune activation is the primary pathogenic event. Taken together, these results suggest that GAL is a promising next-generation target for the treatment of MS.

  6. 13 CFR 310.2 - Pressing need; alleviation of unemployment or underemployment.

    Science.gov (United States)

    2010-01-01

    ... unemployment or underemployment. 310.2 Section 310.2 Business Credit and Assistance ECONOMIC DEVELOPMENT ADMINISTRATION, DEPARTMENT OF COMMERCE SPECIAL IMPACT AREAS § 310.2 Pressing need; alleviation of unemployment or... Special Need. (b) For purposes of this part, excessive unemployment exists if the twenty-four (24)...

  7. Mechanisms of silicon-mediated alleviation of abiotic stresses in higher plants: A review

    International Nuclear Information System (INIS)

    Although silicon (Si) is the second most abundant element both on the surface of the Earth's crust and in soils, it has not yet been listed among the essential elements for higher plants. However, the beneficial role of Si in stimulating the growth and development of many plant species has been generally recognized. Silicon is known to effectively mitigate various abiotic stresses such as manganese, aluminum and heavy metal toxicities, and salinity, drought, chilling and freezing stresses. However, mechanisms of Si-mediated alleviation of abiotic stresses remain poorly understood. The key mechanisms of Si-mediated alleviation of abiotic stresses in higher plants include: (1) stimulation of antioxidant systems in plants, (2) complexation or co-precipitation of toxic metal ions with Si, (3) immobilization of toxic metal ions in growth media, (4) uptake processes, and (5) compartmentation of metal ions within plants. Future research needs for Si-mediated alleviation of abiotic stresses are also discussed. - This review article overviews roles Si plays in alleviating abiotic stress in higher plants and discusses future research directions

  8. Use of goats in poverty alleviation and potential effects on the environment

    DEFF Research Database (Denmark)

    Madsen, Jørgen; Nielsen, Mette Benedicte Olaf; Henriksen, Jørgen

    2009-01-01

    Goats are a powerful tool in assistance to alleviate poverty and they are also a powerful tool to utilize scarce vegetation in areas not suitable for other forms of agricultural production. If goats are kept in a wrong place and not managed well they may, however, destroy the environment. Accordi...

  9. Novel Alleviation Mechanisms of Aluminum Phytotoxicity via Released Biosilicon from Rice Straw-Derived Biochars

    Science.gov (United States)

    Qian, Linbo; Chen, Baoliang; Chen, Mengfang

    2016-07-01

    Replacing biosilicon and biocarbon in soil via biochar amendment is a novel approach for soil amelioration and pollution remediation. The unique roles of silicon (Si)-rich biochar in aluminum (Al) phytotoxicity alleviation have not been discovered. In this study, the alleviation of Al phytotoxicity to wheat plants (root tips cell death) by biochars fabricated from rice straw pyrolyzed at 400 and 700 °C (RS400 and RS700) and the feedstock (RS100) were studied using a slurry system containing typical acidic soils for a 15-day exposure experiment. The distributions of Al and Si in the slurry solution, soil and plant root tissue were monitored by staining methods, chemical extractions and SEM-EDS observations. We found that the biological sourced silicon in biochars served dual roles in Al phytotoxicity alleviation in acidic soil slurry. On one hand, the Si particles reduced the amount of soil exchangeable Al and prevented the migration of Al to the plant. More importantly, the Si released from biochars synchronously absorbed by the plants and coordinated with Al to form Al-Si compounds in the epidermis of wheat roots, which is a new mechanism for Al phytotoxicity alleviation in acidic soil slurry by biochar amendment. In addition, the steady release of Si from the rice straw-derived biochars was a sustainable Si source for aluminosilicate reconstruction in acidic soil.

  10. Foreign direct investment and poverty alleviation : the case of Bulyanhulu and Geita gold mines, Tanzania

    NARCIS (Netherlands)

    Nyankweli, Emmanuel M.

    2012-01-01

    This PhD thesis seeks to quantify the economic, social and environmental effects of the gold mining sector as a component of foreign direct investments in Tanzania and its contribution to poverty alleviation. In addition to highlighting the socio-economic gains and losses, by exploring the corporate

  11. Exogenous calcium alleviates low night temperature stress on the photosynthetic apparatus of tomato leaves.

    Directory of Open Access Journals (Sweden)

    Guoxian Zhang

    Full Text Available The effect of exogenous CaCl2 on photosystem I and II (PSI and PSII activities, cyclic electron flow (CEF, and proton motive force of tomato leaves under low night temperature (LNT was investigated. LNT stress decreased the net photosynthetic rate (Pn, effective quantum yield of PSII [Y(II], and photochemical quenching (qP, whereas CaCl2 pretreatment improved Pn, Y(II, and qP under LNT stress. LNT stress significantly increased the non-regulatory quantum yield of energy dissipation [Y(NO], whereas CaCl2 alleviated this increase. Exogenous Ca2+ enhanced stimulation of CEF by LNT stress. Inhibition of oxidized PQ pools caused by LNT stress was alleviated by CaCl2 pretreatment. LNT stress reduced zeaxanthin formation and ATPase activity, but CaCl2 pretreatment reversed both of these effects. LNT stress caused excess formation of a proton gradient across the thylakoid membrane, whereas CaCl2 pretreatment decreased the said factor under LNT. Thus, our results showed that photoinhibition of LNT-stressed plants could be alleviated by CaCl2 pretreatment. Our findings further revealed that this alleviation was mediated in part by improvements in carbon fixation capacity, PQ pools, linear and cyclic electron transports, xanthophyll cycles, and ATPase activity.

  12. How to alleviate the electricity scarcity in Guangxi : an analysis of electricity pricing

    OpenAIRE

    2006-01-01

    With the rapid economic growth and the increase of the population, Guangxi, a province with abundant hydropower resource, is facing a severe electricity shortage problem. This situation forces Guangxi¡¯s decision makers, the local government, to seek methods to alleviate the problem of electricity scarcity, and among the measures the way of re-pricing electricity seems a proper one.

  13. Poverty alleviation as business strategy? : evaluating commitments of frontrunner Multinational Corporations

    NARCIS (Netherlands)

    A. Kolk; R. van Tulder

    2006-01-01

    In the debate on how to combat poverty, the positive role of MNCs is frequently mentioned nowadays, although doubts and criticism remain. Facing this societal debate, MNCs feel pressure to formulate a position. This paper analyzes MNCs' policies on their poverty-alleviating potential. 'Frontrunner'

  14. Young Children's Ideas about the Nature, Causes, Justification, and Alleviation of Poverty

    Science.gov (United States)

    Chafel, Judith A.; Neitzel, Carin

    2005-01-01

    Sixty-four 8-year-old boys and girls from urban and rural settings and representing different races and socioeconomic status backgrounds responded to questions about the nature, causes, justification, and alleviation of poverty. Much of what the children said indicated that they had not yet internalized prevailing adult norms and values about the…

  15. Load alleviation potential of the Controllable Rubber Trailing Edge Flap (CRTEF) in the INDUFLAP project

    DEFF Research Database (Denmark)

    Barlas, Thanasis K.; Bergami, Leonardo; Hansen, Morten Hartvig; Pedersen, Mads Mølgaard; Thomsen, Kenneth; Aagaard Madsen, Helge

    The load alleviation potential of the Controllable Rubber Trailing Edge Flap (CRTEF) is verified on a full Design Load Base (DLB) setup using the aeroelastic code HAWC2, and by investigating a flap configuration for the NREL 5MW Reference Wind Turbine (RWT) model. The performance of the CRTEF...

