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Sample records for agonist improves cellular

  1. A new adenovirus based vaccine vector expressing an Eimeria tenella derived TLR agonist improves cellular immune responses to an antigenic target.

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    Daniel M Appledorn

    Full Text Available BACKGROUND: Adenoviral based vectors remain promising vaccine platforms for use against numerous pathogens, including HIV. Recent vaccine trials utilizing Adenovirus based vaccines expressing HIV antigens confirmed induction of cellular immune responses, but these responses failed to prevent HIV infections in vaccinees. This illustrates the need to develop vaccine formulations capable of generating more potent T-cell responses to HIV antigens, such as HIV-Gag, since robust immune responses to this antigen correlate with improved outcomes in long-term non-progressor HIV infected individuals. METHODOLOGY/PRINCIPAL FINDINGS: In this study we designed a novel vaccine strategy utilizing an Ad-based vector expressing a potent TLR agonist derived from Eimeria tenella as an adjuvant to improve immune responses from a [E1-]Ad-based HIV-Gag vaccine. Our results confirm that expression of rEA elicits significantly increased TLR mediated innate immune responses as measured by the influx of plasma cytokines and chemokines, and activation of innate immune responding cells. Furthermore, our data show that the quantity and quality of HIV-Gag specific CD8(+ and CD8(- T-cell responses were significantly improved when coupled with rEA expression. These responses also correlated with a significantly increased number of HIV-Gag derived epitopes being recognized by host T cells. Finally, functional assays confirmed that rEA expression significantly improved antigen specific CTL responses, in vivo. Moreover, we show that these improved responses were dependent upon improved TLR pathway interactions. CONCLUSION/SIGNIFICANCE: The data presented in this study illustrate the potential utility of Ad-based vectors expressing TLR agonists to improve clinical outcomes dependent upon induction of robust, antigen specific immune responses.

  2. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

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    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.

  3. Stimulation of α1a adrenergic receptors induces cellular proliferation or antiproliferative hypertrophy dependent solely on agonist concentration.

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    Beilei Lei

    Full Text Available Stimulation of α1aAdrenergic Receptors (ARs is known to have anti-proliferative and hypertrophic effects; however, some studies also suggests this receptor can increase cell proliferation. Surprisingly, we find the α1aAR expressed in rat-1 fibroblasts can produce either phenotype, depending exclusively on agonist concentration. Stimulation of the α1aAR by high dose phenylephrine (>10(-7 M induces an antiproliferative, hypertrophic response accompanied by robust and extended p38 activation. Inhibition of p38 with SB203580 prevented the antiproliferative response, while inhibition of Erk or Jnk had no effect. In stark contrast, stimulation of the α1aAR with low dose phenylephrine (∼10(-8 M induced an Erk-dependent increase in cellular proliferation. Agonist-induced Erk phosphorylation was preceded by rapid FGFR and EGFR transactivation; however, only EGFR inhibition blocked Erk activation and proliferation. The general matrix metalloprotease inhibitor, GM6001, blocked agonist induced Erk activation within seconds, strongly suggesting EGFR activation involved extracellular triple membrane pass signaling. Erk activation required little Ca(2+ release and was blocked by PLCβ or PKC inhibition but not by intracellular Ca(2+ chelation, suggesting Ca(2+ independent activation of novel PKC isoforms. In contrast, Ca(2+ release was essential for PI3K/Akt activation, which was acutely maximal at non-proliferative doses of agonist. Remarkably, our data suggests EGFR transactivation leading to Erk induced proliferation has the lowest activation threshold of any α1aAR response. The ability of α1aARs to induce proliferation are discussed in light of evidence suggesting antagonistic growth responses reflect native α1aAR function.

  4. The impact of improved glycaemic control with GLP-1 receptor agonist therapy on diabetic retinopathy.

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    Varadhan, Lakshminarayanan; Humphreys, Tracy; Walker, Adrian B; Varughese, George I

    2014-03-01

    Rapid improvement in glycaemic control with GLP-1 receptor agonist (RA) therapy has been reported to be associated with significant progression of diabetic retinopathy. This deterioration is transient, and continuing GLP-1 RA treatment is associated with reversal of this phenomenon. Pre-existent maculopathy, higher grade of retinopathy and longer duration of diabetes may be risk factors for persistent deterioration.

  5. Chronic β2 adrenergic agonist, but not exercise, improves glucose handling in older type 2 diabetic mice.

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    Elayan, Hamzeh; Milic, Milos; Sun, Ping; Gharaibeh, Munir; Ziegler, Michael G

    2012-07-01

    Insulin resistant type 2 diabetes mellitus in the obese elderly has become a worldwide epidemic. While exercise can prevent the onset of diabetes in young subjects its role in older diabetic people is less clear. Exercise stimulates the release of the β(2)-agonist epinephrine more in the young. Although epinephrine and β(2)-agonist drugs cause acute insulin resistance, their chronic effect on insulin sensitivity is unclear. We fed C57BL/6 mice a high fat diet to induce diabetes. These overweight animals became very insulin resistant. Exhaustive treadmill exercise 5 days a week for 8 weeks had no effect on their diabetes, nor did the β(2)-blocking drug ICI 118551. In contrast, exercise combined with the β(2)-agonist salbutamol (albuterol) had a beneficial effect on both glucose tolerance and insulin sensitivity after 4 and 8 weeks of exercise. The effect was durable and persisted 5 weeks after exercise and β(2)-agonist had stopped. To test whether β(2)-agonist alone was effective, the animals that had received β(2)-blockade were then given β(2)-agonist. Their response to a glucose challenge improved but their response to insulin was not significantly altered. The β(2)-agonists are commonly used to treat asthma and asthmatics have an increased incidence of obesity and type 2 diabetes. Although β(2)-agonists cause acute hyperglycemia, chronic treatment improves insulin sensitivity, probably by improving muscle glucose uptake.

  6. Temporal modulations of agonist and antagonist muscle activities accompanying improved performance of ballistic movements.

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    Liang, Nan; Yamashita, Takamasa; Ni, Zhen; Takahashi, Makoto; Murakami, Tsuneji; Yahagi, Susumu; Kasai, Tatsuya

    2008-02-01

    Although many studies have examined performance improvements of ballistic movement through practice, it is still unclear how performance advances while maintaining maximum velocity, and how the accompanying triphasic electromyographic (EMG) activity is modified. The present study focused on the changes in triphasic EMG activity, i.e., the first agonist burst (AG1), the second agonist burst (AG2), and the antagonist burst (ANT), that accompanied decreases in movement time and error. Twelve healthy volunteers performed 100 ballistic wrist flexion movements in ten 10-trial sessions under the instruction to "maintain maximum velocity throughout the experiment and to stop the limb at the target as fast and accurately as possible". Kinematic parameters (position and velocity) and triphasic EMG activities from the agonist (flexor carpi radialis) and antagonist (extensor carpi radialis) muscles were recorded. Comparison of the results obtained from the first and the last 10 trials, revealed that movement time, movement error, and variability of amplitudes reduced with practice, and that maximum velocity and time to maximum velocity remained constant. EMG activities showed that AG1 and AG2 durations were reduced, whereas ANT duration did not change. Additionally, ANT and AG2 latencies were reduced. Integrated EMG of AG1 was significantly reduced as well. Analysis of the alpha angle (an index of the rate of recruitment of the motoneurons) showed that there was no change in either AG1 or AG2. Correlation analysis of alpha angles between these two bursts further revealed that the close relationship of AG1 and AG2 was kept constant through practice. These findings led to the conclusion that performance improvement in ballistic movement is mainly due to the temporal modulations of agonist and antagonist muscle activities when maximum velocity is kept constant. Presumably, a specific strategy is consistently applied during practice.

  7. Improved method to label beta-2 agonists in metered-dose inhalers with technetium-99m

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    Ballinger, J.R.; Calcutt, L.E.; Hodder, R.V.; Proulx, A.; Gulenchyn, K.Y. (Ottawa Civic Hospital, Ottawa (Canada). Div. of Nuclear Medicine and Respiratory Unit)

    1993-01-01

    Labelling beta-2 agonists in a metered-dose inhaler (MDI) with technetium-99m allows imaging of the deposition of the aerosol in the respiratory tract. We have developed an improved labeling method in which anhydrous pertechnetate is dissolved in a small volume of ethanol, diluted with a fluorocarbon, and introduced into a commercial MDI. Imaging the MDI demonstrated that the [sup 99m]Tc was associated with the active ingredient, not just the propellant. The method has been used successfully with salbutamol and fenoterol MDIs and should be directly applicable to other MDIs which contain hydrophilic drugs. (Author).

  8. Resveratrol Attenuates Copper-Induced Senescence by Improving Cellular Proteostasis

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    2017-01-01

    Copper sulfate-induced premature senescence (CuSO4-SIPS) consistently mimetized molecular mechanisms of replicative senescence, particularly at the endoplasmic reticulum proteostasis level. In fact, disruption of protein homeostasis has been associated to age-related cell/tissue dysfunction and human disorders susceptibility. Resveratrol is a polyphenolic compound with proved antiaging properties under particular conditions. In this setting, we aimed to evaluate resveratrol ability to attenuate cellular senescence induction and to unravel related molecular mechanisms. Using CuSO4-SIPS WI-38 fibroblasts, resveratrol is shown to attenuate typical senescence alterations on cell morphology, senescence-associated beta-galactosidase activity, and cell proliferation. The mechanisms implicated in this antisenescence effect seem to be independent of senescence-associated genes and proteins regulation but are reliant on cellular proteostasis improvement. In fact, resveratrol supplementation restores copper-induced increased protein content, attenuates BiP level, and reduces carbonylated and polyubiquitinated proteins by autophagy induction. Our data provide compelling evidence for the beneficial effects of resveratrol by mitigating CuSO4-SIPS stressful consequences by the modulation of protein quality control systems. These findings highlight the importance of a balanced cellular proteostasis and add further knowledge on molecular mechanisms mediating resveratrol antisenescence effects. Moreover, they contribute to identifying specific molecular targets whose modulation will prevent age-associated cell dysfunction and improve human healthspan. PMID:28280523

  9. Cellular compatibility of improved scaffold material with deproteinized heterogeneous bone

    Institute of Scientific and Technical Information of China (English)

    LIU Lei; PEI Fu-xing; ZHOU Zong-ke; LI Qi-hong

    2007-01-01

    Objective:To study cellular compatibility of improved scaffold material with deproteinized heterogeneous bone and provide experimental basis on choosing the scaffold material in bone tissue engineering.Methods: Bone marrow stromal cells (BMSC) were co-cultured with heterogeneous deproteinized bone in vitro. The contrast phase microscope, scanning electron microscope, MTT assay, flow cytometry were performed and the BGP content and ALP activities were detected in order to observe the cell growth, adhesion in the material, cell cycle and cell viability.Results: The scaffold material of deproteinized heterogeneous bone had no inhibitory effect on cellular proliferation, differentiation and secretion function of BMSCs.Conclusions: The established heterogeneous deproteinized bone has good biocompatibility with BMSCs and is a potentially ideal scaffold material for bone tissue engineering.

  10. Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia.

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    Wecker, L; Engberg, M E; Philpot, R M; Lambert, C S; Kang, C W; Antilla, J C; Bickford, P C; Hudson, C E; Zesiewicz, T A; Rowell, Peter P

    2013-10-01

    Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.

  11. A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer' disease.

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    He, Pingping; Ouyang, Xinping; Zhou, Shouhong; Yin, Weidong; Tang, Chaoke; Laudon, Moshe; Tian, Shaowen

    2013-06-01

    Previous studies have shown that melatonin is implicated in modulating learning and memory processing. Melatonin also exerts neuroprotective activities against Aβ-induced injury in vitro and in vivo. Neu-P11 (piromelatine, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide) is a novel melatonin (MT1/MT2) receptor agonist and a serotonin 5-HT1A/1D receptor agonist recently developed for the treatment of insomnia. In the present study we firstly investigated whether Neu-P11 and melatonin enhance memory performance in the novel object recognition (NOR) task in rats, and then assessed whether Neu-P11 and melatonin improve neuronal and cognitive impairment in a rat model of Alzheimer' disease (AD) induced by intrahippocampal Aβ(1-42) injection. The results showed that a single morning or afternoon administration of Neu-P11 enhanced object recognition memory measured at 4 or 24h after training. Melatonin was effective in the memory facilitating effects only when administered in the afternoon. Further results showed that intrahippocampal Aβ(1-42) injection resulted in hippocampal cellular loss, as well as decreased learning ability and memory in the Y maze and NOR tasks in rats. Neu-P11 but not melatonin attenuated cellular loss and cognitive impairment in the rat AD model. The current data suggest that Neu-P11 may serve as a novel agent for the treatment of AD.

  12. An Orally Active Allosteric GLP-1 Receptor Agonist Is Neuroprotective in Cellular and Rodent Models of Stroke.

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    Huinan Zhang

    Full Text Available Diabetes is a major risk factor for the development of stroke. Glucagon-like peptide-1 receptor (GLP-1R agonists have been in clinical use for the treatment of diabetes and also been reported to be neuroprotective in ischemic stroke. The quinoxaline 6,7-dichloro-2-methylsulfonyl-3-N-tert- butylaminoquinoxaline (DMB is an agonist and allosteric modulator of the GLP-1R with the potential to increase the affinity of GLP-1 for its receptor. The aim of this study was to evaluate the neuroprotective effects of DMB on transient focal cerebral ischemia. In cultured cortical neurons, DMB activated the GLP-1R, leading to increased intracellular cAMP levels with an EC50 value about 100 fold that of exendin-4. Pretreatment of neurons with DMB protected against necrotic and apoptotic cell death was induced by oxygen-glucose deprivation (OGD. The neuroprotective effects of DMB were blocked by GLP-1R knockdown with shRNA but not by GLP-1R antagonism. In C57BL/6 mice, DMB was orally administered 30 min prior to middle cerebral artery occlusion (MCAO surgery. DMB markedly reduced the cerebral infarct size and neurological deficits caused by MCAO and reperfusion. The neuroprotective effects were mediated by activation of the GLP-1R through the cAMP-PKA-CREB signaling pathway. DMB exhibited anti-apoptotic effects by modulating Bcl-2 family members. These results provide evidence that DMB, a small molecular GLP-1R agonist, attenuates transient focal cerebral ischemia injury and inhibits neuronal apoptosis induced by MCAO. Taken together, these data suggest that DMB is a potential neuroprotective agent against cerebral ischemia.

  13. Tuneable nanoparticle-nanofiber composite substrate for improved cellular adhesion.

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    Nicolini, Ariana M; Toth, Tyler D; Yoon, Jeong-Yeol

    2016-09-01

    This work presents a novel technique using a reverse potential electrospinning mode for fabricating nanoparticle-embedded composites that can be tailored to represent various fiber diameters, surface morphologies, and functional groups necessary for improved cellular adhesion. Polycaprolactone (PCL) nanofibers were electrospun in both traditional positive (PP) and reverse potential (RP) electrical fields. The fibers were incorporated with 300nm polystyrene (PS) fluorescent particles, which contained carboxyl, amine groups, and surfactants. In the unconventional RP, the charged colloidal particles and surfactants were shown to have an exaggerated effect on Taylor cone morphology and fiber diameter caused by the changes in charge density and surface tension of the bulk solution. The RP mode was shown to lead to a decrease in fiber diameter from 1200±100nm (diameter±SE) for the nanofibers made with PCL alone to 440±80nm with the incorporation of colloidal particles, compared to the PP mode ranging from 530±90nm to 350±50nm, respectively. The nanoparticle-nanofiber composite substrates were cultured with human umbilical vein endothelial cells (HUVECs) and evaluated for cellular viability and adhesion for up to 5 days. Adhesion to the nanofibrous substrates was improved by 180±10% with the addition of carboxylated particles and by 480±60% with the functionalization of an RGD ligand compared to the PCL nanofibers. The novel approach of electrospinning in the RP mode with the addition of colloids in order to alter charge density and surface tension could be utilized towards many applications, one being implantable biomaterials and tissue engineered scaffolds as demonstrated in this work.

  14. A synthetic TLR4 agonist formulated in an emulsion enhances humoral and Type 1 cellular immune responses against GMZ2 - A GLURP-MSP3 fusion protein malaria vaccine candidate

    DEFF Research Database (Denmark)

    Lousada-Dietrich, Susana; Jogdand, Prajakta S; Jepsen, Søren;

    2011-01-01

    ) agonists in CB6F1 mice to identify an improved formulation of GMZ2 suitable for further human clinical studies. GMZ2 formulated in an oil-in-water emulsion plus the synthetic TLR4 agonist GLA elicits the highest (a) vaccine-specific IgG2a and total IgG titers, (b) parasite-specific IFA titers, (c) levels...

  15. Improved cellular uptake of functionalized single-walled carbon nanotubes

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    Antonelli, A.; Serafini, S.; Menotta, M.; Sfara, C.; Pierigé, F.; Giorgi, L.; Ambrosi, G.; Rossi, L.; Magnani, M.

    2010-10-01

    Single-walled carbon nanotubes (SWNTs) due to their unique structural and physicochemical properties, have been proposed as delivery systems for a variety of diagnostic and therapeutic agents. However, SWNTs have proven difficult to solubilize in aqueous solution, limiting their use in biological applications. In an attempt to improve SWNTs' solubility, biocompatibility, and to increase cell penetration we have thoroughly investigated the construction of carbon scaffolds coated with aliphatic carbon chains and phospholipids to obtain micelle-like structures. At first, oxidized SWNTs (2370 ± 30 nmol mg - 1 of SWNTs) were covalently coupled with an alcoholic chain (stearyl alcohol, C18H37OH; 816 nmol mg - 1 of SWNTs). Subsequently, SWNTs-COOC18H37 derivatives were coated with phosphatidylethanolamine (PE) or -serine (PS) phospholipids obtaining micelle-like structures. We found that cellular uptake of these constructs by phagocytic cells occurs via an endocytotic mechanism for constructs larger than 400 nm while occurs via diffusion through the cell membrane for constructs up to 400 nm. The material that enters the cell by phagocytosis is actively internalized by macrophages and localizes inside endocytotic vesicles. In contrast the material that enters the cells by diffusion is found in the cell cytosol. In conclusion, we have realized new biomimetic constructs based on alkylated SWNTs coated with phospholipids that are efficiently internalized by different cell types only if their size is lower than 400 nm. These constructs are not toxic to the cells and could now be explored as delivery systems for non-permeant cargoes.