  16. Symptom monitoring, alleviation, and self-care among Mexican Americans during cancer treatment.

    Science.gov (United States)

    Williams, Phoebe D; Lantican, Leticia S; Bader, Julia O; Lerma, Daniela

    2014-10-01

    Monitoring the occurrence and severity of symptoms among Mexican American adults undergoing cancer treatments, along with their self-care to alleviate symptoms, are understudied; the current study aimed to fill this gap in the literature. A total of 67 Mexican Americans receiving outpatient oncology treatments in the southwestern United States participated. Instruments included a patient-report checklist, the Therapy-Related Symptom Checklist (TRSC), the Symptom Alleviation: Self-Care Methods tool, and a demographic and health information form. At least 40% of participants reported the occurrence of 12 symptoms: hair loss, feeling sluggish, nausea, taste change, loss of appetite, depression, difficulty sleeping, weight loss, difficulty concentrating, constipation, skin changes, and numb fingers and toes. More than a third also reported pain, vomiting, decreased interest in sexual activity, cough, and sore throat. The helpful self-care strategies reported included diet and nutrition changes; lifestyle changes; and mind, body control, and spiritual activities. Patient report of symptoms during cancer treatments was facilitated by the use of the TRSC. Patients use symptom alleviation strategies to help relieve symptoms during their cancer treatment. The ability to perform appropriate, effective self-care methods to alleviate the symptoms may influence adherence to the treatment regimen. PMID:25253108

  17. Natural Products for the Prevention and Alleviation of Risk Factors for Diabetes: Chromium and Cinnamon

    Science.gov (United States)

    Natural products are widespread for the alleviation and prevention of the risk factors of the metabolic syndrome and diabetes. We have shown that glucose, insulin, cholesterol, and hemoglobin A1c levels are all improved in people with type 2 diabetes following chromium supplementation in a double-b...

  18. Alleviating the Entrance to Serious Games by Exploring the Use of Commonly Available Tools

    OpenAIRE

    Van Rosmalen, Peter; Klemke, Roland; WESTERA, Wim

    2011-01-01

    Van Rosmalen, P., Klemke, R., & Westera, W. (2011). Alleviating the Entrance to Serious Games by Exploring the Use of Commonly Available Tools. In D. Gouscos, & M. Meimaris (Eds.), Proceedings of the 5th European Conference on Games Based Learning (pp. 613-619), Athens, Greece. 20-21 October 2011.

  19. Structural complexes of the agonist, inverse agonist and antagonist bound C5a receptor: insights into pharmacology and signaling.

    Science.gov (United States)

    Rana, Soumendra; Sahoo, Amita Rani; Majhi, Bharat Kumar

    2016-04-26

    The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. The study attempts to understand the pharmacology at the "orthosteric" site2 of C5aR rationally by generating a highly refined full-blown model structure of C5aR through advanced molecular modeling techniques, and further subjecting it to automated docking and molecular dynamics (MD) studies in the POPC bilayer. The first series of structural complexes of C5aR respectively bound to a linear native peptide agonist ((h)C5a-CT), a small molecule inverse agonist (NDT) and a cyclic peptide antagonist (PMX53) are reported, apparently establishing the unique pharmacological landscape of the "orthosteric" site2, which also illustrates an energetically distinct but coherent competitive chemistry ("cation-π" vs. "π-π" interactions) involved in distinguishing the established ligands known for targeting the "orthosteric" site2 of C5aR. Over a total of 1 μs molecular dynamics (MD) simulation in the POPC bilayer, it is evidenced that while the agonist prefers a "cation-π" interaction, the inverse agonist prefers a "cogwheel/L-shaped" interaction in contrast to the "edge-to-face/T-shaped" type π-π interactions demonstrated by the antagonist by engaging the F275(7.28) of the C5aR. In the absence of a NMR or crystallographically guided model structure of C5aR, the computational model complexes not only

  20. Adaptation to hot climate and strategies to alleviate heat stress in livestock production.

    Science.gov (United States)

    Renaudeau, D; Collin, A; Yahav, S; de Basilio, V; Gourdine, J L; Collier, R J

    2012-05-01

    Despite many challenges faced by animal producers, including environmental problems, diseases, economic pressure, and feed availability, it is still predicted that animal production in developing countries will continue to sustain the future growth of the world's meat production. In these areas, livestock performance is generally lower than those obtained in Western Europe and North America. Although many factors can be involved, climatic factors are among the first and crucial limiting factors of the development of animal production in warm regions. In addition, global warming will further accentuate heat stress-related problems. The objective of this paper was to review the effective strategies to alleviate heat stress in the context of tropical livestock production systems. These strategies can be classified into three groups: those increasing feed intake or decreasing metabolic heat production, those enhancing heat-loss capacities, and those involving genetic selection for heat tolerance. Under heat stress, improved production should be possible through modifications of diet composition that either promotes a higher intake or compensates the low feed consumption. In addition, altering feeding management such as a change in feeding time and/or frequency, are efficient tools to avoid excessive heat load and improve survival rate, especially in poultry. Methods to enhance heat exchange between the environment and the animal and those changing the environment to prevent or limit heat stress can be used to improve performance under hot climatic conditions. Although differences in thermal tolerance exist between livestock species (ruminants > monogastrics), there are also large differences between breeds of a species and within each breed. Consequently, the opportunity may exist to improve thermal tolerance of the animals using genetic tools. However, further research is required to quantify the genetic antagonism between adaptation and production traits to evaluate

  1. Regular exercise alleviates renovascular hypertension-induced cardiac/endothelial dysfunction and oxidative injury in rats.

    Science.gov (United States)

    Kumral, Z N O; Sener, G; Ozgur, S; Koc, M; Suleymanoglu, S; Hurdag, C; Yegen, B C

    2016-02-01

    The importance of physical activity in the management of renovascular diseases is well-known, but lacks evidence of underlying mechanisms. The purpose of the study was to elucidate the protective/therapeutic effects of regular exercise on experimental renovascular hypertension (RVH)-induced oxidative stress and cardiac dysfunction. Wistar albino rats underwent a RVH surgery (2K1C, Goldblatt). Three weeks later half of the rats started swimming exercise for 9 weeks (n = 15), while the sedentary RVH group (n = 15) had no exercise during that period. Sham-operated control rats (n = 10), had the similar surgical procedures but the left renal artery was left unclipped. Body weights were monitored, and blood pressures were measured weekly using tail-cuff. Echocardiographic evaluation was performed on the 3(rd) week and on the 12(th) week of the experiment before the rats were decapitated. Heart and thoracic aorta were removed and serum was collected, while aortic samples were put in a 10% formaldehyde solution for immunochemistry. Cardiac tissue samples obtained from each animal were used for the determination of tissue myeloperoxidase (MPO) and catalase (CAT) activities, malondialdehyde (MDA), and glutathione (GSH) levels. In the sedentary RVH group, aortic contractile response (contraction/relaxation in isolated organ bath), left ventricular diastolic and systolic dimensions, and immunohistochemical staining of aortic inducible nitric oxide synthase (iNOS) were increased, while ejection fraction and aortic endothelial nitric oxide synthase (eNOS) staining were decreased. RVH in the sedentary rats resulted in increased pro-inflammatory cytokines (TNF-α, IL-2, IL-6), lipid peroxidation (malondialdehyde) and neutrophil infiltration (myeloperoxidase activity) along with reductions in antioxidant glutathione and catalase levels in the cardiac tissue. Exercise after RVH increased the immunhistochemical staining of aortic eNOS, decreased iNOS staining and reversed the

  2. 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. PMID:19832688

  3. Suppression of atherosclerosis by synthetic REV-ERB agonist.

    Science.gov (United States)

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M; Solt, Laura A; Burris, Thomas P

    2015-05-01

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. PMID:25800870

  4. Toll-Like Receptor 9 Agonists for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Davide Melisi

    2014-08-01

    Full Text Available The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

  5. How does agonistic behaviour differ in albino and pigmented fish?

    Science.gov (United States)

    Slavík, Ondřej; Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  6. Overexpression of estrogen receptor beta alleviates the toxic effects of beta-amyloid protein on PC12 cells via non-hormonal ligands

    Institute of Scientific and Technical Information of China (English)

    Hui Wang; Lihui Si; Xiaoxi Li; Weiguo Deng; Haimiao Yang; Yuyan Yang; Yan Fu

    2012-01-01

    After binding to the estrogen receptor, estrogen can alleviate the toxic effects of beta-amyloid protein, and thereby exert a therapeutic effect on Alzheimer's disease patients. Estrogen can increase the incidence of breast carcinoma and endometrial cancer in post-menopausal women, so it is not suitable for clinical treatment of Alzheimer's disease. There is recent evidence that the estrogen receptor can exert its neuroprotective effects without estrogen dependence. Real-time quantitative PCR and flow cytometry results showed that, compared with non-transfected PC12 cells, adenovirus-mediated estrogen receptor β gene-transfected PC12 cells exhibited lower expression of tumor necrosis factor α and interleukin 1β under stimulation with beta-amyloid protein and stronger protection from apoptosis. The Akt-specific inhibitor Abi-2 decreased the anti-inflammatory and anti-apoptotic effects of estrogen receptor β gene-transfection. These findings suggest that overexpression of estrogen receptor β can alleviate the toxic effect of beta-amyloid protein on PC12 cells, without estrogen dependence. The Akt pathway is one of the potential means for the anti-inflammatory and anti-apoptotic effects of the estrogen receptor.

  7. An amino acid residue in the second extracellular loop determines the agonist-dependent tolerance property of the human D3 dopamine receptor.

    Science.gov (United States)

    Gil-Mast, Sara; Kortagere, Sandhya; Kota, Kokila; Kuzhikandathil, Eldo V

    2013-06-19

    The D3 dopamine receptor is a therapeutic target for treating various nervous system disorders such as schizophrenia, Parkinson's disease, depression, and addictive behaviors. The crystal structure of the D3 receptor bound to an antagonist was recently described; however, the structural features that contribute to agonist-induced conformational changes and signaling properties are not well understood. We have previously described the conformation-dependent tolerance and slow response termination (SRT) signaling properties of the D3 receptor and identified the C147 residue in the second intracellular loop (IL2) of the D3 receptor as important for the tolerance property. Interestingly, while IL2 and the C147 residue, in particular, were important for dopamine- and quinpirole-induced tolerance, this residue did not affect the severe tolerance induced by the high affinity, D3 receptor-selective agonist, PD128907. Here, we used D2/D3 receptor chimeras and site-specific D3 receptor mutants to identify another residue, D187, in the second extracellular loop (EC2) of the human D3 receptor that mediates the tolerance property induced by PD128907, quinpirole, pramipexole, and dopamine. Molecular dynamics simulations confirmed the distinct conformation adopted by D3 receptor during tolerance and suggested that in the tolerant D3 receptor the D187 residue in EC2 forms a salt bridge with the H354 residue in EC3. Indeed, site-directed mutation of the H354 residue resulted in loss of PD1287907-induced tolerance. The mapping of specific amino acid residues that contribute to agonist-dependent conformation changes and D3 receptor signaling properties refines the agonist-bound D3 receptor pharmacophore model which will help develop novel D3 receptor agonists. PMID:23477444

  8. A GPBAR1 (TGR5 small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces experimental autoimmune encephalitis (EAE in vivo.

    Directory of Open Access Journals (Sweden)

    Nuruddeen D Lewis

    Full Text Available GPBAR1 is a G protein-coupled receptor that is activated by certain bile acids and plays an important role in the regulation of bile acid synthesis, lipid metabolism, and energy homeostasis. Recent evidence suggests that GPBAR1 may also have important effects in reducing the inflammatory response through its expression on monocytes and macrophages. To further understand the role of GPBAR1 in inflammation, we generated a novel, selective, proprietary GPBAR1 agonist and tested its effectiveness at reducing monocyte and macrophage activation in vitro and in vivo. We have used this agonist, together with previously described agonists to study agonism of GPBAR1, and shown that they can all induce cAMP and reduce TLR activation-induced cytokine production in human monocytes and monocyte-derived macrophages in vitro. Additionally, through the usage of RNA sequencing (RNA-Seq, we identified a select set of genes that are regulated by GPBAR1 agonism during LPS activation. To further define the in vivo role of GPBAR1 in inflammation, we assessed GPBAR1 expression and found high levels on circulating mouse monocytes. Agonism of GPBAR1 reduced LPS-induced cytokine production in mouse monocytes ex vivo and serum cytokine levels in vivo. Agonism of GPBAR1 also had profound effects in the experimental autoimmune encephalomyelitis (EAE mouse model of multiple sclerosis, where monocytes play an important role. Mice treated with the GPBAR1 agonist exhibited a significant reduction in the EAE clinical score which correlated with reduced monocyte and microglial activation and reduced trafficking of monocytes and T cells into the CNS. These data confirm the importance of GPBAR1 in controlling monocyte and macrophage activation in vivo and support the rationale for selective agonists of GPBAR1 in the treatment of inflammatory diseases.

  9. Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype?

    Science.gov (United States)

    Hodge, R J; Nunez, D J

    2016-05-01

    The gastrointestinal tract regulates glucose and energy metabolism, and there is increasing recognition that bile acids function as key signalling molecules in these processes. For example, bile acid changes that occur after bariatric surgery have been implicated in the effects on satiety, lipid and cholesterol regulation, glucose and energy metabolism, and the gut microbiome. In recent years, Takeda-G-protein-receptor-5 (TGR5), a bile acid receptor found in widely dispersed tissues, has been the target of significant drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including type 2 diabetes, obesity, atherosclerosis, fatty liver disease and cancer. Although the benefits of targeting the TGR5 receptor are potentially great, drug development work to date has identified risks that include histopathological changes, tumorigenesis, gender differences, and questions about the translation of animal data to humans. The present article reviews the noteworthy challenges that must be addressed along the path of development of a safe and effective TGR5 agonist therapy. PMID:26818602

  10. Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience.