  16. Improved cellular uptake of functionalized single-walled carbon nanotubes

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    Antonelli, A; Serafini, S; Menotta, M; Sfara, C; Pierige, F; Rossi, L; Magnani, M [Department of Biomolecular Sciences, University of Urbino ' Carlo Bo' , Via Saffi 2, 61029 Urbino (Italy); Giorgi, L; Ambrosi, G, E-mail: antonella.antonelli@uniurb.it, E-mail: sonja.serafini@erydel.com, E-mail: michele.menotta@uniurb.it, E-mail: carla.sfara@uniurb.it, E-mail: francesca.pierige@uniurb.it, E-mail: luca.giorgi@uniurb.it, E-mail: gianluca.ambrosi@uniurb.it, E-mail: luigia.rossi@uniurb.it, E-mail: mauro.magnani@uniurb.it [Department of Mathematics, Physics and Informatics, University of Urbino ' Carlo Bo' , Via S Chiara 27, 61029 Urbino (Italy)

    2010-10-22

    Single-walled carbon nanotubes (SWNTs) due to their unique structural and physicochemical properties, have been proposed as delivery systems for a variety of diagnostic and therapeutic agents. However, SWNTs have proven difficult to solubilize in aqueous solution, limiting their use in biological applications. In an attempt to improve SWNTs' solubility, biocompatibility, and to increase cell penetration we have thoroughly investigated the construction of carbon scaffolds coated with aliphatic carbon chains and phospholipids to obtain micelle-like structures. At first, oxidized SWNTs (2370 {+-} 30 nmol mg{sup -1} of SWNTs) were covalently coupled with an alcoholic chain (stearyl alcohol, C{sub 18}H{sub 37}OH; 816 nmol mg{sup -1} of SWNTs). Subsequently, SWNTs-COOC{sub 18}H{sub 37} derivatives were coated with phosphatidylethanolamine (PE) or -serine (PS) phospholipids obtaining micelle-like structures. We found that cellular uptake of these constructs by phagocytic cells occurs via an endocytotic mechanism for constructs larger than 400 nm while occurs via diffusion through the cell membrane for constructs up to 400 nm. The material that enters the cell by phagocytosis is actively internalized by macrophages and localizes inside endocytotic vesicles. In contrast the material that enters the cells by diffusion is found in the cell cytosol. In conclusion, we have realized new biomimetic constructs based on alkylated SWNTs coated with phospholipids that are efficiently internalized by different cell types only if their size is lower than 400 nm. These constructs are not toxic to the cells and could now be explored as delivery systems for non-permeant cargoes.

  17. TLR3 and TLR9 agonists improve postexposure vaccination efficacy of live smallpox vaccines.

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    Israely, Tomer; Melamed, Sharon; Achdout, Hagit; Erez, Noam; Politi, Boaz; Waner, Trevor; Lustig, Shlomo; Paran, Nir

    2014-01-01

    Eradication of smallpox and discontinuation of the vaccination campaign resulted in an increase in the percentage of unvaccinated individuals, highlighting the need for postexposure efficient countermeasures in case of accidental or deliberate viral release. Intranasal infection of mice with ectromelia virus (ECTV), a model for human smallpox, is curable by vaccination with a high vaccine dose given up to 3 days postexposure. To further extend this protective window and to reduce morbidity, mice were vaccinated postexposure with Vaccinia-Lister, the conventional smallpox vaccine or Modified Vaccinia Ankara, a highly attenuated vaccine in conjunction with TLR3 or TLR9 agonists. We show that co-administration of the TLR3 agonist poly(I:C) even 5 days postexposure conferred protection, avoiding the need to increase the vaccination dose. Efficacious treatments prevented death, ameliorated disease symptoms, reduced viral load and maintained tissue integrity of target organs. Protection was associated with significant elevation of serum IFNα and anti-vaccinia IgM antibodies, modulation of IFNγ response, and balanced activation of NK and T cells. TLR9 agonists (CpG ODNs) were less protective than the TLR3 agonist poly(I:C). We show that activation of type 1 IFN by poly(I:C) and protection is achievable even without co-vaccination, requiring sufficient amount of the viral antigens of the infective agent or the vaccine. This study demonstrated the therapeutic potential of postexposure immune modulation by TLR activation, allowing to alleviate the disease symptoms and to further extend the protective window of postexposure vaccination.

  18. TLR3 and TLR9 agonists improve postexposure vaccination efficacy of live smallpox vaccines.

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    Tomer Israely

    Full Text Available Eradication of smallpox and discontinuation of the vaccination campaign resulted in an increase in the percentage of unvaccinated individuals, highlighting the need for postexposure efficient countermeasures in case of accidental or deliberate viral release. Intranasal infection of mice with ectromelia virus (ECTV, a model for human smallpox, is curable by vaccination with a high vaccine dose given up to 3 days postexposure. To further extend this protective window and to reduce morbidity, mice were vaccinated postexposure with Vaccinia-Lister, the conventional smallpox vaccine or Modified Vaccinia Ankara, a highly attenuated vaccine in conjunction with TLR3 or TLR9 agonists. We show that co-administration of the TLR3 agonist poly(I:C even 5 days postexposure conferred protection, avoiding the need to increase the vaccination dose. Efficacious treatments prevented death, ameliorated disease symptoms, reduced viral load and maintained tissue integrity of target organs. Protection was associated with significant elevation of serum IFNα and anti-vaccinia IgM antibodies, modulation of IFNγ response, and balanced activation of NK and T cells. TLR9 agonists (CpG ODNs were less protective than the TLR3 agonist poly(I:C. We show that activation of type 1 IFN by poly(I:C and protection is achievable even without co-vaccination, requiring sufficient amount of the viral antigens of the infective agent or the vaccine. This study demonstrated the therapeutic potential of postexposure immune modulation by TLR activation, allowing to alleviate the disease symptoms and to further extend the protective window of postexposure vaccination.

  19. Combined inhalation of beta2 -agonists improves swim ergometer sprint performance but not high-intensity swim performance.

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    Kalsen, A; Hostrup, M; Bangsbo, J; Backer, V

    2014-10-01

    There is a high prevalence of asthma and airway hyperresponsiveness (AHR) in elite athletes, which leads to a major use of beta2 -agonists. In a randomized double-blinded crossover study, we investigated the effects of combined inhalation of beta2 -agonists (salbutamol, formoterol, and salmeterol), in permitted doses within the World Anti-Doping Agency 2013 prohibited list, in elite swimmers with (AHR, n = 13) or without (non-AHR, n = 17) AHR. Maximal voluntary isometric contraction of m. quadriceps (MVC), sprint performance on a swim ergometer and performance in an exhaustive swim test at 110% of VO2max were determined. Venous plasma interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured post-exercise. No improvement was observed in the exhaustive swim test, but swim ergometer sprint time was improved (P swim performance in elite swimmers. However, swim ergometer sprint performance and MVC were increased, which should be considered when making future anti-doping regulations.

  20. Exenatide (a GLP-1 agonist) improves the antioxidative potential of in vitro cultured human monocytes/macrophages.

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    Bułdak, Łukasz; Łabuzek, Krzysztof; Bułdak, Rafał Jakub; Machnik, Grzegorz; Bołdys, Aleksandra; Okopień, Bogusław

    2015-09-01

    Macrophages are dominant cells in the pathogenesis of atherosclerosis. They are also a major source of reactive oxygen species (ROS). Oxidative stress, which is particularly high in subjects with diabetes, is responsible for accelerated atherosclerosis. Novel antidiabetic drugs (e.g., glucagon-like peptide-1 (GLP-1) agonists) were shown to reduce ROS level. Therefore, we conceived a study to evaluate the influence of exenatide, a GLP-1 agonist, on redox status in human monocytes/macrophages cultured in vitro, which may explain the beneficial effects of incretin-based antidiabetic treatment. Human macrophages obtained from 10 healthy volunteers were in vitro subjected to the treatment with GLP-1 agonist (exenatide) in the presence of lipopolysaccharide (LPS), antagonist of GLP-1 receptors (exendin 9-39), or protein kinase A inhibitor (H89). Afterwards, reactive oxygen species, malondialdehyde level, NADPH oxidase, and antioxidative enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase] expression was evaluated. Finally, we estimated the activity of the abovementioned enzymes in the presence of H89. According to our findings, exenatide reduced ROS and malondialdyhyde (MDA) level by decreasing the expression of ROS-generating NADPH oxidase and by increasing the expression and activities of SOD and GSH-Px. We also showed that this effect was significantly inhibited by exendin 9-39 (a GLP-1 antagonist) and blocked by H89. Exenatide improved the antioxidative potential and reduced oxidative stress in cultured human monocytes/macrophages, and this finding may be responsible for the pleiotropic effects of incretin-based therapies. This effect relied on the stimulation of GLP-1 receptor.

  1. AC-3933, a benzodiazepine partial inverse agonist, improves memory performance in MK-801-induced amnesia mouse model.

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    Hashimoto, Takashi; Iwamura, Yoshihiro

    2016-05-01

    AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N-methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK-801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor.

  2. An Enantiomer of an Oral Small Molecule TSH Receptor Agonist Exhibits Improved Pharmacologic Properties

    Directory of Open Access Journals (Sweden)

    Susanne Neumann

    2016-07-01

    Full Text Available We are developing an orally available small molecule, allosteric TSH receptor (TSHR agonist for follow up diagnostics of patients with thyroid cancer. The agonist C2 (NCGC00161870 that we have studied so far is a racemic mixture containing equal amounts of two enantiomers, E1 and E2. As enantiomers of many drugs exhibit different pharmacologic properties, we assessed the properties of E1 and E2. We separated the two enantiomers by chiral chromatography and determined E2 as the (S-(+ isomer via crystal structure analysis. E1 and E2 were shown to bind differently to a homology model of the transmembrane domain of TSHR in which E2 was calculated to exhibit lower binding energy than E1 and was therefore predicted to be more potent than E1. In HEK293 cells expressing human TSHRs, C2, E1, and E2 were equally efficacious in stimulating cAMP production, but their potencies were different. E2 was more potent (EC50 = 18 nM than C2 (EC50 = 46 nM which was more potent than E1 (EC50 = 217 nM. In primary cultures of human thyrocytes, C2, E1, and E2 stimulated increases in thyroperoxidase mRNA of 92-, 55-, and 137-fold and in sodium-iodide symporter mRNA of 20-fold, 4-fold and 121-fold above basal levels, respectively. In mice, C2 stimulated an increase in radioactive iodine uptake of 1.5-fold and E2 of 2.8-fold above basal level, whereas E1 did not have an effect. C2 stimulated an increase in serum T4 of 2.4-fold, E1 of 1.9-fold, and E2 of 5.6-fold above basal levels, and a 5 day oral dosing regimen of E2 increased serum T4 levels comparable to recombinant human TSH (rhTSH, Thyrogen®. Thus, E2 is more effective than either C2 or E1 in stimulating thyroid function and as efficacious as rhTSH in vivo. E2 represents the next step toward developing an oral drug for patients with thyroid cancer.

  3. A natural history of "agonist".

    Science.gov (United States)

    Russo, Ruth

    2002-01-01

    This paper constructs a brief history of the biochemical term agonist by exploring the multiple meanings of the root agôn in ancient Greek literature and describing how agonist first appeared in the scientific literature of the 20th century in the context of neurophysiologists' debates about the existence and properties of cellular receptors. While the narrow scientific definition of agonist may appear colorless and dead when compared with the web of allusions spun by the ancient Greek agôn, the scientific power and creativity of agonist actually resides precisely in its exact, restricted meaning for biomedical researchers.

  4. Systemic administration of the neurotensin NTS₁-receptor agonist PD149163 improves performance on a memory task in naturally deficient male brown Norway rats.

    Science.gov (United States)

    Keiser, Ashley A; Matazel, Katelin S; Esser, Melissa K; Feifel, David; Prus, Adam J

    2014-12-01

    Agonists for the neurotensin NTS₁ receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS₁-receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS₁ agonists have reported improvements in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, which suggest an ability of NTS₁-receptor agonists to diminish neurocognitive deficits. The present study sought to assess both baseline delay-induced memory performance and the effects of NTS₁-receptor activation on learning and memory consolidation in male Long-Evans and Brown Norway rats using a delayed nonmatch-to-position task radial arm-maze task. In the absence of drugs, Brown Norway rats displayed a significant increase in spatial memory errors following 3-, 7-, and 24-hr delay, whereas Long-Evans rats exhibited an increase in spatial memory errors following only a 7-, and 24-hr delay. With Brown Norway rats, administration of PD149163 before or after an information trial significantly reduced errors during a retention trial after a 24 hr delay. Administration of the NTS(1/2)-receptor antagonist SR142948 prior to the information trial did not affect retention-trial errors. These data are consistent with previous findings that Brown Norway rats have natural cognitive deficits and that they may be useful for assessing putative antipsychotic drugs for cognitive efficacy. Moreover, the results of this study support previous findings suggesting that NTS₁-receptor agonists may improve some aspects of cognitive functioning.

  5. Improved cellular activity of antisense peptide nucleic acids by conjugation to a cationic peptide-lipid (CatLip) domain

    DEFF Research Database (Denmark)

    Koppelhus, Uffe; Shiraishi, Takehiko; Zachar, Vladimir;

    2008-01-01

    Conjugation to cationic cell penetrating peptides (such as Tat, Penetratin, or oligo arginines) efficiently improves the cellular uptake of large hydrophilic molecules such as oligonucleotides and peptide nucleic acids, but the cellular uptake is predominantly via an unproductive endosomal pathwa...

  6. A Novel EPO Receptor Agonist Improves Glucose Tolerance via Glucose Uptake in Skeletal Muscle in a Mouse Model of Diabetes

    Directory of Open Access Journals (Sweden)

    Michael S. Scully

    2011-01-01

    Full Text Available Patients treated with recombinant human Epo demonstrate an improvement in insulin sensitivity. We aimed to investigate whether CNTO 530, a novel Epo receptor agonist, could affect glucose tolerance and insulin sensitivity. A single administration of CNTO 530 significantly and dose-dependently reduced the area under the curve in a glucose tolerance test in diet-induced obese and diabetic mice after 14, 21, and 28 days. HOMA analysis suggested an improvement in insulin sensitivity, and this effect was confirmed by a hyperinsulinemic-euglycemic clamp. Uptake of 14C-2-deoxy-D-glucose indicated that animals dosed with CNTO 530 transported more glucose into skeletal muscle and heart relative to control animals. In conclusion, CNTO530 has a profound effect on glucose tolerance in insulin-resistant rodents likely because of improving peripheral insulin sensitivity. This effect was observed with epoetin-α and darbepoetin-α, suggesting this is a class effect, but the effect with these compounds relative to CNTO530 was decreased in duration and magnitude.

  7. Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles.

    Science.gov (United States)

    Goble, Stephen D; Wang, Liping; Howell, K Lulu; Bansal, Alka; Berger, Richard; Brockunier, Linda; DiSalvo, Jerry; Feighner, Scott; Harper, Bart; He, Jiafang; Hurley, Amanda; Hreniuk, Donna; Parmee, Emma; Robbins, Michael; Salituro, Gino; Sanfiz, Anthony; Streckfuss, Eric; Watkins, Eloisa; Weber, Ann E; Struthers, Mary; Edmondson, Scott D

    2010-03-15

    A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.

  8. New dopamine agonist pramipexole improves parkinsonism and depression in Parkinson's disease.

    Science.gov (United States)

    Harada, Toshihide; Ishizaki, Fumiko; Horie, Nobuko; Nitta, Yumiko; Yamada, Tohru; Sasaki, Tomohiro; Nagakane, Tomoomi; Yasumatsu, Yoshiteru; Nitta, Kohsaku; Katsuoka, Hiroyuki

    2011-12-01

    Previous studies have shown that pramipexole might have the potential to improve depressive symptoms in patients with Parkinson's disease. To provide more evidence, in five Japanese patients at Hoehn & Yahr stage 1-3 we evaluated the Unified Parkinson's Disease Rating Scale (UPDRS), Hamilton Depression Rating Scale (HAMD) and Montgomery Asberg Depression Rating Scale (MADRS) at our hospital. After the pramipexole treatment, each total score of UPDRS, HAMD and MADRS significantly decreased compared with that before the treatment. Our data indicate that pramipexole improves depressive symptoms in patients with Parkinson's disease.

  9. Improvement of metabolic disorders by an EP(2) receptor agonist via restoration of the subcutaneous adipose tissue in pulmonary emphysema.

    Science.gov (United States)

    Tsuji, Takao; Yamaguchi, Kazuhiro; Kikuchi, Ryota; Nakamura, Hiroyuki; Misaka, Ryoichi; Nagai, Atsushi; Aoshiba, Kazutetsu

    2017-03-02

    Chronic obstructive pulmonary disease (COPD) is often associated with co-morbidities. Metabolic disorders like hyperlipidemia and diabetes occur also in underweight COPD patients, although the mechanism is uncertain. Subcutaneous adipose tissue (SAT) plays an important role in energy homeostasis, since restricted capacity to increase fat cell number with increase in fat cell size occurring instead, is associated with lipotoxicity and metabolic disorders. The aim of this study is to show the protective role of SAT for the metabolic disorders in pulmonary emphysema of a murine model. We found ectopic fat accumulation and impaired glucose homeostasis with wasting of SAT in a murine model of elastase-induced pulmonary emphysema (EIE mice) reared on a high-fat diet. ONO-AE1-259, a selective E-prostanoid (EP) 2 receptor agonist, improved angiogenesis and subsequently adipogenesis, and finally improved ectopic fat accumulation and glucose homeostasis with restoration of the capacity for storage of surplus energy in SAT. These results suggest that metabolic disorders like hyperlipidemia and diabetes occured in underweight COPD is partially due to the less capacity for storage of surplus energy in SAT, though the precise mechanism is uncertained. Our data pave the way for the development of therapeutic interventions for metabolic disorders in emphysema patients, e.g., use of pro-angiogenic agents targeting the capacity for storage of surplus energy in the subcutaneous adipose tissue.