    Science.gov (United States)

    Pokorny, Thomas; Preller, Katrin H; Kraehenmann, Rainer; Vollenweider, Franz X

    2016-04-01

    The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (pergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases. PMID:26875114

  11. Cannabinoids: novel medicines for the treatment of Huntington's disease.

    Science.gov (United States)

    Sagredo, Onintza; Pazos, M Ruth; Valdeolivas, Sara; Fernandez-Ruiz, Javier

    2012-04-01

    Cannabinoid pharmacology has experienced a notable increase in the last 3 decades which is allowing the development of novel cannabinoid-based medicines for the treatment of different human pathologies, for example, Cesamet® (nabilone) or Marinol® (synthetic Δ9-tetrahydrocannabinol for oral administration) that were approved in 80s for the treatment of nausea and vomiting associated with chemotherapy treatment in cancer patients and in 90s for anorexiacachexia associated with AIDS therapy. Recently, the british company GW Pharmaceuticals plc has developed an oromucosal spray called Sativex®, which is constituted by an equimolecular combination of Δ9-tetrahydrocannabinol- and cannabidiol- enriched botanical extracts. Sativex® has been approved for the treatment of specific symptoms (i.e. spasticity and pain) of multiple sclerosis patients in various countries (i.e. Canada, UK, Spain, New Zealand). However, this cannabis- based medicine has been also proposed to be useful in other neurological disorders given the analgesic, antitumoral, anti-inflammatory, and neuroprotective properties of their components demonstrated in preclinical models. Numerous clinical trials are presently being conducted to confirm this potential in patients. We are particularly interested in the case of Huntington's disease (HD), an autosomal-dominant inherited disorder caused by an excess of CAG repeats in the genomic allele resulting in a polyQ expansion in the encoded protein called huntingtin, and that affects primarily striatal and cortical neurons thus producing motor abnormalities (i.e. chorea) and dementia. Cannabinoids have been studied for alleviation of hyperkinetic symptoms, given their inhibitory effects on movement, and, in particular, as disease-modifying agents due to their anti-inflammatory, neuroprotective and neuroregenerative properties. This potential has been corroborated in different experimental models of HD and using different types of cannabinoid agonists

  12. The GABAA receptor agonist THIP is neuroprotective in organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Kristensen, Bjarne Winther; Noraberg, Jens; Zimmer, Jens

    2003-01-01

    The potential neuroprotective effects of the GABA(A) receptor agonists THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and muscimol, and the selective GluR5 kainate receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid), which activates GABAergic interneu...

  13. Quantitative phosphoproteomics dissection of 7TM receptor signaling using full and biased agonists

    DEFF Research Database (Denmark)

    Christensen, Gitte Lund; Kelstrup, Christian; Lyngsø, Christina;

    2010-01-01

    performed a global quantitative phosphoproteomics analysis of the AT1R signaling network. We analyzed ligand-stimulated SILAC cells by high-resolution mass spectrometry (LTQ Orbitrap MS) and compared the phosphoproteomes of the AT1R agonist Angiotensin II and the biased agonist SII Angiotensin II, which...

  14. The interplay between agonistic character displacement and reproductive interference in rubyspot damselflies (Hetaerina spp.)

    OpenAIRE

    Drury, Jonathan

    2014-01-01

    Aggressive interactions between species are common despite being relatively understudied. Agonistic character displacement (ACD) theory makes predictions about how selection should act on traits that mediate the occurrence of interspecific aggressive interactions. Previous research on rubyspot damseflies (Hetaerina spp.) documented several cases of divergent agonistic character displacement acting on wing coloration and competitor recognition to diminish wasteful interspecific aggression. How...

  15. Concerns with beta2-agonists in pediatric asthma - a clinical perspective

    NARCIS (Netherlands)

    Kersten, Elin T G; Koppelman, Gerard H; Thio, Bernard J

    2016-01-01

    Beta2-adrenoreceptor agonists (β2-agonists) are extensively used in the treatment of childhood asthma. However, there have been concerns regarding their adverse effects and safety. In 2005, the FDA commissioned a "Black Box Warning" communicating the potential for an increased risk for serious asthm

  16. Computer-aided de novo ligand design and docking/molecular dynamics study of vitamin D receptor agonists.

    Science.gov (United States)

    Shen, Xiu-Long; Takimoto-Kamimura, Midori; Wei, Jing; Gao, Qing-Zhi

    2012-01-01

    1α,25(OH)(2)D(3), which is directly mediated by the vitamin D receptor (VDR), exerts a wide variety of biological actions. However, the treatment with 1α,25(OH)(2)D(3) is limited because of its side effects. Many analogs and several nonsteroidal mimics with potent biological activity have been reported so far, and our rationale for designing the VDR agonists was on the basis of computer-aided drug design method by de novo design of A-ring and C/D-ring position of 1α,25(OH)(2)D(3). Pyrimidine-2,4-diamine was selected as A-ring, and naphthalene and benzene were chosen as C/D-ring. By linking different components, a virtue compound library was obtained. To evaluate the contribution to activity of each component, we performed a series of automated molecular docking operations. Results revealed that the 19-dimethyl derivatives (the C-19 position correspond to C-20 in 1α,25(OH)(2)D(3)) show the favorable docking affinity to VDR. Moreover, the docking results are quite robust when further validated by molecular dynamics simulations. In addition, by free energy analysis using molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method, the driving force of the binding between VDR and the ligands is proved to be hydrophobic interactions. Thus, a possible strategy to design new series of VDR agonists is proposed. The strategy can be successfully applied to explain the high potential activities of the 19-dimethyl derivatives. It is anticipated that the findings reported here may provide useful information for designing effective VDR agonists as well as the therapeutic treatment of VDR-related diseases. PMID:21523537

  17. Long-acting beta(2)-agonists in management of childhood asthma

    DEFF Research Database (Denmark)

    Bisgaard, H

    2000-01-01

    This review assesses the evidence regarding the use of long-acting beta(2)-agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled...... attempted. The onset of action of formoterol is comparable to salbutamol, while salmeterol has a slower onset of action. Partial tolerance develops when long-acting beta(2)-agonists are used as regular treatment, including cross-tolerance to short-acting beta(2)-agonists. Regular treatment with salmeterol...... long-acting beta(2)-agonists, which is reflected by unchanged or increased bronchial hyperreactivity and no reduction of exacerbation rates. The evidence does not support a recommendation for long-acting beta(2)-agonists as monotherapy, nor does it support their general use as regular add-on therapy...

  18. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity.

    Science.gov (United States)

    Crane, James; McGowan, Barbara

    2016-03-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  19. Thrombopoietin-receptor agonists in haematological disorders: The Danish experience

    DEFF Research Database (Denmark)

    Gudbrandsdottir, Sif; Frederiksen, Henrik; Hasselbalch, Hans

    2011-01-01

    received TPO-ra from 2009 to 1 May 2011 were available for data collection and included in the study. Of these patients, 15 received TPO-ra for refractory primary ITP, 7 for secondary ITP (chronic lymphatic leukaemia, systemic lupus erythematosus, Evans syndrome, human immunodeficiency virus and celiac......The objective of this study was to investigate the use of thrombopoietin-receptor agonists (TPO-ra) in patients with refractory primary immune thrombocytopenia (ITP) as well as off-label use of TPO-ra in Danish haematology departments. Hospital medical records from 32 of the 39 patients having...... primary ITP patients, 57% of patients with secondary ITP and 40% of patients with non-ITP. There were four deaths in the cohort, three of which were related to pre-existing medical conditions. Otherwise adverse effects were in general mild. This Danish retrospective registration study has demonstrated...

  20. Extending the structure-activity relationship of anthranilic acid derivatives as farnesoid X receptor modulators: development of a highly potent partial farnesoid X receptor agonist.