  10. Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists.

    Science.gov (United States)

    Nakashima, Ryutaro; Yano, Tatsuya; Ogawa, Junko; Tanaka, Naomi; Toda, Narihiro; Yoshida, Masao; Takano, Rieko; Inoue, Masahiro; Honda, Takeshi; Kume, Shoen; Matsumoto, Koji

    2014-08-15

    G protein-coupled receptor 40 (GPR40) is a Gq-coupled receptor for free fatty acids predominantly expressed in pancreatic β-cells. In recent years, GPR40 agonists have been investigated for use as novel therapeutic agents in the treatment of type 2 diabetes. We discovered a novel small molecule GPR40 agonist, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (DS-1558). The GPR40-mediated effects of DS-1558 on glucose-stimulated insulin secretion were evaluated in isolated islets from GPR40 knock-out and wild-type (littermate) mice. The GPR40-mediated effects on glucose tolerance and insulin secretion were also confirmed by an oral glucose tolerance test in these mice. Furthermore, oral administration of DS-1558 (0.03, 0.1 and 0.3mg/kg) significantly and dose-dependently improved hyperglycemia and increased insulin secretion during the oral glucose tolerance test in Zucker fatty rats, the model of insulin resistance and glucose intolerance. Next, we examined the combination effects of DS-1558 with glucagon like peptide-1 (GLP-1). DS-1558 not only increased the glucose-stimulated insulin secretion by GLP-1 but also potentiated the maximum insulinogenic effects of GLP-1 after an intravenous glucose injection in normal Sprague Dawley rats. Furthermore, the glucose lowering effects of exendin-4, a GLP-1 receptor agonist, were markedly potentiated by the DS-1558 (3mg/kg) add-on in diabetic db/db mice during an intraperitoneal glucose tolerance test. In conclusion, our results indicate that add-on GPR40 agonists to GLP-1 related agents might be a potential treatment compared to single administration of these compounds. Therefore the combinations of these agents are a novel therapeutic option for type 2 diabetes.

  11. Small cationic DDA:TDB liposomes as protein vaccine adjuvants obviate the need for TLR agonists in inducing cellular and humoral responses.

    Science.gov (United States)

    Milicic, Anita; Kaur, Randip; Reyes-Sandoval, Arturo; Tang, Choon-Kit; Honeycutt, Jared; Perrie, Yvonne; Hill, Adrian V S

    2012-01-01

    Most subunit vaccines require adjuvants in order to induce protective immune responses to the targeted pathogen. However, many of the potent immunogenic adjuvants display unacceptable local or systemic reactogenicity. Liposomes are spherical vesicles consisting of single (unilamellar) or multiple (multilamellar) phospholipid bi-layers. The lipid membranes are interleaved with an aqueous buffer, which can be utilised to deliver hydrophilic vaccine components, such as protein antigens or ligands for immune receptors. Liposomes, in particular cationic DDA:TDB vesicles, have been shown in animal models to induce strong humoral responses to the associated antigen without increased reactogenicity, and are currently being tested in Phase I human clinical trials. We explored several modifications of DDA:TDB liposomes--including size, antigen association and addition of TLR agonists--to assess their immunogenic capacity as vaccine adjuvants, using Ovalbumin (OVA) protein as a model protein vaccine. Following triple homologous immunisation, small unilamellar vesicles (SUVs) with no TLR agonists showed a significantly higher capacity for inducing spleen CD8 IFNγ responses against OVA in comparison with the larger multilamellar vesicles (MLVs). Antigen-specific antibody reponses were also higher with SUVs. Addition of the TLR3 and TLR9 agonists significantly increased the adjuvanting capacity of MLVs and OVA-encapsulating dehydration-rehydration vesicles (DRVs), but not of SUVs. Our findings lend further support to the use of liposomes as protein vaccine adjuvants. Importantly, the ability of DDA:TDB SUVs to induce potent CD8 T cell responses without the need for adding immunostimulators would avoid the potential safety risks associated with the clinical use of TLR agonists in vaccines adjuvanted with liposomes.

  12. Cannabinoid 2 Receptor Agonist Improves Systemic Sensitivity to Insulin in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Xiuyuan Zhang

    2016-12-01

    Full Text Available Background/Aims: The endocannabinoid signalling (ECS system has been known to regulate glucose homeostasis. Previous studies have suggested that the cannabinoid 2 (CB2 receptor may play a regulatory role on insulin secretion, immune modulation and insulin resistance. Given that diabetes and insulin resistance are attributable to elevated inflammatory tone, we investigated the role of CB2 receptor on glucose tolerance and insulin sensitivity in high-fat diet (HFD/streptozotocin (STZ-induced mice. Methods: Diabetes was induced in male ICR mice by HFD/STZ and exposed to a CB2 receptor agonist, SER601, for 2- or 4-weeks via subcutaneous implantation of osmotic minipumps. Glucose and insulin tolerance tests were performed at the end of treatment. Islets were isolated for assessment of β-cell function. Pancreases and skeletal muscles were also obtained for histological analyses. Results: Despite a lack of impact on glucose tolerance, substantial improvement on insulin sensitivity was observed in SER601-treated mice, which could partly be attributed to improved islet β-cell function, shown as increased glucose-induced insulin secretion and insulin content. No changes on islet macrophage infiltration or skeletal muscle fat deposition were detectable from SER601-treated mice. However, a major decrease in body weight was recorded at the end of 4-week SER601 exposure, accompanied by a lack of epididymal adipose mass in SER601-treated mice. Conclusion: Our data suggest a lipolytic role of SER601 in HFD/STZ-induced diabetic mice, which results in significant improvement of systemic insulin sensitivity. Thus, the CB2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes.

  13. Small molecule TBTC as a new selective retinoid X receptor α agonist improves behavioral deficit in Alzheimer's disease model mice.

    Science.gov (United States)

    Sun, Yanyan; Fan, Jun; Zhu, Zhiyuan; Guo, Xiaodan; Zhou, Tingting; Duan, Wenhu; Shen, Xu

    2015-09-01

    Alzheimer's disease (AD) is a neurodegenerative disease, which is characterized by progressive cognitive impairments. The β-amyloid (Aβ)-induced neurodegeneration is determined as the main pathogenesis of AD, and either decrease of Aβ production or increase of Aβ clearance is beneficial in the treatment of AD, while Aβ clearance regulation seems to be more attractive as a promising therapeutic strategy against AD based on the fact that the insufficient clearance of Aβ is tightly associated with the late onset of AD that is represented as the majority of AD cases. Here, we report that the small molecular compound, methyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (TBTC), as a selective agonist of retinoid X receptor α (RXRα) can effectively activate the heterodimerization of RXRα with either liver X receptor α (LXRα) or peroxisome proliferator activated receptor γ (PPARγ), stimulate the expressions of the genes of apoE, ABCA1 and ABCG1, and decrease Aβ content both in cells and animal models. In addition, administration of TBTC (30mg/kg/day) in the transgenic APP-PS1 mice could also reduce the formation of senile plaques and improve the daily living activity of the mice. Therefore, our findings have suggested that TBTC might hold the potential as a drug lead compound for the treatment of AD.

  14. The prototypical histamine H3 receptor inverse agonist thioperamide improves multiple aspects of memory processing in an inhibitory avoidance task.

    Science.gov (United States)

    Charlier, Yana; Brabant, Christian; Serrano, Maria Elisa; Lamberty, Yves; Tirelli, Ezio

    2013-09-15

    Numerous studies have found that histamine plays a major role in memory and that the histamine H3 receptor (H3R) inverse agonist thioperamide improves cognitive performance in various animal models. However, little is known about the stages of memory that are specifically affected by thioperamide. The purpose of the present study was to investigate the effects of thioperamide on acquisition, consolidation and retrieval processes in a one-trial inhibitory avoidance task in female C57BL/6J mice. In addition, potential state-dependency effects were studied by injecting thioperamide before the training and the test sessions in order to induce similar physiological states during acquisition and retrieval. Our results indicate that post-training systemic administration of thioperamide facilitated consolidation. Moreover, the administration of thioperamide before the training session had no effect on latency to enter the black compartment during training but enhanced memory during the retention test. The administration of thioperamide before the retention test also increased performance, which indicates that this compound ameliorates memory retrieval. Finally, when animals received thioperamide before the training session and before the retention test, the cognitive enhancing effects of thioperamide were not significantly changed. Together, our results show that thioperamide improves cognitive performance in an inhibitory avoidance task through actions on different memory stages. Furthermore, inducing a similar physiological state with thioperamide during acquisition and retrieval do not significantly affect cognitive enhancement. Our results suggest that the blockade of H3R can be helpful for the treatment of neuropsychiatric conditions characterized by deficits affecting several stages of memory processing.

  15. An improved multi-value cellular automata model for heterogeneous bicycle traffic flow

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Sheng [College of Civil Engineering and Architecture, Zhejiang University, Hangzhou, 310058 China (China); Qu, Xiaobo [Griffith School of Engineering, Griffith University, Gold Coast, 4222 Australia (Australia); Xu, Cheng [Department of Transportation Management Engineering, Zhejiang Police College, Hangzhou, 310053 China (China); College of Transportation, Jilin University, Changchun, 130022 China (China); Ma, Dongfang, E-mail: mdf2004@zju.edu.cn [Ocean College, Zhejiang University, Hangzhou, 310058 China (China); Wang, Dianhai [College of Civil Engineering and Architecture, Zhejiang University, Hangzhou, 310058 China (China)

    2015-10-16

    This letter develops an improved multi-value cellular automata model for heterogeneous bicycle traffic flow taking the higher maximum speed of electric bicycles into consideration. The update rules of both regular and electric bicycles are improved, with maximum speeds of two and three cells per second respectively. Numerical simulation results for deterministic and stochastic cases are obtained. The fundamental diagrams and multiple states effects under different model parameters are analyzed and discussed. Field observations were made to calibrate the slowdown probabilities. The results imply that the improved extended Burgers cellular automata (IEBCA) model is more consistent with the field observations than previous models and greatly enhances the realism of the bicycle traffic model. - Highlights: • We proposed an improved multi-value CA model with higher maximum speed. • Update rules are introduced for heterogeneous bicycle traffic with maximum speed 2 and 3 cells/s. • Simulation results of the proposed model are consistent with field bicycle data. • Slowdown probabilities of both regular and electric bicycles are calibrated.

  16. The novel GLP-1-gastrin dual agonist ZP3022 improves glucose homeostasis and increases β-cell mass without affecting islet number in db/db mice.

    Science.gov (United States)

    Dalbøge, Louise S; Almholt, Dorthe L C; Neerup, Trine S R; Vrang, Niels; Jelsing, Jacob; Fosgerau, Keld

    2014-08-01

    Antidiabetic treatments aiming to preserve or even to increase β-cell mass are currently gaining increased interest. Here we investigated the effect of chronic treatment with the novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist ZP3022 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2) on glycemic control, β-cell mass and proliferation, and islet number. Male db/db mice were treated with ZP3022, liraglutide, or vehicle for 2, 4, or 8 weeks, with terminal assessment of hemoglobin A1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of β-cell mass, islet numbers, proliferation, and apoptosis. Treatment with ZP3022 or liraglutide led to a significant improvement in glycemic control. ZP3022 treatment resulted in a sustained increase in β-cell mass after 4 and 8 weeks of treatment, whereas the effect of liraglutide was transient. The expansion in β-cell mass observed in the ZP3022-treated mice appeared to be driven by increased β-cell proliferation in existing islets rather than by formation of new islets, as mean islet mass increased but the number of islets remained constant. Our data demonstrate that the GLP-1-gastrin dual agonist ZP3022 causes a sustained improvement in glycemic control accompanied by an increase in β-cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1-gastrin dual agonist increases β-cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of antidiabetic treatments.

  17. Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties.

    Science.gov (United States)

    Richter, Hans G F; Benson, G M; Bleicher, K H; Blum, D; Chaput, E; Clemann, N; Feng, S; Gardes, C; Grether, U; Hartman, P; Kuhn, B; Martin, R E; Plancher, J-M; Rudolph, M G; Schuler, F; Taylor, S

    2011-02-15

    Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.

  18. An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients.

    OpenAIRE

    Lin, Jian Sheng; Dauvilliers, Yves; Arnulf, Isabelle; Bastuji, Hélène; Anaclet, Christelle; Parmentier, Régis; Kocher, Laurence; Yanagisawa, Masashi; Lehert, Philippe; Ligneau, Xavier; Perrin, David; Robert, Philippe; Roux, Michel; Lecomte, Jeanne-Marie; Schwartz, Jean-Charles

    2008-01-01

    International audience; Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, direct onsets of rapid eye movement (REM) sleep from wakefulness (DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H(3)-receptor agonist. In narcoleptic orexin(-/...

  19. Improving cellularity and quality of liquid-based cytology slides processed from pancreatobiliary tract brushings.

    Science.gov (United States)

    Campion, Michael B; Kipp, Benjamin R; Humphrey, Sandra K; Zhang, Jun; Clayton, Amy C; Henry, Michael R

    2010-09-01

    Cytology has been reported to have suboptimal sensitivity for detecting pancreatobiliary tract cancer in biliary tract specimens partly as a result of low specimen cellularity and obscuring noncellular components. The goal of this study was to determine if the use of a glacial acetic acid wash prior to processing would increase the cellularity and improve the quality of ThinPrep slides when compared to standard non-gyn ThinPrep processing. Fifty consecutive pancreatobiliary tract specimens containing 20 ml of sample/PreservCyt were divided equally for standard non-gyn ThinPrep (STP) and glacial acetic acid ThinPrep processing (GATP). A manual drop preparation was also performed on residual STP specimen to determine the number of cells left in the vial during STP processing. Twenty-six (52%) specimens had more epithelial cell groupings with the GATP methodology while 19 (38%) had equivalent cellularity with both methods. The STP method produced more epithelial cell groupings in 5 (10%) of the specimens. Of the 26 specimens that had less cells with the STP method, 14 (54%) had > or = 50 cell groupings on the manual drop slide processed from the residual STP specimen suggesting that many cells remain in the vial after STP processing. The GATP method was preferred in 25 (50%) of the specimens, the STP method in 5 (10%), while both methodologies provided similar findings in the remaining 20 (40%) of specimens. The data from this study suggests that the GATP method results in more cells being placed on the slide and was preferred over the STP method in a majority of specimens.

  20. An improved cellular automaton model considering the effect of traffic lights and driving behaviour

    Institute of Scientific and Technical Information of China (English)

    He Hong-Di; Lu Wei-Zhen; Dong Li-Yun

    2011-01-01

    This paper proposes an improved cellular automaton model to describe the urban traffic flow with the consideration of traffic light and driving behaviour effects. Based on the model, the characteristics of the urban traffic flow on a singlelane road are investigated under three different control strategies, i.e., the synchronized, the green wave and the random strategies. The fundamental diagrams and time-space patterns of the traffic flows are provided for these strategies respectively. It finds that the dynamical transition to the congested flow appears when the vehicle density is higher than a critical level. The saturated flow is less dependent on the cycle time and the strategies of the traffic light control,while the critical vehicle density varies with the cycle time and the strategies. Simulated results indicate that the green wave strategy is proven to be the most effective one among the above three control strategies.

  1. An improved cellular automaton model considering the effect of traffic lights and driving behaviour

    Science.gov (United States)

    He, Hong-Di; Lu, Wei-Zhen; Dong, Li-Yun

    2011-04-01

    This paper proposes an improved cellular automaton model to describe the urban traffic flow with the consideration of traffic light and driving behaviour effects. Based on the model, the characteristics of the urban traffic flow on a single-lane road are investigated under three different control strategies, i.e., the synchronized, the green wave and the random strategies. The fundamental diagrams and time-space patterns of the traffic flows are provided for these strategies respectively. It finds that the dynamical transition to the congested flow appears when the vehicle density is higher than a critical level. The saturated flow is less dependent on the cycle time and the strategies of the traffic light control, while the critical vehicle density varies with the cycle time and the strategies. Simulated results indicate that the green wave strategy is proven to be the most effective one among the above three control strategies.

  2. Fasiglifam/TAK-875, a Selective GPR40 Agonist, Improves Hyperglycemia in Rats Unresponsive to Sulfonylureas and Acts Additively with Sulfonylureas.

    Science.gov (United States)

    Ito, Ryo; Tsujihata, Yoshiyuki; Suzuki, Masami; Miyawaki, Kazumasa; Matsuda, Kae; Takeuchi, Koji

    2016-04-01

    Sulfonylureas (SUs) are widely used insulin secretagogues, but they have adverse effects including hypoglycemia and secondary failure. Fasiglifam/TAK-875, a selective GPR40 agonist, enhances glucose-stimulated insulin secretion and improves hyperglycemia. In the present study, we compared the in vivo glucose-lowering effects of fasiglifam with SUs. The risk of secondary failure of fasiglifam and the efficacy in rats desensitized to SUs were also evaluated. Moreover, we assessed whether fasiglifam was effective when combined with SUs. In diabetic neonatally streptozotocin-induced rats 1.5 days after birth (N-STZ-1.5), oral administrations of fasiglifam (3-30 mg/kg) dose dependently improved glucose tolerance; the effect was greater than that of glibenclamide at maximal effective doses (glucose AUC: fasiglifam, -37.6%; glibenclamide, -12.3%). Although the glucose-lowering effects of glibenclamide (10 mg/kg/day) were completely diminished in N-STZ-1.5 rats after 4 weeks of treatment, effects were maintained in rats receiving fasiglifam (10 mg/kg/day), even after 15 weeks. Fasiglifam (3-10 mg/kg) was still effective in two models desensitized to SUs: 15-week glibenclamide-treated N-STZ-1.5 rats and aged Zucker diabetic fatty (ZDF) rats. Acute administration of fasiglifam (3 mg/kg) and glimepiride (10 mg/kg) in combination additively decreased glucose AUC (fasiglifam, -25.3%; glimepiride, -20.0%; combination, -43.1%). Although glimepiride (10 mg/kg) decreased plasma glucose below normal in nonfasted control rats, fasiglifam (3 mg/kg) maintained normoglycemia, and no further exaggeration of hypoglycemia was observed with combination treatment. These results indicate that GPR40 agonists could be more effective and durable than SUs. Our results also provide new insights into GPR40 pharmacology and rationale for the use of GPR40 agonists in diabetic patients with SU failure.

  3. Targeting cellular memory to reprogram the epigenome, restore potential, and improve somatic cell nuclear transfer.

    Science.gov (United States)

    Eilertsen, K J; Power, R A; Harkins, L L; Misica, P

    2007-03-01

    Successful cloning by somatic cell nuclear transfer (SCNT) is thought to require reprogramming of a somatic nucleus to a state of restored totipotentiality [Dean, W., Santos, F., Reik, W., 2003. Epigenetic programming in early mammalian development and following somatic cell nuclear transfer. Semin. Cell. Dev. Biol. 14, 93-100; Jouneau, A., Renard, J.P., 2003. Reprogramming in nuclear transfer. Curr. Opin. Genet. Dev. 13, 486-491; ]. Though SCNT-induced reprogramming is reminiscent of the reprogramming that occurs after fertilization, reprogramming a differentiated nucleus to an embryonic state is delayed and incomplete in comparison (for review, see ). This is likely due to the existence of an epigenetic-based cellular memory, or program, that serves to regulate global patterns of gene expression, and is the basis of a genome defense mechanism that silences viruses and transposons. The mechanisms of this memory include CpG methylation and modification of histones. Recent evidence by Feng et al. [Feng, Y.-Q., Desprat, R., Fu, H., Olivier, E., Lin, C.M., Lobell, A., Gowda, S.N., Aladjem, M.I., Bouhasira, E.E., 2006. DNA methylation supports intrinsic epigenetic memory in mammalian cells. PLOS Genet. 2, 0461-0470], using a transgenic experimental system, indicates that these marks may be acquired in more than one order and thus, silent heterochromatic structure can be initiated by either methylation of CpG dinucleotides or by histone modifications. In this system, however, CpG methylation appears to differ from histone modifications because it bestows a persistent epigenetic, or cellular, memory. In other words, CpG methylation can independently confer cellular memory, whereas histone modifications appear to be limited in this capacity. Therefore, in the context of genomic reprogramming induced by SCNT, efficient demethylation is likely a key (if not the only) rate-limiting step to improving the efficiency and outcomes of SCNT cloning. This review discusses the

  4. Co-agonist of glucagon and GLP-1 reduces cholesterol and improves insulin sensitivity independent of its effect on appetite and body weight in diet-induced obese C57 mice.

    Science.gov (United States)

    Patel, Vishal; Joharapurkar, Amit; Dhanesha, Nirav; Kshirsagar, Samadhan; Patel, Kartik; Bahekar, Rajesh; Shah, Gaurang; Jain, Mukul

    2013-12-01

    Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduce body weight without inducing hyperglycemia in rodents. However, the effect of a co-agonist on insulin sensitivity and lipid metabolism has not been thoroughly assessed. Diet-induced obese (DIO) mice received 0.5 mg·kg(-1) of co-agonist or 2.5 mg·kg(-1) of glucagon or 8 μg·kg(-1) of exendin-4 by subcutaneous route, twice daily, for 28 days. A separate group of mice was pair-fed to the co-agonist-treated group for 28 days. Co-agonist treatment reduced food intake and reduced body weight up to 28 days. In addition, it reduced leptin levels and increased fibroblast growth factor 21 (FGF21) levels in plasma, when compared with control and pair-fed groups. Co-agonist treatment decreased triglyceride levels in serum and liver and reduced serum cholesterol, mainly due to reduction in low-density lipoprotein (LDL) cholesterol. These changes were not seen with pair-fed controls. Co-agonist treatment improved glucose tolerance and increased insulin sensitivity, as observed during glucose and insulin-tolerance test, hyperinsulinemic clamp, and reduced gluconeogenesis, as observed in pyruvate-tolerance test. The effects on insulin sensitivity and lipid levels are mostly independent of the food intake or body weight lowering effect of the co-agonist.

  5. S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice

    Science.gov (United States)

    Guilloux, Jean-Philippe; Samuels, Benjamin A.; Mendez-David, Indira; Hu, Alice; Levinstein, Marjorie; Faye, Charlène; Mekiri, Maryam; Mocaer, Elisabeth; Gardier, Alain M.; Hen, René; Sors, Aurore; David, Denis J.

    2017-01-01

    Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3 receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer’s disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent “context discrimination (CS) test” in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits. PMID:28218311

  6. S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice.

    Science.gov (United States)

    Guilloux, Jean-Philippe; Samuels, Benjamin A; Mendez-David, Indira; Hu, Alice; Levinstein, Marjorie; Faye, Charlène; Mekiri, Maryam; Mocaer, Elisabeth; Gardier, Alain M; Hen, René; Sors, Aurore; David, Denis J

    2017-02-20

    Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3 receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer's disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent "context discrimination (CS) test" in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits.

  7. The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction.

    Science.gov (United States)

    Nathan, Pradeep J; Watson, Jeannette; Lund, Jesper; Davies, Ceri H; Peters, Gary; Dodds, Chris M; Swirski, Bridget; Lawrence, Philip; Bentley, Graham D; O'Neill, Barry V; Robertson, Jon; Watson, Stephen; Jones, Gareth A; Maruff, Paul; Croft, Rodney J; Laruelle, Marc; Bullmore, Edward T

    2013-05-01

    Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

  8. Improved cellular response of chemically crosslinked collagen incorporated hydroxyethyl cellulose/poly(vinyl) alcohol nanofibers scaffold.

    Science.gov (United States)

    Zulkifli, Farah Hanani; Jahir Hussain, Fathima Shahitha; Abdull Rasad, Mohammad Syaiful Bahari; Mohd Yusoff, Mashitah

    2015-02-01

    The aim of this research is to develop biocompatible nanofibrous mats using hydroxyethyl cellulose with improved cellular adhesion profiles and stability and use these fibrous mats as potential scaffold for skin tissue engineering. Glutaraldehyde was used to treat the scaffolds water insoluble as well as improve their biostability for possible use in biomedical applications. Electrospinning of hydroxyethyl cellulose (5 wt%) with poly(vinyl alcohol) (15 wt%) incorporated with and without collagen was blended at (1:1:1) and (1:1) ratios, respectively, and was evaluated for optimal criteria as tissue engineering scaffolds. The nanofibrous mats were crosslinked and characterized by scanning electron microscope, Fourier transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. Scanning electron microscope images showed that the mean diameters of blend nanofibers were gradually increased after chemically crosslinking with glutaraldehyde. Fourier transform infrared spectroscopy was carried out to understand chemical interactions in the presence of aldehyde groups. Thermal characterization results showed that the stability of hydroxyethyl cellulose/poly(vinyl alcohol) and hydroxyethyl cellulose/poly(vinyl alcohol)/collagen nanofibers was increased with glutaraldehyde treatment. Studies on cell-scaffolds interaction were carried out by culturing human fibroblast (hFOB) cells on the nanofibers by assessing the growth, proliferation, and morphologies of cells. The scanning electron microscope results show that better cell proliferation and attachment appeared on hydroxyethyl cellulose/poly(vinyl alcohol)/collagen substrates after 7 days of culturing, thus, promoting the potential of electrospun scaffolds as a promising candidate for tissue engineering applications.

  9. Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy.

    Science.gov (United States)

    Katz, N K; Ryals, J M; Wright, D E

    2015-01-29

    Diabetic peripheral neuropathy is a common complication of diabetes mellitus, and a significant proportion of individuals suffer debilitating pain that significantly affects their quality of life. Unfortunately, symptomatic treatment options have limited efficacy, and often carry significant risk of systemic adverse effects. Activation of the adenosine A1 receptor (A1R) by the analgesic small molecule adenosine has been shown to have antinociceptive benefits in models of inflammatory and neuropathic pain. The current study used a mouse model of painful diabetic neuropathy to determine the effect of diabetes on endogenous adenosine production, and if central or peripheral delivery of adenosine receptor agonists could alleviate signs of mechanical allodynia in diabetic mice. Diabetes was induced using streptozocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Hydrolysis of AMP into adenosine by ectonucleotidases was determined in the dorsal root ganglia (DRG) and spinal cord at 8 weeks post-induction of diabetes. AMP, adenosine and the specific A1R agonist, N(6)-cyclopentyladenosine (CPA), were administered both centrally (intrathecal) and peripherally (intraplantar) to determine the effect of activation of adenosine receptors on mechanical allodynia in diabetic mice. Eight weeks post-induction, diabetic mice displayed significantly decreased hydrolysis of extracellular AMP in the DRG; at this same time, diabetic mice displayed significantly decreased mechanical withdrawal thresholds compared to nondiabetic controls. Central delivery AMP, adenosine and CPA significantly improved mechanical withdrawal thresholds in diabetic mice. Surprisingly, peripheral delivery of CPA also improved mechanical allodynia in diabetic mice. This study provides new evidence that diabetes significantly affects endogenous AMP hydrolysis, suggesting that altered adenosine production could contribute to the development of

  10. A Novel Long-Acting Glucagon-Like Peptide-1 Agonist with Improved Efficacy in Insulin Secretion and β-Cell Growth

    Directory of Open Access Journals (Sweden)

    Hee Young Kim

    2014-09-01

    Full Text Available BackgroundGlucagon-like peptide-1 (GLP-1 is an incretin hormone produced by cleavage of proglucagon in intestinal L-cells. In the pancreas, GLP-1 stimulates post-prandial insulin secretion, promotes insulin biosynthesis, and improves insulin sensitivity. Because of its insulinotropic activity, GLP-1 has been considered a good candidate drug for treatment of diabetes mellitus. However, clinical use of GLP-1 has been limited by its short half-life, as a result of rapid degradation by dipeptidyl peptidase-IV (DPP-IV.MethodsWe designed a novel GLP-1 analog, Xenopus GLP-1 (xGLP-E4. The Ala residue in the second position of xGLP was replaced with a Ser residue to increase the half-life in the body. The C-terminal tail of exendin-4 was added to enhance the binding affinity for the GLP-1 receptor (GLP1R. The potency of GLP-1 and its analogs was determined by luciferase assay. The stability of GLP1R agonists was evaluated by determining the activity of agonists that had been preincubated in the presence of fetal bovine serum, which contains innate DPP-IV activity. The effects of xGLP-E4 on insulin secretion and β-cell growth were investigated using insulin enzyme-linked immunosorbent assay and cell counting.ResultsxGLP-E4 exhibited improved stability against DPP-IV activity and increased potency to GLP1R, compared with GLP-1. An increase in glucose-dependent insulin secretion was observed in xGLP-E4-treated pancreatic β-cells. The effect of xGLP-E4 on β-cell growth was greater than that of GLP-1.ConclusionWe developed a novel GLP-1 analog, xGLP-E4, that shows prolonged longevity and improved efficacy. This analog is a potential candidate for treatment of type 2 diabetes.

  11. Modeling rice metabolism: from elucidating environmental effects on cellular phenotype to guiding crop improvement

    Directory of Open Access Journals (Sweden)

    Meiyappan Lakshmanan

    2016-11-01

    Full Text Available Crop productivity is severely limited by various biotic and abiotic stresses. Thus, it is highly needed to understand the underlying mechanisms of environmental stress response and tolerance in plants, which could be addressed by systems biology approach. To this end, high-throughput omics profiling and in silico modeling can be considered to explore the environmental effects on phenotypic states and metabolic behaviors of rice crops at the systems level. Especially, the advent of constraint-based metabolic reconstruction and analysis paves a way to characterize the plant cellular physiology under various stresses by combining the mathematical network models with multi-omics data. Rice metabolic networks have been reconstructed since 2013 and currently 6 such networks are available, where 5 are at genome-scale. Since their publication, these models have been utilized to systematically elucidate the rice abiotic stress responses and identify agronomic traits for crop improvement. In this review, we summarize the current status of the existing rice metabolic networks and models with their applications. Furthermore, we also highlight future directions of rice modeling studies, particularly stressing how these models can be used to contextualize the affluent multi-omics data that are readily available in the public domain. Overall, we envisage a number of studies in the future, exploiting the available metabolic models to enhance the yield and quality of rice and other food crops.

  12. Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes.

    Science.gov (United States)

    Kreienkamp, Ray; Croke, Monica; Neumann, Martin A; Bedia-Diaz, Gonzalo; Graziano, Simona; Dusso, Adriana; Dorsett, Dale; Carlberg, Carsten; Gonzalo, Susana

    2016-05-24

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating incurable premature aging disease caused by accumulation of progerin, a toxic lamin A mutant protein. HGPS patient-derived cells exhibit nuclear morphological abnormalities, altered signaling pathways, genomic instability, and premature senescence. Here we uncover new molecular mechanisms contributing to cellular decline in progeria. We demonstrate that HGPS cells reduce expression of vitamin D receptor (VDR) and DNA repair factors BRCA1 and 53BP1 with progerin accumulation, and that reconstituting VDR signaling via 1α,25-dihydroxyvitamin D3 (1,25D) treatment improves HGPS phenotypes, including nuclear morphological abnormalities, DNA repair defects, and premature senescence. Importantly, we discovered that the 1,25D/VDR axis regulates LMNA gene expression, as well as expression of DNA repair factors. 1,25D dramatically reduces progerin production in HGPS cells, while stabilizing BRCA1 and 53BP1, two key factors for genome integrity. Vitamin D/VDR axis emerges as a new target for treatment of HGPS and potentially other lamin-related diseases exhibiting VDR deficiency and genomic instability. Because progerin expression increases with age, maintaining vitamin D/VDR signaling could keep the levels of progerin in check during physiological aging.

  13. Quality of service improvement, Handoff Prioritization and Channel utilization for Cellular Network

    Directory of Open Access Journals (Sweden)

    Anoop Kumar Gangwar

    2014-10-01

    Full Text Available In this paper Call admission control (CAC is a significant component in wireless networks to promise quality of service requirements and also to improve the network flexibility. The reliability is measured in terms of quality of service (QoS and grade of service (GoS. GoS is a call‐level factor, which comprises of a new call blocking probability and handoff call blocking probability. So a robust Call Admission and Power Control Mechanism are desired. An admission control method considering the quality of service (QoS requirements is accountable for deciding whether an incoming call/connection can be accepted or not. One major challenge in designing a CAC creates due to the fact that the cellular network has to service two major types of calls: new calls and handoff calls. The QoS performances related to these two types of calls are generally measured by new call blocking probability and handoff call dropping probability. Our work advance the dropping and handoff loss probabilities and present a coherent framework for comparative studies of presented approaches, but also helps future researches and developments of new call admission policies.

  14. A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice.

    Science.gov (United States)

    Valdecantos, M Pilar; Pardo, Virginia; Ruiz, Laura; Castro-Sánchez, Luis; Lanzón, Borja; Fernández-Millán, Elisa; García-Monzón, Carmelo; Arroba, Ana I; González-Rodríguez, Águeda; Escrivá, Fernando; Álvarez, Carmen; Rupérez, Francisco J; Barbas, Coral; Konkar, Anish; Naylor, Jacqui; Hornigold, David; Santos, Ana Dos; Bednarek, Maria; Grimsby, Joseph; Rondinone, Cristina M; Valverde, Ángela M

    2017-03-01

    Because nonalcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon-like peptide-1/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or a methionine and choline-deficient (MCD) diet for 1 week were divided into 4 groups: control (chow diet), MCD diet, chow diet plus G49, and M+G49 (MCD diet plus G49). Mice fed a high-fat diet (HFD) for 10 weeks were divided into groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed, and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration, and comprehensive genomic and metabolic profiling were conducted. NASH was ameliorated in the M+G49 group, manifested by reduced inflammation, steatosis, oxidative stress, and apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose use through the pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored the cytokine-mediated priming phase, and enhanced the proliferative capacity and hepatic regeneration ratio in mice on the MCD diet. NASH markers remained decreased in M+G49 mice after PH, and glucose use was shifted to the pentose phosphate cycle and oxidative metabolism. G49 administered immediately after PH was also effective at alleviating the pathological changes induced by the MCD diet. Benefits in terms of liver regeneration were also found in mice fed HFD and treated with G49.

  15. Improvement of vascular function by acute and chronic treatment with the GPR30 agonist G1 in experimental diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Zi-lin Li

    Full Text Available The G-protein coupled estrogen receptor 30 (GPR30 is a seven-transmembrane domain receptor that mediates rapid estrogen responses in a wide variety of cell types. This receptor is highly expressed in the cardiovascular system, and exerts vasodilatory effects. The objective of the present study was to investigate the effects of GPR30 on vascular responsiveness in diabetic ovariectomized (OVX rats and elucidate the possible mechanism involved. The roles of GPR30 were evaluated in the thoracic aorta and cultured endothelial cells. The GPR30 agonist G1 induced a dose-dependent vasodilation in the thoracic aorta of the diabetic OVX rats, which was partially attenuated by the nitric oxide synthase (NOS inhibitor, nitro-L-arginine methylester (L-NAME and the GPR30-selective antagonist G15. Dose-dependent vasoconstrictive responses to phenylephrine were attenuated significantly in the rings of the thoracic aorta following the acute G1 administration in the diabetic OVX rats. This effect of G1 was abolished partially by L-NAME and G15. The acute administration of G1 increased significantly the eNOS activity and the concentration of NO in the endothelial cells exposed to high glucose. G1 treatment induced an enhanced endothelium-dependent relaxation to acetylcholine (Ach in the diabetic OVX rats. Further examination revealed that G1 induced vasodilation in the diabetic OVX rats by increasing the phosphorylation of eNOS. These findings provide preliminary evidence that GPR30 activation leads to eNOS activation, as well as vasodilation, to a certain degree and has beneficial effects on vascular function in diabetic OVX rats.