    Science.gov (United States)

    Merk, Daniel; Lamers, Christina; Ahmad, Khalil; Carrasco Gomez, Roberto; Schneider, Gisbert; Steinhilber, Dieter; Schubert-Zsilavecz, Manfred

    2014-10-01

    The ligand activated transcription factor nuclear farnesoid X receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the receptor to the full extent which might be disadvantageous over a longer time period. Hence, partial FXR activators are required for long-term treatment of metabolic disorders. We here report the SAR of anthranilic acid derivatives as FXR modulators and development, synthesis, and characterization of compound 51, which is a highly potent partial FXR agonist in a reporter gene assay with an EC50 value of 8 ± 3 nM and on mRNA level in liver cells. PMID:25255039

  1. Treatment with TUG891, a free fatty acid receptor 4 agonist, restores adipose tissue metabolic dysfunction following chronic sleep fragmentation in mice

    DEFF Research Database (Denmark)

    Gozal, D; Qiao, Z; Almendros, I;

    2016-01-01

    BACKGROUND: Sleep fragmentation (SF), a frequent occurrence in multiple sleep and other diseases leads to increased food intake and insulin resistance via increased macrophage activation and inflammation in visceral white adipose tissue (VWAT). Free fatty acid receptor 4 (FFA4) is reduced in pedi...... FFA4 activity may serve as potentially useful adjunctive therapies for sleep disorders accompanied by metabolic morbidity.International Journal of Obesity accepted article preview online, 16 March 2016. doi:10.1038/ijo.2016.37....... in pediatric sleep apnea patients and FFA4 agonists have been proposed in the treatment of obesity and metabolic dysfunction. METHODS: Male mice were subjected to SF exposures for 6 weeks, and treated during the last 2 weeks with either TUG891, a potent and selective FFA4 agonist, or vehicle (Veh). Glucose...

  2. Theory of partial agonist activity of steroid hormones

    Directory of Open Access Journals (Sweden)

    Carson C. Chow

    2015-04-01

    Full Text Available The different amounts of residual partial agonist activity (PAA of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS, which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists.

  3. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Directory of Open Access Journals (Sweden)

    Guido eFrank

    2014-11-01

    Full Text Available Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  4. Could dopamine agonists aid in drug development for anorexia nervosa?

    Science.gov (United States)

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  5. Pathogenesis of Alcoholic Liver Disease.

    Science.gov (United States)

    Dunn, Winston; Shah, Vijay H

    2016-08-01

    Alcoholic liver disease includes a broad clinical-histological spectrum from simple steatosis, cirrhosis, acute alcoholic hepatitis with or without cirrhosis to hepatocellular carcinoma as a complication of cirrhosis. The pathogenesis of alcoholic liver disease can be conceptually divided into (1) ethanol-mediated liver injury, (2) inflammatory immune response to injury, (3) intestinal permeability and microbiome changes. Corticosteroids may improve outcomes, but this is controversial and probably only impacts short-term survival. New pathophysiology-based therapies are under study, including antibiotics, caspase inhibition, interleukin-22, anakinra, FXR agonist and others. These studies provide hope for better future outcomes for this difficult disease. PMID:27373608

  6. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs.

    Science.gov (United States)

    DeVree, Brian T; Mahoney, Jacob P; Vélez-Ruiz, Gisselle A; Rasmussen, Soren G F; Kuszak, Adam J; Edwald, Elin; Fung, Juan-Jose; Manglik, Aashish; Masureel, Matthieu; Du, Yang; Matt, Rachel A; Pardon, Els; Steyaert, Jan; Kobilka, Brian K; Sunahara, Roger K

    2016-07-01

    G-protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other. Upon activation by extracellular agonists, these seven-transmembrane-domain-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades. Crystallographic evidence from a prototypic GPCR, the β2-adrenergic receptor (β2AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide-binding pocket of the G protein α-subunit to catalyse GDP release, the key step required for GTP binding and activation of G proteins. The structure also offers hints about how G-protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G-protein coupling to the β2AR stabilizes a ‘closed’ receptor conformation characterized by restricted access to and egress from the hormone-binding site. Surprisingly, the effects of G protein on the hormone-binding site can be observed in the absence of a bound agonist, where G-protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and inverse agonists. The ability of bound ligands to dissociate from the receptor is also hindered, providing a structural explanation for the G-protein-mediated enhancement of agonist affinity, which has been observed for many GPCR–G-protein pairs. Our data also indicate that, in contrast to agonist binding alone, coupling of a G protein in the absence of an agonist stabilizes large structural changes in a GPCR. The effects of nucleotide-free G protein on ligand-binding kinetics are shared by other members of the superfamily of GPCRs, suggesting that a common mechanism may underlie G-protein-mediated enhancement of agonist affinity. PMID:27362234

  7. Alleviating Poverty

    DEFF Research Database (Denmark)

    Svendsen, Gunnar L.H.; Svendsen, Gert Tinggaard

    2001-01-01

    Why do we find entrepreneurship within larger groups? This question has challenged the social sciences since Olson (1965) showed that it does not pay an individual to provide collective goods voluntarily, if the individual economic gain from doing this is negative. However, the fact that larger g...

  8. Novel controller design demonstration for vibration alleviation of helicopter rotor blades

    Science.gov (United States)

    Ulker, Fatma Demet; Nitzsche, Fred

    2012-04-01

    This paper presents an advanced controller design methodology for vibration alleviation of helicopter rotor sys- tems. Particularly, vibration alleviation in a forward ight regime where the rotor blades experience periodically varying aerodynamic loading was investigated. Controller synthesis was carried out under the time-periodic H2 and H∞ framework and the synthesis problem was solved based on both periodic Riccati and Linear Matrix Inequality (LMI) formulations. The closed-loop stability was analyzed using Floquet-Lyapunov theory, and the controller's performance was validated by closed-loop high-delity aeroelastic simulations. To validate the con- troller's performance an actively controlled trailing edge ap strategy was implemented. Computational cost was compared for both formulations.

  9. Herbaspirillum sp. strain GW103 alleviates salt stress in Brassica rapa L. ssp. pekinensis.

    Science.gov (United States)

    Lee, Gun Woong; Lee, Kui-Jae; Chae, Jong-Chan

    2016-05-01

    Mutual interactions between plant and rhizosphere bacteria facilitate plant growth and reduce risks of biotic and abiotic stresses. The present study demonstrates alleviation of salt stress in Brassica rapa L. ssp. perkinensis (Chinese cabbage) by Herbaspirillum sp. strain GW103 isolated from rhizosphere soil of Phragmites australis. The strain was capable of producing plant beneficial factors, such as auxin, siderophore, and 1-aminocylopropane-1-carboxylic acid deaminase. Treatment of strain GW103 on Chinese cabbage under salt stress increased K(+)/Na(+) ratio in roots generating balance in the ratio of ion homeostasis and consequently contributed to the increase of biomass. In addition, root colonization potential of the strain was observed by green fluorescent protein (GFP)-tagging approach. These results strongly suggest the beneficial impact of strain GW103 by inducing the alleviation of salt stress and development of stress tolerance in Chinese cabbage via plant-microbe interaction. PMID:26358119

  10. Study on vibration alleviating properties of glass fiber reinforced polymer concrete through orthogonal tests

    International Nuclear Information System (INIS)