  16. AVE8134, a novel potent PPARα agonist, improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Hans Ludwig SCH(A)FER; Wolfgang LINZ; Eugen FALK; Maike GLIEN; Heiner GLOMBIK; Mlarcus KORN; Wolfgang WEN-DLER; Andreas W HERLING; Hartmut R(U)TTEN

    2012-01-01

    AVE8134 is a structurally novel potent PPARα agonist.The aim of this study is to investigate the efficacy of AVE8134 on lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.Methods:A cell based PPAR Gal4 transactivation assay was constructed for testing the activities of AVE8134 at 3 different PPAR isoforms in vitro.Transgenic human Apo A1 (hApo A1) mice and insulin-resistant ZDF rats were used to evaluate the effects of AVE8134 in vivo.Results:AVE8134 was a full PPARα dominated PPAR agonist (the values of EC5o for human and rodent PPARα receptor were 0.01 and 0.3 μmol/L,respectively).AVE8134 was not active at PPARδ receptor.In female hApo A1 mice,AVE8134 (1-30 mg·kg-1-d-1,po for 12 d)dose-dependently lowered the plasma triglycerides,and increased the serum HDL-cholesterol,hApo A1 and mouse Apo E levels.In female ZDF rats,AVE8134 (3-30 mg·kg-1-d-1 for 2 weeks) improved insulin-sensitivity index.In pre-diabetic male ZDF rats (at the age of 7 weeks),AVE8134 (10 mg·kg-1-d-1 for 8 weeks) produced an anti-diabetic action comparable to rosiglitazone,without the PPARy mediated adverse effects on body weight and heart weight.In male ZDF rats (at the age of 6 weeks),AVE8134 (20 mg·kg-1-d-1 for 12 weeks) increased mRNA levels of the target genes LPL and PDK4 about 20 fold in the liver,and there was no relevant effect with rosiglitazone.Conclusion:AVE8134 improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.

  17. GLP-1 Receptor Agonists

    Science.gov (United States)

    ... in Balance › GLP-1 Receptor Agonists Fact Sheet GLP-1 Receptor Agonists May, 2012 Download PDFs English Espanol Editors Silvio ... are too high or too low. What are GLP-1 receptor agonist medicines? GLP-1 receptor agonist medicines, also called ...

  18. The Parenteral Vitamin C Improves Sepsis and Sepsis-Induced Multiple Organ Dysfunction Syndrome via Preventing Cellular Immunosuppression

    Science.gov (United States)

    Chai, Yan-Fen

    2017-01-01

    Cellular immunosuppression appears to be involved in sepsis and sepsis-induced multiple organ dysfunction syndrome (MODS). Recent evidence showed that parenteral vitamin C (Vit C) had the ability to attenuate sepsis and sepsis-induced MODS. Herein, we investigated the impact of parenteral Vit C on cellular immunosuppression and the therapeutic value in sepsis. Using cecal ligation and puncture (CLP), sepsis was induced in WT and Gulo−/− mice followed with 200 mg/Kg parenteral Vit C administration. The immunologic functions of CD4+CD25+ regulatory T cells (Tregs) and CD4+CD25− T cells, as well as the organ functions, were determined. Administration of parenteral Vit C per se markedly improved the outcome of sepsis and sepsis-induced MODS of WT and Gulo−/− mice. The negative immunoregulation of Tregs was inhibited, mainly including inhibiting the expression of forkhead helix transcription factor- (Foxp-) 3, cytotoxic T lymphocyte associated antigen- (CTLA-) 4, membrane associated transforming growth factor-β (TGF-βm+), and the secretion of inhibitory cytokines [including TGF-β and interleukin- (IL-) 10], as well as CD4+ T cells-mediated cellular immunosuppression which was improved by parenteral Vit C in WT and Gulo−/− septic mice. These results suggested that parenteral Vit C has the ability to improve the outcome of sepsis and sepsis-induced MODS and is associated with improvement in cellular immunosuppression. PMID:28210072

  19. PWZ-029, an inverse agonist selective for α₅ GABAA receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats.

    Science.gov (United States)

    Milić, Marija; Timić, Tamara; Joksimović, Srđan; Biawat, Poonam; Rallapalli, Sundari; Divljaković, Jovana; Radulović, Tamara; Cook, James M; Savić, Miroslav M

    2013-03-15

    Inverse agonism at the benzodiazepine site of α(5) subunit-containing GABA(A) receptors is an attractive approach for the development of putative cognition-enhancing compounds, which are still far from clinical application. Several ligands with binding and/or functional selectivity for α(5) GABA(A) receptors have been synthesized and tested in a few animal models. PWZ-029 is an α(5) GABA(A) selective inverse agonist whose memory enhancing effects were demonstrated in the passive avoidance task in rats and in Pavlovian fear conditioning in mice. In the present study we investigated the effects of PWZ-029 administration in novel object recognition test and Morris water maze, in normal and scopolamine-treated rats. All the three doses of PWZ-029 (2, 5 and 10 mg/kg) improved object recognition after the 24-h delay period, as shown by significant differences between the exploration times of the novel and old object, and the respective discrimination indices. PWZ-029 (2 mg/kg) also successfully reversed the 0.3 mg/kg scopolamine-induced deficit in recognition memory after the 1-h delay. In the Morris water maze test, PWZ-029 (5, 10 and 15 mg/kg) did not significantly influence swim patterns, either during five acquisition days or during the treatment-free probe trial. PWZ-029 (2, 5 and 10 mg/kg) also proved to be ineffective in the reversal of the 1mg/kg scopolamine-induced memory impairment in the water maze. The present mixed results encourage use of a variety of tests and experimental conditions in order to increase the predictability of preclinical testing of selective α(5) GABA(A) inverse agonists.

  20. Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington's disease.

    Science.gov (United States)

    Jiang, Mali; Peng, Qi; Liu, Xia; Jin, Jing; Hou, Zhipeng; Zhang, Jiangyang; Mori, Susumu; Ross, Christopher A; Ye, Keqiang; Duan, Wenzhen

    2013-06-15

    Huntington's disease (HD) is a fatal neurodegenerative disease characterized by abnormal motor coordination, cognitive decline and psychiatric disorders. This disease is caused by an expanded CAG trinucleotide repeat in the gene encoding the protein huntingtin. Reduced levels of brain-derived neurotrophic factor (BDNF) in the brain, which results from transcriptional inhibition and axonal transport deficits mediated by mutant huntingtin, have been suggested as critical factors underlying selective neurodegeneration in both HD patients and HD mouse models. BDNF activates its high-affinity receptor TrkB and promotes neuronal survival; restoring BDNF signaling is thus of particular therapeutic interest. In the present study, we evaluated the ability of a small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and its synthetic derivative 4'-dimethylamino-7,8- dihydroxyflavone (4'-DMA-7,8-DHF) to protect neurons in the well-characterized N171-82Q HD mouse model. We found that chronic administration of 7, 8-DHF (5 mg/kg) or 4'-DMA-7,8-DHF (1 mg/kg) significantly improved motor deficits, ameliorated brain atrophy and extended survival in these N171-82Q HD mice. Moreover, 4'-DMA-7,8-DHF preserved DARPP32 levels in the striatum and rescued mutant huntingtin-induced impairment of neurogenesis in the N171-82Q HD mice. These data highlight consideration of TrkB as a therapeutic target in HD and suggest that small-molecule TrkB agonists that penetrate the brain have high potential to be further tested in clinical trials of HD.

  1. NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats.

    Science.gov (United States)

    She, Meihua; Deng, Xiaojian; Guo, Zhenyu; Laudon, Moshe; Hu, Zhuowei; Liao, Duanfang; Hu, Xiaobo; Luo, Yi; Shen, Qingyun; Su, Zehong; Yin, Weidong

    2009-04-01

    Evidences indicate that a complex relationship exists among sleep disorders, obesity and insulin resistance. NEU-P11 is a novel melatonin agonist used in treatment of psychophysiological insomnia, and in animal studies NEU-P11 showed sleep-promoting effect. In this study, we applied NEU-P11 on obese rats to assess its potential melatoninergic effects in vivo. Obese models were established using high-fat/high-sucrose-fed for 5 months. NEU-P11 (10mg/kg)/melatonin (4mg/kg)/vehicle were administered by a daily intraperitoneal injection respectively for 8 weeks. Our results showed that NEU-P11 or melatonin inhibited both body weight gain and deposit of abdominal fat with no influence on food intake. The impaired insulin sensitivity and antioxidative potency were improved and the levels of plasma glucose, total cholesterol (TC), triglycerides (TG) decreased with an increased in HDL-cholesterol (HDL-c) after NEU-P11 or melatonin administration. These data suggest that NEU-P11, like melatonin, decreased body weight gain and improved insulin sensitivity and metabolic profiles in obese rats. We conclude that NEU-P11 has a melatoninergic effect on regulating body weight in obese rats and also improving metabolic profiles and efficiently enhancing insulin sensitivity.

  2. A Simple Scheme for Improved Performance of Fixed Outage Rate Cellular System

    Directory of Open Access Journals (Sweden)

    Hussein M.A. Basi

    2004-01-01

    Full Text Available The traffic characteristic of mobile cellular systems is rather distinct from that of a fixed telephone network. However the system planning and design are still carried out with the tools of conventional traffic theory. In the recent days much work is being done in the performance evaluation of mobile or cellular communication systems in order to develop a system with greater efficiency. The useful parameters to estimate the performance of the system are voice quality, frequency spectrum efficiency and Grade of Service (GOS. The grade of service will be affected due to outage of channels. In this study, a new scheme is proposed to reduce lost calls due to channel outage in the fixed rate outage cellular system. In this proposed scheme the call will never dropped but may be delayed. The system performance is evaluated for different conditions and the results are discussed.

  3. Three-dimensional detonation cellular structures in rectangular ducts using an improved CESE scheme

    Science.gov (United States)

    Shen, Yang; Shen, Hua; Liu, Kai-Xin; Chen, Pu; Zhang, De-Liang

    2016-11-01

    The three-dimensional premixed H2-O2 detonation propagation in rectangular ducts is simulated using an in-house parallel detonation code based on the second-order space-time conservation element and solution element (CE/SE) scheme. The simulation reproduces three typical cellular structures by setting appropriate cross-sectional size and initial perturbation in square tubes. As the cross-sectional size decreases, critical cellular structures transforming the rectangular or diagonal mode into the spinning mode are obtained and discussed in the perspective of phase variation as well as decreasing of triple point lines. Furthermore, multiple cellular structures are observed through examples with typical aspect ratios. Utilizing the visualization of detailed three-dimensional structures, their formation mechanism is further analyzed. Project supported by the National Natural Science Foundation of China (Grant Nos. 10732010 and 10972010).

  4. Three-dimensional detonation cellular structures in rectangular ducts using an improved CESE scheme

    KAUST Repository

    Shen, Yang

    2016-11-01

    The three-dimensional premixed H2-O2 detonation propagation in rectangular ducts is simulated using an in-house parallel detonation code based on the second-order space–time conservation element and solution element (CE/SE) scheme. The simulation reproduces three typical cellular structures by setting appropriate cross-sectional size and initial perturbation in square tubes. As the cross-sectional size decreases, critical cellular structures transforming the rectangular or diagonal mode into the spinning mode are obtained and discussed in the perspective of phase variation as well as decreasing of triple point lines. Furthermore, multiple cellular structures are observed through examples with typical aspect ratios. Utilizing the visualization of detailed three-dimensional structures, their formation mechanism is further analyzed.

  5. An improved instrumental characterization of mechanical and acoustic properties of crispy cellular solid food

    NARCIS (Netherlands)

    Vliet, T. van; Castro-Prada, E.M.; Luyten, H.; Lichtendonk, W.; Hamer, R.J.

    2007-01-01

    A detailed study was performed to simultaneously measure the mechanical and acoustic properties of crispy cellular solid foods. Different critical aspects are discussed in order to assess optimal test conditions. These are primarily data sampling rate, microphone positioning, frequency spectrum of i

  6. The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD

    Directory of Open Access Journals (Sweden)

    Sagvolden Terje

    2006-12-01

    Full Text Available Abstract Background ADHD is currently defined as a cognitive/behavioral developmental disorder where all clinical criteria are behavioral. Overactivity, impulsiveness, and inattentiveness are presently regarded as the main clinical symptoms. There is no biological marker, but there is considerable evidence to suggest that ADHD behavior is associated with poor dopaminergic and noradrenergic modulation of neuronal circuits that involve the frontal lobes. The best validated animal model of ADHD, the Spontaneously Hypertensive Rat (SHR, shows pronounced overactivity, impulsiveness, and deficient sustained attention. While dopamine release is decreased in SHR prefrontal cortex, norepinephrine concentrations are elevated. The noradrenergic system appears to be hyperactive as a result of impaired alpha-2A adrenoceptor regulation. Thus, the present study tested behavioral effects of the centrally acting alpha-2A adrenoceptor agonist guanfacine on SHR behavior. Methods The present study tested behavioral effects of guanfacine at doses of 0.075, 0.15, 0.30 and 0.60 mg base/kg i.p. in both male SHRs and their controls, the Wistar Kyoto rat (WKY. ADHD-like behavior was tested with a visual discrimination task measuring overactivity, impulsiveness and inattentiveness. Results The striking impulsiveness, overactivity, and reduced sustained attention during baseline conditions in the SHR improved by treatment with guanfacine. The most pronounced improvement in SHR behavior was seen following the two highest doses (0.3 and 0.6 mg/kg of guanfacine when SHR behaviors virtually normalized. The positive effects of the drug were most marked towards the end of the session. Conclusion The results indicate that guanfacine improved poor noradrenergic modulation of neuronal circuits that involve the frontal lobes in an animal model of ADHD. The present results support the beneficial effects of guanfacine on ADHD behavior reported clinically and experimentally in primate

  7. Improved Hypertension Control with the Imidazoline Agonist Moxonidine in a Multinational Metabolic Syndrome Population: Principal Results of the MERSY Study.

    Science.gov (United States)

    Chazova, Irina; Schlaich, Markus P

    2013-01-01

    This study was designed to assess the effects of moxonidine on blood pressure and aspects of the metabolic syndrome in racially diverse population of patients encountered in routine medical practice. Physicians collected data on a minimum of three consecutive patients with uncontrolled essential hypertension and criteria for metabolic syndrome, eligible to receive moxonidine (0.2-0.4 mg once daily) for 6 months, either as monotherapy or as adjunct therapy to current antihypertensive treatment. Systolic and diastolic blood pressure (BP) declined by an average of 24.5 + 14.3 mmHg and 12.6 + 9.1 mmHg, respectively. BP responder rates defined as attaining BP < 140/90 mmHg were significantly (P < 0.001) and substantially higher among younger patients, nonpostmenopausal women, and patients receiving monotherapy. While potentially relevant improvements in the entire cohort were observed in regard to body weight (-2.1 ± 5.4 kg), fasting plasma glucose (from 6.8 to 6.2 mmol/L), and triglycerides (2.4 to 2.0 mmol/L), statistically significant changes in metabolic parameters could only be detected in subgroup analyses. Moxonidine therapy reduced blood pressure and improved rates of blood pressure control in this group of patients. While the observed trend towards improvement in various metabolic parameters merits further investigation, the overall effect of moxonidine treatment is consistent with a reduction of total cardiovascular risk in this hypertensive metabolic syndrome cohort.

  8. Improved Hypertension Control with the Imidazoline Agonist Moxonidine in a Multinational Metabolic Syndrome Population: Principal Results of the MERSY Study

    Directory of Open Access Journals (Sweden)

    Irina Chazova

    2013-01-01

    Full Text Available This study was designed to assess the effects of moxonidine on blood pressure and aspects of the metabolic syndrome in racially diverse population of patients encountered in routine medical practice. Physicians collected data on a minimum of three consecutive patients with uncontrolled essential hypertension and criteria for metabolic syndrome, eligible to receive moxonidine (0.2–0.4 mg once daily for 6 months, either as monotherapy or as adjunct therapy to current antihypertensive treatment. Systolic and diastolic blood pressure (BP declined by an average of 24.5+14.3 mmHg and 12.6+9.1 mmHg, respectively. BP responder rates defined as attaining BP < 140/90 mmHg were significantly (P<0.001 and substantially higher among younger patients, nonpostmenopausal women, and patients receiving monotherapy. While potentially relevant improvements in the entire cohort were observed in regard to body weight (-2.1±5.4 kg, fasting plasma glucose (from 6.8 to 6.2 mmol/L, and triglycerides (2.4 to 2.0 mmol/L, statistically significant changes in metabolic parameters could only be detected in subgroup analyses. Moxonidine therapy reduced blood pressure and improved rates of blood pressure control in this group of patients. While the observed trend towards improvement in various metabolic parameters merits further investigation, the overall effect of moxonidine treatment is consistent with a reduction of total cardiovascular risk in this hypertensive metabolic syndrome cohort.

  9. The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test.

    Science.gov (United States)

    Isacson, Ruben; Nielsen, Elisabet; Dannaeus, Karin; Bertilsson, Göran; Patrone, Cesare; Zachrisson, Olof; Wikström, Lilian

    2011-01-10

    We have earlier shown that the glucagon-like peptide 1 receptor agonist exendin-4 stimulates neurogenesis in the subventricular zone and excerts anti-parkinsonian behavior. The aim of this study was to assess the effects of exendin-4 treatment on hippocampus-associated cognitive and mood-related behavior in adult rodents. To investigate potential effects of exendin-4 on hippocampal function, radial maze and forced swim test were employed. The time necessary to solve a radial maze task and the duration of immobility in the forced swim test were significantly reduced compared to respective vehicle groups if the animals had received exendin-4 during 1-2weeks before testing. In contrast to the positive control imipramine, single administration of exendin-4 1h before the challenge in the forced swim test had no effect. Immunohistochemical analysis showed that the incorporation of bromodeoxyuridine, a marker for DNA synthesis, as well as doublecortin expression was increased in the hippocampal dentate gyrus following chronic treatment with exendin-4 compared to vehicle-treated controls. The neurogenic effect of exendin-4 on hippocampus was confirmed by quantitative PCR showing an upregulation of mRNA expression for Ki-67, doublecortin and Mash-1. Since exendin-4 significantly improves hippocampus-associated behavior in adult rodents, it may be a candidate for alleviation of mood and cognitive disorders.

  10. Improvements to parallel plate flow chambers to reduce reagent and cellular requirements

    Directory of Open Access Journals (Sweden)

    Larson Richard S

    2001-09-01

    Full Text Available Abstract Background The parallel plate flow chamber has become a mainstay for examination of leukocytes under physiologic flow conditions. Several design modifications have occurred over the years, yet a comparison of these different designs has not been performed. In addition, the reagent requirements of many designs prohibit the study of rare leukocyte populations and require large amounts of reagents. Results In this study, we evaluate modifications to a newer parallel plate flow chamber design in comparison to the original parallel plate flow chamber described by Lawrence et al. We show that modifications in the chamber size, internal tubing diameters, injection valves, and a recirculation design may dramatically reduce the cellular and reagent requirements without altering measurements. Conclusions These modifications are simple and easily implemented so that study of rare leukocyte subsets using scarce or expensive reagents can occur.

  11. Quantum Dots Encapsulated with Canine Parvovirus-Like Particles Improving the Cellular Targeted Labeling.

    Directory of Open Access Journals (Sweden)

    Dan Yan

    Full Text Available Quantum dots (QDs have a promising prospect in live-cell imaging and sensing because of unique fluorescence features. QDs aroused significant interest in the bio-imaging field through integrating the fluorescence properties of QDs and the delivery function of biomaterial. The natural tropism of Canine Parvovirus (CPV to the transferrin receptor can target specific cells to increase the targeting ability of QDs in cell imaging. CPV virus-like particles (VLPs from the expression of the CPV-VP2 capsid protein in a prokaryotic expression system were examined to encapsulate the QDs and deliver to cells with an expressed transferrin receptor. CPV-VLPs were used to encapsulate QDs that were modified using 3-mercaptopropionic acid. Gel electrophoresis, fluorescence spectrum, particle size, and transmission electron microscopy verified the conformation of a complex, in which QDs were encapsulated in CPV-VLPs (CPV-VLPs-QDs. When incubated with different cell lines, CPV-VLPs-QDs significantly reduced the cytotoxicity of QDs and selectively labeled the cells with high-level transferrin receptors. Cell-targeted labeling was achieved by utilizing the specific binding between the CPV capsid protein VP2 of VLPs and cellular receptors. CPV-VLPs-QDs, which can mimic the native CPV infection, can recognize and attach to the transferrin receptors on cellular membrane. Therefore, CPV-VLPs can be used as carriers to facilitate the targeted delivery of encapsulated nanomaterials into cells via receptor-mediated pathways. This study confirmed that CPV-VLPs can significantly promote the biocompatibility of nanomaterials and could expand the application of CPV-VLPs in biological medicine.

  12. Rhizobacterial Strain Bacillus megaterium BOFC15 Induces Cellular Polyamine Changes that Improve Plant Growth and Drought Resistance

    Directory of Open Access Journals (Sweden)

    Cheng Zhou

    2016-06-01

    Full Text Available Plant-growth-promoting rhizobacteria can improve plant growth, development, and stress adaptation. However, the underlying mechanisms are still largely unclear. We investigated the effects of Bacillus megaterium BOFC15 on Arabidopsis plants. BOFC15 produced and secreted spermidine (Spd, a type of polyamine (PA that plays an important role in plant growth. Moreover, BOFC15 induced changes in the cellular PAs of plants that promoted an increase of free Spd and spermine levels. However, these effects were remarkably abolished by the addition of dicyclohexylamine (DCHA, a Spd biosynthetic inhibitor. Additionally, the inoculation with BOFC15 remarkably increased plant biomass, improved root system architecture, and augmented photosynthetic capacity. Inoculated plants also displayed stronger ability to tolerate drought stress than non-inoculated (control plants. Abscisic acid (ABA content was notably higher in the inoculated plants than in the control plants under drought stress and polyethylene glycol (PEG-induced stress conditions. However, the BOFC15-induced ABA synthesis was markedly inhibited by DCHA. Thus, microbial Spd participated in the modulation of the ABA levels. The Spd-producing BOFC15 improved plant drought tolerance, which was associated with altered cellular ABA levels and activated adaptive responses.

  13. Evaluation of dual trigger with gonadotropin-releasing hormone agonist and human chorionic gonadotropin in improving oocyte maturity rates: A prospective randomized study

    Directory of Open Access Journals (Sweden)

    Nalini Mahajan

    2016-01-01

    Full Text Available BACKGROUND: Mature oocytes are prerequisite for achieving the process of in vitro fertilization. Human chorionic gonadotropin (hCG is the standard trigger used for stimulating ovulation but is associated with ovarian hyperstimulation syndrome (OHSS. Gonadotropin-releasing hormone agonist trigger achieves oocyte maturation and lowers the incidence of OHSS, but it has limitations of higher pregnancy loss rate and miscarriage rates. Coadministration of both hormones is found to improve the pregnancy rates and the number of mature oocytes retrieved. We aimed to assess if the dual trigger is better than the conventional hCG in triggering oocyte maturation. METHODOLOGY: The study included 76 female patients aged 24–43 years who were randomly divided into two groups with 38 patients in each arm. The study included patients with antimullerian hormone (AMH 4 ng/ml and AFC/ovary >12 to avoid OHSS risk with hCG trigger. RESULTS: The study showed statistically insignificant differences between dual group versus hCG group in terms of the number of oocytes retrieved (10.0 ± 5.6 vs. 8.7 ± 5.0; P = 0.2816, the number of mature oocytes recovered (8.4 ± 5.0 vs. 7.2 ± 4.0; P = 0.2588, fertilization rate (5.9 ± 4.2 vs. 5.6 ± 3.3; P = 0.7390, and the number of usable embryos on day 3 (4.0 ± 3.0 vs. 4.0 ± 2.4; P = 0.8991. CONCLUSION: The dual trigger is equivalent to hCG in triggering oocyte maturation.

  14. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart;

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  15. Engineering cellular redox balance in Saccharomyces cerevisiae for improved production of L-lactic acid.

    Science.gov (United States)

    Lee, Ju Young; Kang, Chang Duk; Lee, Seung Hyun; Park, Young Kyoung; Cho, Kwang Myung

    2015-04-01

    Owing to the growing market for the biodegradable and renewable polymer, polylactic acid, world demand for lactic acid is rapidly increasing. However, the very high concentrations desired for industrial production of the free lactic acid create toxicity and low pH concerns for manufacturers. Saccharomyces cerevisiae is the most well characterized eukaryote, a preferred microbial cell factory for the largest industrial biotechnology product (bioethanol), and a robust, commercially compatible workhorse to be exploited for the production of diverse chemicals. S. cerevisiae has also been explored as a host for lactic acid production because of its high acid tolerance. Here, we constructed an L-lactic acid-overproducing S. cerevisiae by redirecting cellular metabolic fluxes to the production of L-lactic acid. To this end, we deleted the S. cerevisiae genes encoding pyruvate decarboxylase 1 (PDC1), L-lactate cytochrome-c oxidoreductase (CYB2), and glycerol-3-phosphate dehydrogenase (GPD1), replacing them with a heterologous L-lactate dehydrogenase (LDH) gene. Two new target genes encoding isoenzymes of the external NADH dehydrogenase (NDE1 and NDE2), were also deleted from the genome to re-engineer the intracellular redox balance. The resulting strain was found to produce L-lactic acid more efficiently (32.6% increase in final L-lactic acid titer). When tested in a bioreactor in fed-batch mode, this engineered strain produced 117 g/L of L-lactic acid under low pH conditions. This result demonstrates that the redox balance engineering should be coupled with the metabolic engineering in the construction of L-lactic acid-overproducing S. cerevisiae.

  16. Optimization of the Design of Pre-Signal System Using Improved Cellular Automaton

    Directory of Open Access Journals (Sweden)

    Yan Li

    2014-01-01

    Full Text Available The pre-signal system can improve the efficiency of intersection approach under rational design. One of the main obstacles in optimizing the design of pre-signal system is that driving behaviors in the sorting area cannot be well evaluated. The NaSch model was modified by considering slow probability, turning-deceleration rules, and lane changing rules. It was calibrated with field observed data to explore the interactions among design parameters. The simulation results of the proposed model indicate that the length of sorting area, traffic demand, signal timing, and lane allocation are the most important influence factors. The recommendations of these design parameters are demonstrated. The findings of this paper can be foundations for the design of pre-signal system and show promising improvement in traffic mobility.

  17. Optimization of the design of pre-signal system using improved cellular automaton.

    Science.gov (United States)

    Li, Yan; Li, Ke; Tao, Siran; Wan, Xia; Chen, Kuanmin

    2014-01-01

    The pre-signal system can improve the efficiency of intersection approach under rational design. One of the main obstacles in optimizing the design of pre-signal system is that driving behaviors in the sorting area cannot be well evaluated. The NaSch model was modified by considering slow probability, turning-deceleration rules, and lane changing rules. It was calibrated with field observed data to explore the interactions among design parameters. The simulation results of the proposed model indicate that the length of sorting area, traffic demand, signal timing, and lane allocation are the most important influence factors. The recommendations of these design parameters are demonstrated. The findings of this paper can be foundations for the design of pre-signal system and show promising improvement in traffic mobility.

  18. Arbutin encapsulated micelles improved transdermal delivery and suppression of cellular melanin production

    OpenAIRE

    Liang, Ke; Xu, Keming; Bessarab, Dmitri; Obaje, Jonathan; Xu, Chenjie

    2016-01-01

    Background Hyperpigmentation is a skin disorder characterized by elevated production of melanin. Current treatment approaches mainly rely on the application of skin lightening chemicals, most of which have safety issues. Efficacy of delivery of the active ingredients to the target organ has also been a challenge. Transdermal based drug delivery platform has been shown to improve drug bioavailability, avoiding the hepatic first pass metabolism, decrease gastrointestinal side effects, and event...

  19. KenVACS: Improving Vaccination of Children through Cellular Network Technology in Developing Countries

    Directory of Open Access Journals (Sweden)

    George Gatuha

    2015-04-01

    Full Text Available Health Data collection is one of the major components of public health systems. Decision makers, policy makers, and medical service providers need accurate and timely data in order to improve the quality of health services. The rapid growth and use of mobile technologies has exerted pressure on the demand for mobile-based data collection solutions to bridge the information gaps in the health sector. We propose a prototype using open source data collection frameworks to test its feasibility in improving the vaccination data collection in Kenya. KenVACS, the proposed prototype, offers ways of collecting vaccination data through mobile phones and visualizes the collected data in a web application; the system also sends reminder short messages service (SMS to remind parents on the date of the next vaccination. Early evaluation demonstrates the benefits of such a system in supporting and improving vaccination of children. Finally, we conducted a qualitative study to assess challenges in remote health data collection and evaluated usability and functionality of KenVACS.

  20. Solid lipid nanoparticles for oral drug delivery: chitosan coating improves stability, controlled delivery, mucoadhesion and cellular uptake.

    Science.gov (United States)

    Luo, Yangchao; Teng, Zi; Li, Ying; Wang, Qin

    2015-05-20

    The poor stability of solid lipid nanoparticles (SLN) under acidic condition resulted in large aggregation in gastric environment, limiting their application as oral delivery systems. In this study, a series of SLN was prepared to investigate the effects of surfactant/cosurfactant and chitosan coating on their physicochemical properties as well as cellular uptake. SLN was prepared from Compritol 888 ATO using a low-energy method combining the solvent-diffusion and hot homogenization technique. Poloxamer 188 and polyethylene glycol (PEG) were effective emulsifiers to produce SLN with better physicochemical properties than SLN control. Chitosan-coated SLN exhibited the best stability under acidic condition by forming a thick layer around the lipid core, as clearly observed by transmission electron microscope. The intermolecular interactions in different formulations were monitored by Fourier transform infrared spectroscopy. Chitosan coating also significantly improved the mucoadhesive property of SLN as determined by Quartz Crystal Microbalance. In vitro drug delivery assays, cytotoxicity, and cellular uptake of SLN were studied by incorporating coumarin 6 as a fluorescence probe. Overall, chitosan-coated SLN was superior to other formulations and held promising features for its application as a potential oral drug delivery system for hydrophobic drugs.

  1. Condensed cellular seeded collagen gel as an improved biomaterial for tissue engineering of articular cartilage.

    Science.gov (United States)

    Mueller-Rath, Ralf; Gavénis, Karsten; Andereya, Stefan; Mumme, Torsten; Albrand, Monique; Stoffel, Marcus; Weichert, Dieter; Schneider, Ulrich

    2010-01-01

    Three-dimensional autologous chondrocyte implantation based on collagen gel as matrix scaffold has become a clinically applied treatment for focal defects of articular cartilage. However, the low biomechanical properties of collagen gel makes intraoperative handling difficult and creates the risk of early damages to the vulnerable implant. The aim of the study was to create a stabilized form of collagen gel and to evaluate its biomechanical and biochemical properties.Collagen type-I gel was seeded with human articular chondrocytes. 20 samples were subject to condensation which was achieved mechanically by compression and filtration. Control samples were left uncondensed. From both types of gels 10 samples were used for initial biomechanical evaluation by means of unconfined compression and 10 samples were cultivated under standard conditions in vitro. Following cultivation the samples were evaluated by conventional histology and immunohistochemistry. The proliferation rate was calculated and matrix gene expression was quantified by real-time PCR.The biomechanical tests revealed a higher force carrying capacity of the condensed specimens. Strain rate dependency and relaxation was seen in both types of collagen gel representing viscoelastic material properties. Cells embedded within the condensed collagen gel were able to produce extracellular matrix proteins and showed proliferation.Condensed collagen gel represents a mechanically improved type of biomaterial which is suitable for three-dimensional autologous chondrocyte implantation.

  2. Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells: A NOVEL ROLE FOR PROTEIN KINASE D (PKD).

    Science.gov (United States)

    Wang, Jia; Sinnett-Smith, James; Stevens, Jan V; Young, Steven H; Rozengurt, Enrique

    2016-08-19

    We examined the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in intestinal epithelial cells. Our results show that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II, a potent mitogen for these cells, induced rapid translocation of YAP from the nucleus to the cytoplasm (within 15 min) and a concomitant increase in YAP phosphorylation at Ser(127) and Ser(397) Angiotensin II elicited YAP phosphorylation and cytoplasmic accumulation in a dose-dependent manner (ED50 = 0.3 nm). Similar YAP responses were provoked by stimulation with vasopressin or serum. Treatment of the cells with the protein kinase D (PKD) family inhibitors CRT0066101 and kb NB 142-70 prevented the increase in YAP phosphorylation on Ser(127) and Ser(397) via Lats2, YAP cytoplasmic accumulation, and increase in the mRNA levels of YAP/TEAD-regulated genes (Ctgf and Areg). Furthermore, siRNA-mediated knockdown of PKD1, PKD2, and PKD3 markedly attenuated YAP nuclear-cytoplasmic shuttling, phosphorylation at Ser(127), and induction of Ctgf and Areg expression in response to GPCR activation. These results identify a novel role for the PKD family in the control of biphasic localization, phosphorylation, and transcriptional activity of YAP in intestinal epithelial cells. In turn, YAP and TAZ are necessary for the stimulation of the proliferative response of intestinal epithelial cells to GPCR agonists that act via PKD. The discovery of interaction between YAP and PKD pathways identifies a novel cross-talk in signal transduction and demonstrates, for the first time, that the PKDs feed into the YAP pathway.

  3. Structure of modified [epsilon]-polylysine micelles and their application in improving cellular antioxidant activity of curcuminoids

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Hailong; Li, Ji; Shi, Ke; Huang, Qingrong (Rutgers)

    2015-10-15

    The micelle structure of octenyl succinic anhydride modified {var_epsilon}-polylysine (M-EPL), an anti-microbial surfactant prepared from natural peptide {var_epsilon}-polylysine in aqueous solution has been studied using synchrotron small-angle X-ray scattering (SAXS). Our results revealed that M-EPLs formed spherical micelles with individual size of 24-26 {angstrom} in aqueous solution which could further aggregate to form a larger dimension with averaged radius of 268-308 {angstrom}. Furthermore, M-EPL micelle was able to encapsulate curcuminoids, a group of poorly-soluble bioactive compounds from turmeric with poor oral bioavailability, and improve their water solubility. Three loading methods, including solvent evaporation, dialysis, and high-speed homogenization were compared. The results indicated that the dialysis method generated the highest loading capacity and curcuminoids water solubility. The micelle encapsulation was confirmed as there were no free curcuminoid crystals detected in the differential scanning calorimetry analysis. It was also demonstrated that M-EPL encapsulation stabilized curcuminoids against hydrolysis at pH 7.4 and the encapsulated curcuminoids showed elevated cellular antioxidant activity compared with free curcuminoids. This work suggested that M-EPL could be used as new biopolymer micelles for delivering poorly soluble drugs/phytochemicals and improving their bioactivities.

  4. Crystal Structures of the Nuclear Receptor, Liver Receptor Homolog 1, Bound to Synthetic Agonists.

    Science.gov (United States)

    Mays, Suzanne G; Okafor, C Denise; Whitby, Richard J; Goswami, Devrishi; Stec, Józef; Flynn, Autumn R; Dugan, Michael C; Jui, Nathan T; Griffin, Patrick R; Ortlund, Eric A

    2016-12-02

    Liver receptor homolog 1 (NR5A2, LRH-1) is an orphan nuclear hormone receptor that regulates diverse biological processes, including metabolism, proliferation, and the resolution of endoplasmic reticulum stress. Although preclinical and cellular studies demonstrate that LRH-1 has great potential as a therapeutic target for metabolic diseases and cancer, development of LRH-1 modulators has been difficult. Recently, systematic modifications to one of the few known chemical scaffolds capable of activating LRH-1 failed to improve efficacy substantially. Moreover, mechanisms through which LRH-1 is activated by synthetic ligands are entirely unknown. Here, we use x-ray crystallography and other structural methods to explore conformational changes and receptor-ligand interactions associated with LRH-1 activation by a set of related agonists. Unlike phospholipid LRH-1 ligands, these agonists bind deep in the pocket and do not interact with residues near the mouth nor do they expand the pocket like phospholipids. Unexpectedly, two closely related agonists with similar efficacies (GSK8470 and RJW100) exhibit completely different binding modes. The dramatic repositioning is influenced by a differential ability to establish stable face-to-face π-π-stacking with the LRH-1 residue His-390, as well as by a novel polar interaction mediated by the RJW100 hydroxyl group. The differing binding modes result in distinct mechanisms of action for the two agonists. Finally, we identify a network of conserved water molecules near the ligand-binding site that are important for activation by both agonists. This work reveals a previously unappreciated complexity associated with LRH-1 agonist development and offers insights into rational design strategies.