    Polymer concrete (PC), because of its good vibration alleviating properties, is a proper material for elementary machine parts in high-precision machine tools. Glass fiber was applied in PC to improve its mechanical properties, and the material obtained is called glass fiber reinforced polymer concrete (GFRPC). The best parameter to estimate the vibration alleviating property is damping ratio. Orthogonal tests were carried out to prepare GFRPC specimens with different component proportions. Damping ratio of the GFRPC specimens was measured. The effect of the factors considered in the experiments on damping ratio of GFRPC was studied. Results of the tests show that granite proportion plays the most important role in determining damping ratio of GFRPC, then flexibilizer dosage and glass fiber length, while epoxy resin dosage and glass fiber dosage play a comparatively less important part. Detailed descriptions were made about how the considered factors affect damping ratio of GFRPC in this paper

  11. Study on vibration alleviating properties of glass fiber reinforced polymer concrete through orthogonal tests

    Energy Technology Data Exchange (ETDEWEB)

    Bai Wenfeng [School of Mechanical Engineering, Shandong University, Jinan, Shandong Province 250061 (China)], E-mail: wfbai@yahoo.com.cn; Zhang Jianhua [School of Mechanical Engineering, Shandong University, Jinan, Shandong Province 250061 (China)], E-mail: jhzhang@sdu.edu.cn; Yan Peng [School of Mechanical Engineering, Shandong University, Jinan, Shandong Province 250061 (China); Wang Xinli [Design Department, Shanghai Haima Automobile R and D Co., Ltd., Shanghai 201201 (China)

    2009-04-15

    Polymer concrete (PC), because of its good vibration alleviating properties, is a proper material for elementary machine parts in high-precision machine tools. Glass fiber was applied in PC to improve its mechanical properties, and the material obtained is called glass fiber reinforced polymer concrete (GFRPC). The best parameter to estimate the vibration alleviating property is damping ratio. Orthogonal tests were carried out to prepare GFRPC specimens with different component proportions. Damping ratio of the GFRPC specimens was measured. The effect of the factors considered in the experiments on damping ratio of GFRPC was studied. Results of the tests show that granite proportion plays the most important role in determining damping ratio of GFRPC, then flexibilizer dosage and glass fiber length, while epoxy resin dosage and glass fiber dosage play a comparatively less important part. Detailed descriptions were made about how the considered factors affect damping ratio of GFRPC in this paper.

  12. Extractive sector politics in Latin America and their impact on poverty alleviation

    DEFF Research Database (Denmark)

    Pacheco Cueva, Vladimir

    There is widespread recognition that extractive industries such as mining, oil and gas have the potential to alleviate poverty in rural and remote areas and contribute positively to national development efforts in the global South. The industry record in this regard is, however, uneven and very...... investment regimes. Within this context, only a handful of countries and regions in the global South appear to be managing their non-renewables in ways that would avoid the so called ‘resource curse’ and use it toward national development and poverty alleviation. In Latin America, Mexico, Chile and Peru are...... cases in point. What sets these countries and regions apart from the rest? Similarly, what sets some regions and countries apart when they question the introduction of industrial scale mining in their economic landscape? This paper will firstly review the rise of resource dependence in the global South...

  13. Alleviation Effect of Lanthanum on Cadmium Stress in Seedling Hydroponic Culture of Kidney Bean and Corn

    Institute of Scientific and Technical Information of China (English)

    Huang Xiaohua; Zhou Qing

    2006-01-01

    The seedling hydroponic culture experiment of kidney bean (Phaseolus vulgaris) and corn (Zea mays) was conducted to investigate the alleviation effect of lanthanum on Cd stress.It is found that growth is seriously inhibited and metabolism is maladjusted in the two crops under 30 and 300 μmol·L-1 Cd2+ stress.Plant height, taproot length, leaf area, and fresh or dry weight of root, stem, and leaf are all obviously decreased.Further, chlorophyll content decreases, membrane permeability, malonydialdehyde (MDA) content, activities of catalase (CAT) and peroxidase (POD) increases under Cd stress, as compared with the control.The damage to these two crops becomes more conspicuous with the prolongation of Cd stress.It is suggested that lanthanum might help kidney bean and corn seedlings alleviate Cd stress by improving the photosynthetic capacity, reducing membrane permeability and MDA content, and maintaining the activities of CAT and POD of these two crops.

  14. Adaptive Trailing Edge Flaps for Active Load Alleviation in a Smart Rotor Configuration

    DEFF Research Database (Denmark)

    Bergami, Leonardo

    The work investigates the development of an active smart rotor concept from an aero-servo-elastic perspective. An active smart rotor is a wind turbine rotor that, through a combination of sensors, control units and actuators, is able to alleviate the fluctuating part of the aerodynamic loads it has...... to withstand. The investigation focuses on a specific actuator type: the Adaptive Trailing Edge Flap (ATEF), which introduces a continuous deformation of the aft part of the airfoil camber-line. An aerodynamic model that accounts for the steady and unsteady effects of the flap deflection on a 2D...... energy capture below rated conditions by using the flaps. Two model based control algorithms are developed to actively alleviate the fatigue loads on the smart rotor with ATEF. The first algorithm features a linear quadratic regulator with periodic disturbance rejection, and controls the deflection of...

  15. Protected areas alleviate climate change effects on northern bird species of conservation concern

    OpenAIRE

    Virkkala, Raimo; Pöyry, Juha; Heikkinen, Risto K.; Lehikoinen, Aleksi; Valkama, Jari

    2014-01-01

    Global climate change is a major threat to biodiversity, posing increasing pressures on species to adapt in situ or shift their ranges. A protected area network is one of the main instruments to alleviate the negative impacts of climate change. Importantly, protected area networks might be expected to enhance the resilience of regional populations of species of conservation concern, resulting in slower species loss in landscapes with a significant amount of protected habitat compared to unpro...

  16. Poverty Alleviation through Optimizing the Marketing of Garcinia kola and Irvingia gabonensis in Ondo State, Nigeria

    OpenAIRE

    Agbelade, A. D.; Onyekwelu, J. C.

    2013-01-01

    The paper examines poverty alleviation through optimizing the marketing of Garcinia kola and Irvingia gabonensis in Ondo State, Nigeria. Data for this study were collected using structured questionnaire. Two categories of pretested structured questionnaires were used to obtain information from the respondents (farmers and the marketers of the species). Data analysis was done using descriptive analysis, and Student t-test was used to compare the income generated by the producers and the market...

  17. The role of tourism in poverty alleviation at Sedibeng District Municipality / Fusi Amelia Msibi.

    OpenAIRE

    Msibi, Fusi Amelia

    2010-01-01

    Local Authorities have a duty to promote the economic, social and environmental wellbeing of their communities. The study deals with the promotion of community involvement and other stakeholders by municipality in ensuring the tourism sustainability. The objectives of this research are to explain the theoretical analysis of the concepts: tourism and poverty alleviation; mechanisms and procedures to be used to encourage community participation in making tourism economically viable around Sedib...

  18. Contribution Of Human Development Index On Per Capita Income Growth And Poverty Alleviation In Indonesia

    OpenAIRE

    Sudarlan

    2015-01-01

    Abstract The development of a country usually determined by the human development index HDI. Per capita income education and health are the three most important components of human development index. The purpose of this research is to understand the relationship among human development index to income per capita growth and poverty alleviation in Indonesia with cross-section data from 30 provinces period 2002 2011 year. The result of this research were a income per capita growth was not sign...

  19. Impact of micro-credit programmes on poverty alleviation in Bangladesh

    OpenAIRE

    Khatun, Mst Asma; Islam, Mohammad Amirul; Majumder, Shankar

    2012-01-01

    This present study examines the impact of micro-credit programmes of six government organisations (GO), non-government organisations (NGO) and micro-finance institutes (MFI) on poverty alleviation in Bangladesh using a purposive sample of 406 credit receivers. Alongside respondent’s perceived change in poverty situation this study devised an alternative measure of poverty change based on the change in household wealth and education of a household. Two-level binary logistic regression and mult...

  20. Role of Islamic Microfinance in Poverty Alleviation in Pakistan: An Empirical Approach

    OpenAIRE

    Muhammad Naveed Aslam

    2014-01-01

    After 2008 world economic crises, banks and other financial institutes move towards Islamic financing not only in Muslims countries but also in non-Muslim countries of the world. In view of this, some micro financial institutions also introduce Islamic micro financing products in Pakistan. The present study was conducted to analyze the role of Islamic microfinance to alleviate poverty in Pakistan its impacts, people satisfaction level and assess the future of it in Pakistan. An Empirical appr...

  1. HEALTHY AGRICULTURE (Agricultura saludable®) Agricultural conversion to alleviate hunger and poverty

    OpenAIRE

    Sánchez, Myriam

    2010-01-01

    Healthy agriculture: Agricultural conversion to alleviate hunger and poverty, is a concept, a Program and a brand, that Corporación Biotec and a group of institutions, companies and associations of producers are developing in Colombia, promoting a new culture of social, environmental and market competitiveness, in the production of food, mainly tropical fruits productive chains. Some world wide challenges, ask for biomass as raw material for different sectors: food security, energy supply and...

  2. Poverty Alleviation through Pro-Poor Tourism: The Role of Botswana Forest Reserves

    OpenAIRE

    Haretsebe Manwa; Farai Manwa

    2014-01-01

    Both government and international donor agencies now promote the use of tourism to alleviate poverty. The Botswana government has embraced tourism as a meaningful and sustainable economic activity and diversification opportunity, which now ranks second after mining in its contribution to the country’s gross domestic product. The study reported in this paper investigates perceptions of stakeholders on the opportunities that would be created for the poor by opening up Botswana’s forest rese...

  3. Alleviation of rural poverty in Malaysia: the role of Zakat, a case study

    OpenAIRE

    Mahamod, Lukman Hakim

    2011-01-01

    This study focuses on the factors contributing to the lack of emphasis by the Kedah Department of Zakat (KDoZ), Malaysia on the alleviation of poverty among the rural poor through zakat capital assistance programmes and employment opportunities. In this study, seven research questions were outlined. A mixed-methods study was developed to answer research questions 1, 2, 3 and 4. Research questions 5, 6 and 7 were answered using qualitative data. Quantitative data was collected f...

  4. Development of township enterprise and alleviation of the employment problem in rural China

    OpenAIRE

    Zhou, Zhang Y.; John L Dillon; Wan, Guang H.

    1992-01-01

    In contrast to the situation in western countries at the time of their industrialization, it has been and still is impossible for rural labour in China to move to the urban sector for employment. For this and other reasons, including shortage of arable land and population growth, lack of employment opportunities continues to be a serious problem in rural China. This article discusses the development of township enterprise in rural areas and its role in the alleviation of China's rural employm...

  5. Increasing the contribution of small-scale fisheries to poverty alleviation and food security

    OpenAIRE

    Bolan, Tom

    2005-01-01

    The objectives of these Technical Guidelines are to provide a focus on small-scale fisheries and their current and potential role in contributing to poverty alleviation and food security by expanding on the guidance on small-scale fisheries offered by the Code. The Guidelines are complementary to existing Technical Guidelines for Responsible Fisheries. Most small-scale fishers are in developing countries and many live in communities characterized by poverty and food insecurity. Small-scale f...

  6. COMPARATIVE STUDY OF ONDANSETRON WITH LIGNOCAINE TO ALLEVIATE PAIN DURING INJECTION OF PROPOFOL

    OpenAIRE

    Prashant J .; Sonal A; Abhimanyu S; Ganesh K

    2014-01-01

    Propofol is commonly used newer induction agent of choice with smooth and rapid recovery from anaesthesia. It has one adverse effect which is restricting its use i.e. pain during injection. We in present study are comparing Ondansetron with Lignocaine to alleviate pain during injection of Propofol, as ondansetron is routinely used to prevent post-operative nausea and vomiting, so it can have both effects viz prevention of pain on injection of Propofol and prevention of pos...

  7. Solar Energy Utilization As A Tool For Poverty Alleviation In Nigeria

    International Nuclear Information System (INIS)

    The depletable nature of conventional sources of energy (fossil fuel) and their affects on the environment are highlighted in this paper. The prospects and limitations of solar energy as an alternative source of energy to fossil fuels are also presented. The applications of solar energy and their effect in poverty alleviation are discussed. We conclude that investments in solar energy development be stepped up to save our depletable energy resources as well as preserve our environment

  8. Alleviating aluminium toxicity on an acid sulphate soils in Peninsular Malaysia with application of calcium silicate

    OpenAIRE

    A. A. Elisa; Ninomiya, S.; J. Shamshuddin; Roslan, I.

    2015-01-01

    A study was conducted to alleviate Al toxicity of an acid sulphate soils collected from paddy cultivation area in Kedah, Peninsular Malaysia. For this purpose, the collected acid sulphate soils were treated with calcium silicate. The treated soils were incubated for 120 days in submerged condition in a glasshouse. Subsamples were collected every 30 days throughout the incubation period. Soil pH and exchangeable Al showed positive effect; soil pH increased from ...

  9. AVRDC- The World Vegetables Center: Role of horticulture in poverty alleviation

    OpenAIRE

    Mubarik, A.

    2006-01-01

    This presentation highlights the work of AVRDC- The World Vegetable Center, whose mission is to alleviate poverty and malnutrition in the developing world through increased production, marketing and consumption of safe vegetables. The presentation outlines the issue of poverty and nutrient deficiency in the world, and the economic and health benefits to producing vegetables in developing countries. It outlines the research currently being conducted at global stations, as well as achievements ...

  10. Ginsenoside Rh2 alleviates tumor-associated depression in a mouse model of colorectal carcinoma

    OpenAIRE

    Wang, Jia; Chen, Yueming; Dai, Chunxiao; Shang, Yushan; Xie, Jian

    2016-01-01

    Previous studies reported remarkable high incidence of depression in cancer patients compared with the general population. Colorectal carcinoma (CRC) is one of the most frequent malignancies worldwide and has been found to be one of the malignancies with the highest incidence of patient depression. Thus, strategies that may alleviate CRC-associated depression may significantly improve the patients’ life quality and outcome of the therapy. Ginsenoside Rh2 (GRh2) has been reported to have thera...

  11. HEAT STRESS IN POULTRY. II. METHODS AND TECHNIQUES FOR PREVENTION AND ALLEVIATION (review)

    OpenAIRE

    V.I. FISININ; A.Sh. KAVTARASHVILI

    2015-01-01

    An adverse effect of heat stress in poultry depends on both the external factors such as diet, water supply, rearing technology, birds’ population density, air humidity and flow rate, etc., and the internal factors, particularly, poultry species and breed specificity, physiological conditions, etc. Herein, the approaches to prevention and alleviation of heat stress in poultry are summarized and discussed. Different strategies were proposed for lowering of body heat production and for better h...