  5. An improved Cellular Automata model to simulate the behavior of high density crowd and validation by experimental data

    Science.gov (United States)

    Feliciani, Claudio; Nishinari, Katsuhiro

    2016-06-01

    In this article we present an improved version of the Cellular Automata floor field model making use of a sub-mesh system to increase the maximum density allowed during simulation and reproduce phenomena observed in dense crowds. In order to calibrate the model's parameters and to validate it we used data obtained from an empirical observation of bidirectional pedestrian flow. A good agreement was found between numerical simulation and experimental data and, in particular, the double outflow peak observed during the formation of deadlocks could be reproduced in numerical simulations, thus allowing the analysis of deadlock formation and dissolution. Finally, we used the developed high density model to compute the flow-ratio dependent fundamental diagram of bidirectional flow, demonstrating the instability of balanced flow and predicting the bidirectional flow behavior at very high densities. The model we presented here can be used to prevent dense crowd accidents in the future and to investigate the dynamics of the accidents which already occurred in the past. Additionally, fields such as granular and active matter physics may benefit from the developed framework to study different collective phenomena.

  6. Dual-drug delivery by porous silicon nanoparticles for improved cellular uptake, sustained release, and combination therapy.

    Science.gov (United States)

    Wang, Chang-Fang; Mäkilä, Ermei M; Kaasalainen, Martti H; Hagström, Marja V; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

    2015-04-01

    Dual-drug delivery of antiangiogenic and chemotherapeutic drugs can enhance the therapeutic effect for cancer therapy. Conjugation of methotrexate (MTX) to porous silicon (PSi) nanoparticles (MTX-PSi) with positively charged surface can improve the cellular uptake of MTX and inhibit the proliferation of cancer cells. Herein, MTX-PSi conjugates sustained the release of MTX up to 96 h, and the released fragments including MTX were confirmed by mass spectrometry. The intracellular distribution of the MTX-PSi nanoparticles was confirmed by transmission electron microscopy. Compared to pure MTX, the MTX-PSi achieved similar inhibition of cell proliferation in folate receptor (FR) over-expressing U87 MG cancer cells, and a higher effect in low FR-expressing EA.hy926 cells. Nuclear fragmentation analysis demonstrated programmed cell apoptosis of MTX-PSi in the high/low FR-expressing cancer cells, whereas PSi alone at the same dose had a minor effect on cell apoptosis. Finally, the porous structure of MTX-PSi enabled a successful concomitant loading of another anti-angiogenic hydrophobic drug, sorafenib, and considerably enhanced the dissolution rate of sorafenib. Overall, the MTX-PSi nanoparticles can be used as a platform for combination chemotherapy by simultaneously enhancing the dissolution rate of a hydrophobic drug and sustaining the release of a conjugated chemotherapeutic drug.

  7. PPAR Agonists and Cardiovascular Disease in Diabetes

    Directory of Open Access Journals (Sweden)

    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, PPAR 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 PPAR agonists, and more recently dual PPAR/ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPAR 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.

  8. PPAR Agonists and Cardiovascular Disease in Diabetes

    Science.gov (United States)

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    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. PMID:18288280

  9. PPAR Agonists and Cardiovascular Disease in Diabetes.

    Science.gov (United States)

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

    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, PPARalpha 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 PPARgamma agonists, and more recently dual PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARgamma 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.

  10. Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea.

    Science.gov (United States)

    Sato, Hiroyuki; Genet, Cédric; Strehle, Axelle; Thomas, Charles; Lobstein, Annelise; Wagner, Alain; Mioskowski, Charles; Auwerx, Johan; Saladin, Régis

    2007-11-03

    Olive tree (Olea europeaea) leaves are well known for their effect on metabolism in particular as a traditional anti-diabetic and anti-hypertensive herbal drug. These properties are until now only attributed to oleuropein, the major secoiridoid of olive leaves. Here we describe the isolation and the identification of another constituent implicated in the anti-diabetic effect of this plant, i.e. oleanolic acid. We show that this triterpene is an agonist for TGR5, a member of G-protein coupled receptor activated by bile acids and which mediates some of their various cellular and physiological effect. Oleanolic acid lowers serum glucose and insulin levels in mice fed with a high fat diet and it enhances glucose tolerance. Our data suggest that both oleuropein and oleanolic acid are involved in the anti-diabetic effect of olive leaves and further emphasize the potential role of TGR5 agonists to improve metabolic disorders.

  11. APD668, a G protein-coupled receptor 119 agonist improves fat tolerance and attenuates fatty liver in high-trans fat diet induced steatohepatitis model in C57BL/6 mice.

    Science.gov (United States)

    Bahirat, Umakant Ashok; Shenoy, Rekha Raghuveer; Goel, Rajan Naresh; Nemmani, Kumar V S

    2017-04-15

    G-protein coupled receptor 119 (GPR119) receptor is a rhodopsin-like, class A Gαs-coupled receptor, predominantly expressed in pancreatic islet cells and intestinal entero-endocrine cells. GPR119 has been emerged as a novel therapeutic target for the treatment of dyslipidemia in type 2 diabetes. In this study, we investigated the effect of APD668, a GPR119 agonist alone and in combination with linagliptin, a DPPIV inhibitor on oral fat tolerance test. Our findings demonstrate that APD668, a GPR119 agonist inhibits the intestinal triglyceride absorption after acute fat load in mice. Single dose administration of APD668 increases incretin secretion and enhances total PYY levels in presence of fat load in mice. We found that, the anti-dyslipidemic action of APD668 was reversed in presence of exendin-3 in oral fat tolerance test. In addition, our results showed that exendin-3 (9-39) failed to block the effect of APD668 on gastric emptying indicating that gastric emptying effects of APD668 are indeed mediated through GPR119 receptor dependent mechanism. Combined administration of APD668 and linagliptin significantly increased plasma active GLP-1 levels in-vivo and showed improvement in fat tolerance. However, APD668 failed to show anti-dyslipidemic activity in tyloxapol-induced hyperlipidemia in mice. Furthermore, we investigated the chronic effects of APD668 on hepatic steatosis in high trans-fat diet fed steatohepatitis model in mice. Oral administration of APD668 in HTF diet fed mice ameliorated hepatic endpoints such as plasma ALT, AST, liver weight and steatosis. These findings suggest that GPR119 agonists may represent a promising therapeutic strategy for the treatment of dyslipidemia and non-alcoholic steatohepatitis.

  12. [Melatonin receptor agonist].

    Science.gov (United States)

    Uchiyama, Makoto

    2015-06-01

    Melatonin is a hormone secreted by the pineal gland and is involved in the regulation of human sleep-wake cycle and circadian rhythms. The melatonin MT1 and MT2 receptors located in the suprachiasmatic nucleus in the hypothalamus play a pivotal role in the sleep-wake regulation. Based on the fact that MT1 receptors are involved in human sleep onset process, melatonin receptor agonists have been developed to treat insomnia. In this article, we first reviewed functions of melatonin receptors with special reference to MT1 and MT2, and properties and clinical application of melatonin receptor agonists as hypnotics.

  13. Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density and improve heart function in a rat cellular cardiomyoplasty model

    Institute of Scientific and Technical Information of China (English)

    SDAVANI; NMERSIN; BROYER; BKANTELIP; JPKANTELIP

    2004-01-01

    AIM: Cellular cardiomyoplasty is promising for improving postinfarcted cardiac function. Over the past decade, a variety of cell types have been proposed including mononuclear bone marrow cells. The latter contains different lineages including mesenchymal stem cells (MSCs). The aim of this study was to analyse the differentiation pathways of engrafted syngenic mesenchymal progenitor cells (MPCs) obtained in culture from bone marrow

  14. Insights into the mechanisms of ifosfamide encephalopathy: drug metabolites have agonistic effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and induce cellular acidification in mouse cortical neurons.

    Science.gov (United States)

    Chatton, J Y; Idle, J R; Vågbø, C B; Magistretti, P J

    2001-12-01

    Therapeutic value of the alkylating agent ifosfamide has been limited by major side effects including encephalopathy. Although the underlying biochemical processes of the neurotoxic side effects are still unclear, they could be attributed to metabolites rather than to ifosfamide itself. In the present study, the effects of selected ifosfamide metabolites on indices of neuronal activity have been investigated, in particular for S-carboxymethylcysteine (SCMC) and thiodiglycolic acid (TDGA). Because of structural similarities of SCMC with glutamate, the Ca(2+)(i) response of single mouse cortical neurons to SCMC and TDGA was investigated. SCMC, but not TDGA, evoked a robust increase in Ca(2+)(i) concentration that could be abolished by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but only partly diminished by the N-methyl-D-aspartate receptor antagonist 10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK=801). Cyclothiazide (CYZ), used to prevent AMPA/kainate receptor desensitization, potentiated the response to SCMC. Because activation of AMPA/kainate receptors is known to induce proton influx, the intracellular pH (pH(i)) response to SCMC was investigated. SCMC caused a concentration-dependent acidification that was amplified by CYZ. Since H(+)/monocarboxylate transporter (MCT) activity leads to similar cellular acidification, we tested its potential involvement in the pH(i) response. Application of the lactate transport inhibitor quercetin diminished the pH(i) response to SCMC and TDGA by 43 and 51%, respectively, indicating that these compounds may be substrates of MCTs. Taken together, this study indicates that hitherto apparently inert ifosfamide metabolites, in particular SCMC, activate AMPA/kainate receptors and induce cellular acidification. Both processes could provide the biochemical basis of the observed ifosfamide-associated encephalopathy.

  15. PARTIAL AGONISTS, FULL AGONISTS, ANTAGONISTS - DILEMMAS OF DEFINITION

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

    1993-01-01

    The absence of selective antagonists makes receptor characterization difficult, and largely dependent on the use of agonists. However, there has been considerable debate as to whether certain drugs acting at G protein-coupled receptors are better described as agonists, partial agonists or antagonist

  16. Early controlled release of peroxisome proliferator-activated receptor β/δ agonist GW501516 improves diabetic wound healing through redox modulation of wound microenvironment.

    Science.gov (United States)

    Wang, Xiaoling; Sng, Ming Keat; Foo, Selin; Chong, Han Chung; Lee, Wei Li; Tang, Mark Boon Yang; Ng, Kee Woei; Luo, Baiwen; Choong, Cleo; Wong, Marcus Thien Chong; Tong, Benny Meng Kiat; Chiba, Shunsuke; Loo, Say Chye Joachim; Zhu, Pengcheng; Tan, Nguan Soon

    2015-01-10

    Diabetic wounds are imbued with an early excessive and protracted reactive oxygen species production. Despite the studies supporting PPARβ/δ as a valuable pharmacologic wound-healing target, the therapeutic potential of PPARβ/δ agonist GW501516 (GW) as a wound healing drug was never investigated. Using topical application of polymer-encapsulated GW, we revealed that different drug release profiles can significantly influence the therapeutic efficacy of GW and consequently diabetic wound closure. We showed that double-layer encapsulated GW microparticles (PLLA:PLGA:GW) provided an earlier and sustained dose of GW to the wound and reduced the oxidative wound microenvironment to accelerate healing, in contrast to single-layered PLLA:GW microparticles. The underlying mechanism involved an early GW-mediated activation of PPARβ/δ that stimulated GPx1 and catalase expression in fibroblasts. GPx1 and catalase scavenged excessive H2O2 accumulation in diabetic wound beds, prevented H2O2-induced ECM modification and facilitated keratinocyte migration. The microparticles with early and sustained rate of GW release had better therapeutic wound healing activity. The present study underscores the importance of drug release kinetics on the therapeutic efficacy of the drug and warrants investigations to better appreciate the full potential of controlled drug release.

  17. A novel Dual Amylin and Calcitonin Receptor Agonist (DACRA), KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference

    DEFF Research Database (Denmark)

    Gydesen, Sofie; Hjuler, Sara Toftegaard; Freving, Zenia

    2017-01-01

    amylin and calcitonin receptor agonist (DACRA), KBP-089, on bodyweight, glucose homeostasis, and fatty acid accumulation in liver and muscle tissue, food preference was investigated. Further, we elucidate weight-independent effects of KBP-089 using a weight-matched group. Key Results High fat diet fed......Background and Purpose Obesity and associated co-morbidities, such as type 2 diabetes and non-alcoholic fatty liver disease, are major health challenges – hence, development of weight loss therapies with the ability to reduce the co-morbidities is key. Experimental Approach The effect of the dual...... rats were treated with KBP-089 s.c., at 0.625, 1.25, 2.5 µg∙kg-1 and vehicle resulting in a dose-dependent and sustained ~17% weight loss by the 2.5 µg∙kg-1 (p fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBP-089...

  18. Improved cellular uptake of antisense Peptide nucleic acids by conjugation to a cell-penetrating Peptide and a lipid domain

    DEFF Research Database (Denmark)

    Shiraishi, Takehiko; Nielsen, Peter E

    2011-01-01

    Unaided cellular uptake of RNA interference agents such as antisense oligonucleotides and siRNA is extremely poor, and in vivo bioavailability is also limited. Thus, effective delivery strategies for such potential drugs are in high demand. Recently, a novel approach using a class of short cationic...

  19. Melatonin agonists and insomnia.

    Science.gov (United States)

    Ferguson, Sally A; Rajaratnam, Shantha M W; Dawson, Drew

    2010-02-01

    The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials.

  20. Endogenous Receptor Agonists: Resolving Inflammation

    Directory of Open Access Journals (Sweden)

    Gerhard Bannenberg

    2007-01-01

    Full Text Available 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 polyunsaturated fatty acids (PUFA–derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS–based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA. These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.

  1. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    Science.gov (United States)

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation.

  2. Structural modifications of the serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-biphenyl)-1-piperazinehexanamide (LP-211) to improve in vitro microsomal stability: A case study.

    Science.gov (United States)

    Lacivita, Enza; Podlewska, Sabina; Speranza, Luisa; Niso, Mauro; Satała, Grzegorz; Perrone, Roberto; Perrone-Capano, Carla; Bojarski, Andrzej J; Leopoldo, Marcello

    2016-09-14

    The 5-HT7 serotonin receptor is revealing a promising target for innovative therapeutic strategies of neurodevelopmental and neuropsychiatric disorders. Here, we report the synthesis of thirty long-chain arylpiperazine analogs of the selective and brain penetrant 5-HT7 receptor agonist LP-211 (1) designed to enhance stability towards microsomal oxidative metabolism. Commonly used medicinal chemistry strategies were used (i.e., reduction of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metabolism), and in vitro microsomal stability was tested. The data showed that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compounds was related to the presence of specific substituents in well-defined regions of the molecule. The collected data allowed for the construction of a machine learning model that, in a given chemical space, is able to describe and quantitatively predict the metabolic stability of the compounds. The majority of the synthesized compounds maintained high affinity for 5-HT7 receptors and showed selectivity towards 5-HT6 and dopamine D2 receptors and different selectivity for 5-HT1A and α1 adrenergic receptors. Compound 50 showed 3-fold higher in vitro stability towards oxidative metabolism than 1 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 receptor in a shorter time and at a lower concentration than the agonist 1. A preliminary disposition study in mice revealed that compound 50 was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 receptor in vivo.

  3. Carbon dioxide enrichment alleviates heat stress by improving cellular redox homeostasis through an ABA-independent process in tomato plants.

    Science.gov (United States)

    Li, X; Ahammed, G J; Zhang, Y Q; Zhang, G Q; Sun, Z H; Zhou, J; Zhou, Y H; Xia, X J; Yu, J Q; Shi, K

    2015-01-01

    Plant responses to elevated CO₂ and high temperature are critically regulated through a complex network of phytohormones and redox homeostasis. However, the involvement of abscisic acid (ABA) in plant adaptation to heat stress under elevated CO₂ conditions has not been thoroughly studied. This study investigated the interactive effects of elevated CO₂ (800 μmol·mol(-1) ) and heat stress (42 °C for 24 h) on the endogenous level of ABA and the cellular redox state of two genotypes of tomato with different ABA biosynthesis capacities. Heat stress significantly decreased maximum photochemical efficiency of PSII (Fv/Fm) and leaf water potential, but also increased levels of malondialdehyde (MDA) and electrolyte leakage (EL) in both genotypes. Heat-induced damage was more severe in the ABA-deficient mutant notabilis (not) than in its parental cultivar Ailsa Craig (Ailsa), suggesting that a certain level of endogenous ABA is required to minimise the heat-induced oxidative damage to the photosynthetic apparatus. Irrespective of genotype, the enrichment of CO₂ remarkably stimulated Fv/Fm, MDA and EL in heat-stressed plants towards enhanced tolerance. In addition, elevated CO₂ significantly strengthened the antioxidant capacity of heat-stressed tomato seedlings towards a reduced cellular redox state for a prolonged period, thereby mitigating oxidative stress. However, elevated CO₂ and heat stress did not alter the endogenous level of ABA or the expression of its biosynthetic gene NCED2 in either genotype, indicating that ABA is not involved in elevated CO₂ -induced heat stress alleviation. The results of this study suggest that elevated CO₂ alleviated heat stress through efficient regulation of the cellular redox poise in an ABA-independent manner in tomato plants.