  12. Poverty Alleviation and Social Safety Net Schemes for Economies in Transition

    OpenAIRE

    Gillian Paull

    1991-01-01

    Inspired by the current Polish economic restructuring program, this paper attempts to develop a general income support scheme that could serve as a model to alleviate poverty in developed economies in the transitional phase. The proposed scheme has the advantage that no part of the poor population is omitted from eligibility for support sufficient to remove them from poverty. The concept of the simplified model is protection against poverty through income maintenance that is conditional upon ...

  13. Distinct physiological responses of tomato and cucumber plants in silicon-mediated alleviation of cadmium stress

    OpenAIRE

    Wu, Jiawen; Guo, Jia; Hu, Yanhong; Gong, Haijun

    2015-01-01

    The alleviative effects of silicon (Si) on cadmium (Cd) toxicity were investigated in cucumber (Cucumis sativus L.) and tomato (Solanum lycopersicum L.) grown hydroponically. The growth of both plant species was inhibited by 100 μM Cd, but Si application counteracted the adverse effects on growth. Si application significantly decreased the Cd concentrations in shoots of both species and roots of cucumber. The root-to-shoot transport of Cd was depressed by added Si in tomato whereas it was inc...

  14. Oral Methylphenidate Alleviates the Fine Motor Dysfunction Caused by Chronic Postnatal Manganese Exposure in Adult Rats

    OpenAIRE

    Beaudin, Stéphane A.; Strupp, Barbara J.; Lasley, Stephen M.; Fornal, Casimir A.; Mandal, Shyamali; Smith, Donald R

    2015-01-01

    Developmental manganese (Mn) exposure is associated with motor dysfunction in children and animal models, but little is known about the underlying neurochemical mechanisms or the potential for amelioration by pharmacotherapy. We investigated whether methylphenidate (MPH) alleviates fine motor dysfunction due to chronic postnatal Mn exposure, and whether Mn exposure impairs brain extracellular dopamine (DA) and norepinephrine (NE) in the prefrontal cortex (PFC) and striatum in adult animals. R...

  15. Mobilizing Informal Workers for Urban Resilience: Linking Poverty Alleviation and Disaster Preparedness

    OpenAIRE

    Cleveland, Bradley

    2013-01-01

    Cooperatives and associations of informal sector workers could become key players in global efforts to alleviate extreme poverty and enhance disaster resilience in urban slums and informal settlements. By engaging these worker-led organizations in community-based efforts to reduce disaster risk, the urban poor who live in informal settlements and work informal jobs can exert their collective power to overcome their social and economic marginalization. Such a strategy can build safer communiti...

  16. Optimal Participation Income and Negative Income Tax in Poverty Alleviation Programs.

    OpenAIRE

    D. Lanzi; F. Delbono

    2002-01-01

    We compare two different redistributive policies specifically designed to alleviate poverty. The first one is inspired to the idea of participation income, the second focused on the introduction of a negative income tax. Briefly characterizing an economy with workers and non-workers and using income as evaluation space for poverty, we determine optimality conditions of both measures under a flat rate labor income tax. Finally, we emphasize a necessary condition for these measures to mitigate ...

  17. Energy poverty alleviation and climate change mitigation: Is there a trade off?

    OpenAIRE

    Chakravarty, Shoibal; Tavoni, Massimo

    2013-01-01

    Energy poverty alleviation has become an important political issue in the most recent years. Several initiatives and policies have been proposed to deal with poor access to modern sources of energy in many developing countries. Given the large number of people lacking basic energy services, an important question is whether providing universal access to modern energy could significantly increase CO2 emissions. This paper provides one of the few formal assessments of this problem by means of a ...

  18. Poverty alleviation programs, FDI-led growth and child labour under agricultural dualism

    OpenAIRE

    Dwibedi, Jayanta; Chaudhuri, Sarbajit

    2011-01-01

    The paper is aimed at providing a theoretical explanation why policies that affect only the supply side of the child labour problem may not be able to mitigate the incidence of child labour in a developing economy in terms of a three-sector general equilibrium model with agricultural dualism and child labour. Although a poverty alleviation program like subsidization of backward agriculture exerts a downward pressure on the child labour incidence through the supply side by raising adult wage i...

  19. Diets enriched in trans-11 vaccenic acid alleviate ectopic lipid accumulation in a rat model of NAFLD and metabolic syndrome.

    Science.gov (United States)

    Jacome-Sosa, M Miriam; Borthwick, Faye; Mangat, Rabban; Uwiera, Richard; Reaney, Martin J; Shen, Jianheng; Quiroga, Ariel D; Jacobs, René L; Lehner, Richard; Proctor, Spencer D; Nelson, Randal C

    2014-07-01

    Trans11-18:1 (vaccenic acid, VA) is one of the most predominant naturally occurring trans fats in our food chain and has recently been shown to exert hypolipidemic effects in animal models. In this study, we reveal new mechanism(s) by which VA can alter body fat distribution, energy utilization and dysfunctional lipid metabolism in an animal model of obesity displaying features of the metabolic syndrome (MetS). Obese JCR:LA-cp rats were assigned to a control diet that included dairy-derived fat or the control diet supplemented with 1% VA. VA reduced total body fat (-6%), stimulated adipose tissue redistribution [reduced mesenteric fat (-17%) while increasing inguinal fat mass (29%)] and decreased adipocyte size (-44%) versus control rats. VA supplementation also increased metabolic rate (7%) concomitantly with an increased preference for whole-body glucose utilization for oxidation and increased insulin sensitivity [lower HOMA-IR (-59%)]. Further, VA decreased nonalcoholic fatty liver disease activity scores (-34%) and reduced hepatic (-27%) and intestinal (-39%) triglyceride secretion relative to control diet, while exerting differential transcriptional regulation of SREBP1 and FAS amongst other key genes in the liver and the intestine. Adding VA to dairy fat alleviates features of MetS potentially by remodeling adipose tissue and attenuating ectopic lipid accumulation in a rat model of obesity and MetS. Increasing VA content in the diet (naturally or by fortification) may be a useful approach to maximize the health value of dairy-derived fats. PMID:24775093

  20. Methotrexate Promotes Platelet Apoptosis via JNK-Mediated Mitochondrial Damage: Alleviation by N-Acetylcysteine and N-Acetylcysteine Amide.

    Directory of Open Access Journals (Sweden)

    Manoj Paul

    Full Text Available Thrombocytopenia in methotrexate (MTX-treated cancer and rheumatoid arthritis (RA patients connotes the interference of MTX with platelets. Hence, it seemed appealing to appraise the effect of MTX on platelets. Thereby, the mechanism of action of MTX on platelets was dissected. MTX (10 μM induced activation of pro-apoptotic proteins Bid, Bax and Bad through JNK phosphorylation leading to ΔΨm dissipation, cytochrome c release and caspase activation, culminating in apoptosis. The use of specific inhibitor for JNK abrogates the MTX-induced activation of pro-apoptotic proteins and downstream events confirming JNK phosphorylation by MTX as a key event. We also demonstrate that platelet mitochondria as prime sources of ROS which plays a central role in MTX-induced apoptosis. Further, MTX induces oxidative stress by altering the levels of ROS and glutathione cycle. In parallel, the clinically approved thiol antioxidant N-acetylcysteine (NAC and its derivative N-acetylcysteine amide (NACA proficiently alleviate MTX-induced platelet apoptosis and oxidative damage. These findings underpin the dearth of research on interference of therapeutic drugs with platelets, despite their importance in human health and disease. Therefore, the use of antioxidants as supplementary therapy seems to be a safe bet in pathologies associated with altered platelet functions.