  4. The cytotoxicity of polycationic iron oxide nanoparticles: Common endpoint assays and alternative approaches for improved understanding of cellular response mechanism

    Directory of Open Access Journals (Sweden)

    Hoskins Clare

    2012-04-01

    Full Text Available Abstract Background Iron oxide magnetic nanoparticles (MNP's have an increasing number of biomedical applications. As such in vitro characterisation is essential to ensure the bio-safety of these particles. Little is known on the cellular interaction or effect on membrane integrity upon exposure to these MNPs. Here we synthesised Fe3O4 and surface coated with poly(ethylenimine (PEI and poly(ethylene glycol (PEG to achieve particles of varying surface positive charges and used them as model MNP's to evaluate the relative utility and limitations of cellular assays commonly applied for nanotoxicity assessment. An alternative approach, atomic force microscopy (AFM, was explored for the analysis of membrane structure and cell morphology upon interacting with the MNPs. The particles were tested in vitro on human SH-SY5Y, MCF-7 and U937 cell lines for reactive oxygen species (ROS production and lipid peroxidation (LPO, LDH leakage and their overall cytotoxic effect. These results were compared with AFM topography imaging carried out on fixed cell lines. Results Successful particle synthesis and coating were characterised using FTIR, PCS, TEM and ICP. The particle size from TEM was 30 nm (−16.9 mV which increased to 40 nm (+55.6 mV upon coating with PEI and subsequently 50 nm (+31.2 mV with PEG coating. Both particles showed excellent stability not only at neutral pH but also in acidic environment of pH 4.6 in the presence of sodium citrate. The higher surface charge MNP-PEI resulted in increased cytotoxic effect and ROS production on all cell lines compared with the MNP-PEI-PEG. In general the effect on the cell membrane integrity was observed only in SH-SY5Y and MCF-7 cells by MNP-PEI determined by LDH leakage and LPO production. AFM topography images showed consistently that both the highly charged MNP-PEI and the less charged MNP-PEI-PEG caused cell morphology changes possibly due to membrane disruption and cytoskeleton remodelling. Conclusions

  5. Pharmacogenetics of β2-Agonists

    OpenAIRE

    Nobuyuki Hizawa

    2011-01-01

    Short-acting β2-agonists (SABAs) and long-acting β2-agonists (LABAs) are both important for treatment of asthma and chronic obstructive pulmonary disease (COPD) because of their bronchodilator and bronchoprotective effects. However, the use of these agonists, at least for asthma, has generated some controversy because of their association with increased mortality. Pharmacogenetics is the study of genetically determined variation in response to medications, which might prove useful for target ...

  6. 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...

  7. On the area spectral efficiency improvement of heterogeneous network by exploiting the integration of macro-femto cellular networks

    KAUST Repository

    Shakir, Muhammad

    2012-06-01

    Heterogeneous networks are an attractive means of expanding mobile network capacity. A heterogeneous network is typically composed of multiple radio access technologies (RATs) where the base stations are transmitting with variable power. In this paper, we consider a Heterogeneous network where we complement the macrocell network with low-power low-cost user deployed nodes, such as femtocell base stations to increase the mean achievable capacity of the system. In this context, we integrate macro-femto cellular networks and derive the area spectral efficiency of the proposed two tier Heterogeneous network. We consider the deployment of femtocell base stations around the edge of the macrocell such that this configuration is referred to as femto-on-edge (FOE) configuration. Moreover, FOE configuration mandates reduction in intercell interference due to the mobile users which are located around the edge of the macrocell since these femtocell base stations are low-power nodes which has significantly lower transmission power than macrocell base stations. We present a mathematical analysis to calculate the instantaneous carrier to interference ratio (CIR) of the desired mobile user in macro and femto cellular networks and determine the total area spectral efficiency of the Heterogeneous network. Details of the simulation processes are included to support the analysis and show the efficacy of the proposed deployment. It has been shown that the proposed setup of the Heterogeneous network offers higher area spectral efficiency which aims to fulfill the expected demand of the future mobile users. © 2012 IEEE.

  8. Green propolis phenolic compounds act as vaccine adjuvants, improving humoral and cellular responses in mice inoculated with inactivated vaccines

    Directory of Open Access Journals (Sweden)

    Geferson Fischer

    2010-11-01

    Full Text Available Adjuvants play an important role in vaccine formulations by increasing their immunogenicity. In this study, the phenolic compound-rich J fraction (JFR of a Brazilian green propolis methanolic extract stimulated cellular and humoral immune responses when co-administered with an inactivated vaccine against swine herpesvirus type 1 (SuHV-1. When compared to control vaccines that used aluminium hydroxide as an adjuvant, the use of 10 mg/dose of JFR significantly increased (p < 0.05 neutralizing antibody titres against SuHV-1, as well as the percentage of protected animals following SuHV-1 challenge (p < 0.01. Furthermore, addition of phenolic compounds potentiated the performance of the control vaccine, leading to increased cellular and humoral immune responses and enhanced protection of animals after SuHV-1 challenge (p < 0.05. Prenylated compounds such as Artepillin C that are found in large quantities in JFR are likely to be the substances that are responsible for the adjuvant activity.

  9. 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...

  10. Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Han, Xiang Hua [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Hak-Ju [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of); Hwang, Bang Yeon, E-mail: byhwang@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Sung-Joon, E-mail: junelee@korea.ac.kr [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

  11. Cellular automata

    CERN Document Server

    Codd, E F

    1968-01-01

    Cellular Automata presents the fundamental principles of homogeneous cellular systems. This book discusses the possibility of biochemical computers with self-reproducing capability.Organized into eight chapters, this book begins with an overview of some theorems dealing with conditions under which universal computation and construction can be exhibited in cellular spaces. This text then presents a design for a machine embedded in a cellular space or a machine that can compute all computable functions and construct a replica of itself in any accessible and sufficiently large region of t

  12. Synthetic High-Density Lipoprotein-Like Nanocarrier Improved Cellular Transport of Lysosomal Cholesterol in Human Sterol Carrier Protein-Deficient Fibroblasts.

    Science.gov (United States)

    Nam, Da-Eun; Kim, Ok-Kyung; Park, Yoo Kyoung; Lee, Jeongmin

    2016-01-01

    Sterol carrier protein-2 (SCP-2), which is not found in tissues of people with Zellweger syndrome, facilitates the movement of cholesterol within cells, resulting in abnormal accumulation of cholesterol in SCP-2-deficient cells. This study investigated whether synthetic high-density lipoprotein-like nanocarrier (sHDL-NC) improves the cellular transport of lysosomal cholesterol to plasma membrane in SCP-2-deficient fibroblasts. Human SCP-2-deficient fibroblasts were incubated with [(3)H-cholesterol]LDL as a source of cholesterol and sHDL-NC. The cells were fractionated by centrifugation permit tracking of [(3)H]-cholesterol from lysosome into plasma membrane. Furthermore, cellular content of cholesteryl ester as a storage form and mRNA expression of low-density lipoprotein (LDL) receptor were measured to support the cholesterol transport to plasma membrane. Incubation with sHDL-NC for 8 h significantly increased uptake of [(3)H]-cholesterol to lysosome by 53% and further enhanced the transport of [(3)H]-cholesterol to plasma membrane by 32%. Treatment with sHDL-NC significantly reduced cellular content of cholesteryl ester and increased mRNA expression of LDL receptor (LDL-R). In conclusion, sHDL-NC enables increased transport of lysosomal cholesterol to plasma membrane. In addition, these data were indirectly supported by decreased cellular content of cholesteryl ester and increased gene expression of LDL-R. Therefore, sHDL-NC may be a useful vehicle for transporting cholesterol, which may help to prevent accumulation of cholesterol in SCP-2-deficient fibroblasts.

  13. Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats

    Directory of Open Access Journals (Sweden)

    Chen Z

    2012-07-01

    Full Text Available Zhongya Chen,1,2 Jiaxin Deng,1,2 Yan Zhao,1,2 Tao Tao1,21National Pharmaceutical Engineering Research Center, 2Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of ChinaBackground: Integrins αvβ3 and αvβ5, both of which specifically recognize the Arg-Gly-Asp (RGD motif, are overexpressed on many solid tumors and in tumor neovasculature. Thus, coupling the RGD motif to the liposomal surface for achieving active targeting can be a promising strategy for the treatment of tumors.Methods: Cyclo(Arg-Gly-Asp-D-Phe-Cys (cRGD was covalently coupled with the liposomal membrane surface, followed by coating with poly(ethylene glycol (PEG using the post-insertion technique. The coupling efficiency of cRGD was determined. Doxorubicin as a model anticancer drug was loaded into liposomes using an ammonium sulfate gradient method to investigate the encapsulation efficiency, cellular uptake by the integrin-overexpressing human glioma cell line U87MG in vitro, and pharmacokinetic properties in Sprague-Dawley rats.Results: cRGD was conjugated to the liposomal surface by a thiol-maleimide coupling reaction. The coupling efficiency reached 98%. The encapsulation efficiency of doxorubicin in liposomes was more than 98%. The flow cytometry test result showed that cRGD-modified liposomes (RGD-DXRL-PEG had higher cell uptake by U87MG cells, compared with nontargeted liposomes (DXRL-PEG. The cellular uptake was significantly inhibited in the presence of excess free cRGD. Both the targeted (t1/2 = 24.10 hours and non-targeted (t1/2 = 25.32 hours liposomes showed long circulating properties in rat plasma. The area under the curve of the targeted and nontargeted liposomes was 6.4-fold and 8.3-fold higher than that of doxorubicin solution, respectively.Conclusion: This study indicates preferential targeting and long circulating properties for cRGD-modified liposomes in vivo, which could be used as

  14. Sublingual administration of an adenovirus serotype 5 (Ad5)-based vaccine confirms Toll-like receptor agonist activity in the oral cavity and elicits improved mucosal and systemic cell-mediated responses against HIV antigens despite preexisting Ad5 immunity.

    Science.gov (United States)

    Appledorn, Daniel M; Aldhamen, Yasser A; Godbehere, Sarah; Seregin, Sergey S; Amalfitano, Andrea

    2011-01-01

    HIV/AIDS continue to devastate populations worldwide. Recent studies suggest that vaccines that induce beneficial immune responses in the mucosal compartment may improve the efficacy of HIV vaccines. Adenovirus serotype 5 (Ad5)-based vectors remain a promising platform for the development of effective vaccines. In an effort to improve the efficacy of Ad5-based vaccines, even in the presence of preexisting Ad5 immunity, we evaluated the potential for an Ad5-based HIV vaccine to induce antigen-specific immune responses following sublingual (s.l.) administration, a route not previously tested in regard to Ad-based vaccines. s.l. vaccination with an Ad5-based HIV-Gag vaccine resulted in a significant induction of Gag-specific cytotoxic T-lymphocyte (CTL) responses in both the systemic and the mucosal compartment. We also show that s.l. immunization not only avoided preexisting Ad5 immunity but also elicited a broad repertoire of antigen-specific CTL clones. Additionally, we confirm for the first time that oral delivery of a vaccine expressing a potent Toll-like receptor (TLR) agonist can stimulate innate immune responses through induction of cytokines and chemokines and activation of NK cells, NKT cells, and macrophages in vivo. These results positively correlated with improved antigen-specific CTL responses. These results could be achieved both in Ad5-naïve mice and in mice with preexisting immunity to Ad5. The simplicity of the s.l. vaccination regimen coupled with augmentation of TLR-dependent pathways active in the oral cavity makes s.l. delivery a promising method for HIV vaccine development specifically, as well as for many other vaccine applications in general.

  15. (Val(8))GLP-1-Glu-PAL: a GLP-1 agonist that improves hippocampal neurogenesis, glucose homeostasis, and β-cell function in high-fat-fed mice.

    Science.gov (United States)

    Lennox, Rachael; Porter, David W; Flatt, Peter R; Gault, Victor A

    2013-04-01

    This study examined the biological properties of a novel GLP-1 peptide, (Val(8))GLP-1-Glu-PAL, engineered with an Ala(8)→Val(8) substitution and additional incorporation of a C(16) fatty acid moiety at Lys(26) via a glutamic acid linker. GLP-1 underwent 75 % degradation by DPP-IV over 8 h, whereas (Val(8))GLP-1 and (Val(8))GLP-1-Glu-PAL remained intact. All GLP-1 peptides significantly stimulated insulin secretion at 5.6 mM (1.3- to 4.9-fold, pGLP-1-Glu-PAL was significantly more potent at stimulating insulin secretion (1.2- to 1.3-fold, pGLP-1 peptides significantly lowered plasma glucose concentrations (41-66 % decrease, pGLP-1-Glu-PAL eliciting protracted glucose-lowering actions (32-59 % decrease, pGLP-1-Glu-PAL in high-fat-fed mice for 21 days had no effect on bodyweight or food intake, but significantly lowered non-fasting plasma glucose (43-46 % decrease, pGLP-1-Glu-PAL markedly decreased glycemic excursion following intraperitoneal glucose (32-48 % decrease, pGLP-1-Glu-PAL therapy. Treatment with (Val(8))GLP-1-Glu-PAL resulted in a significant increase in BrdU-positive cells (1.3-fold, pGLP-1-Glu-PAL is a long-acting GLP-1 peptide that significantly improves hippocampal neurogenesis, glucose homeostasis, and insulin secretion in high-fat-fed mice.

  16. Improving Spectral Capacity and Wireless Network Coverage by Cognitive Radio Technology and Relay Nodes in Cellular Systems

    DEFF Research Database (Denmark)

    Frederiksen, Flemming Bjerge

    2008-01-01

    Methods to enhance the use of the frequency spectrum by automatical spectrum sensing plus spectrum sharing in a cognitive radio technology context have been presented and discussed in this paper. Ideas to improve the wireless transmission by orthogonal OFDM-based communication and to increase the...

  17. Strategies for improvement of spectrum capacity for WiMax cellular systems by Cognitive Radio Technology supported by Relay Stations

    DEFF Research Database (Denmark)

    Frederiksen, Flemming Bjerge; Prasad, Ramjee

    2007-01-01

    Methods to enhance the use of the frequency spectrum by automatical spectrum sensing plus spectrum sharing in a cognitive radio technology context will be presented and discussed in this paper. Ideas to improve the wireless transmission by orthogonal OFDM-based communication and to increase the c...

  18. Histamine H3-receptor inverse agonists as novel antipsychotics.

    Science.gov (United States)

    Ito, Chihiro

    2009-06-01

    Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.

  19. 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

  20. Dopamine Agonists and Pathologic Behaviors

    Directory of Open Access Journals (Sweden)

    Brendan J. Kelley

    2012-01-01

    Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

  1. Divalent folate modification on PEG: an effective strategy for improving the cellular uptake and targetability of PEGylated polyamidoamine-polyethylenimine copolymer.

    Science.gov (United States)

    Cao, Duanwen; Tian, Shouqin; Huang, Huan; Chen, Jianhai; Pan, Shirong

    2015-01-05

    The stability and targeting ability of nanocarrier gene delivery systems are necessary conditions to ensure the good therapeutic effect and low nonspecific toxicity of cancer treatment. Poly(ethylene glycol) (PEG) has been widely applied for improving stability and as a spacer for linking ligands and nanocarriers to improve targetability. However, the cellular uptake and endosomal escape capacity of nanocarriers has been seriously harmed due to the introduction of PEG. In the present study, we synthesized a new gene delivery vector by coupling divalent folate-PEG (PEG3.4k-FA2) onto polyamidoamine-polyethylenimine (PME) copolymer (PME-(PEG3.4k-FA2)1.72). Both PEG and monovalent folate-PEG (PEG3.4k-FA1) modified PME were prepared as control polymers, which were named as PME-(PEG3.5k)1.69 and PME-(PEG3.4k-FA1)1.66, respectively. PME-(PEG3.4k-FA2)1.72 exhibited strong DNA condensation capacity like parent polymer PME which was not significantly influenced by PEG. PME-(PEG3.4k-FA2)1.72/DNA complexes at N/P = 10 had a diameter ∼143 nm and zeta potential ∼13 mV and showed the lowest cytotoxicity and hemolysis and the highest transfection efficiency among all tested polymers. In folate receptor positive (FR-positive) cells, the cellular uptake and transfection efficiency were increased with the increase in the number of folates coupled on PEG; the order was PME-(PEG3.4k-FA2)1.72 > PME-(PEG3.4k-FA1)1.66 > PME-(PEG3.5k)1.69. Folate competition assays showed that PME-(PEG3.4k-FA2)1.72 complexes had stronger targeting ability than PME-(PEG3.5k)1.69 and PME-(PEG3.4k-FA1)1.66 complexes due to their higher folate density per PEG molecule. Cellular uptake mechanism study showed that the folate density on PEG could change the endocytosis pathway of PME-(PEG3.5k)1.69 from clathrin-mediated endocytosis to caveolae-mediated endocytosis, leading to less lysosomal degradation. Distribution and uptake in 3D multicellular spheroid assays showed that divalent folate could offer PME

  2. Development of second generation peptides modulating cellular adiponectin receptor responses

    Science.gov (United States)

    Otvos, Laszlo; Knappe, Daniel; Hoffmann, Ralf; Kovalszky, Ilona; Olah, Julia; Hewitson, Tim; Stawikowska, Roma; Stawikowski, Maciej; Cudic, Predrag; Lin, Feng; Wade, John; Surmacz, Eva; Lovas, Sandor

    2014-10-01

    The adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active adipokines, including adiponectin. Recently we developed and characterized a first-in-class peptide-based adiponectin receptor agonist by using in vitro and in vivo models of glioblastoma and breast cancer (BC). In the current study, we further explored the effects of peptide ADP355 in additional cellular models and found that ADP355 inhibited chronic myeloid leukemia (CML) cell proliferation and renal myofibroblast differentiation with mid-nanomolar IC50 values. According to molecular modeling calculations, ADP355 was remarkably flexible in the global minimum with a turn present in the middle of the peptide. Considering these structural features of ADP355 and the fact that adiponectin normally circulates as multimeric complexes, we developed and tested the activity of a linear branched dimer (ADP399). The dimer exhibited approximately 20-fold improved cellular activity inhibiting K562 CML and MCF-7 cell growth with high pM - low nM relative IC50 values. Biodistribution studies suggested superior tissue dissemination of both peptides after subcutaneous administration relative to intraperitoneal inoculation. After screening of a 397-member adiponectin active site library, a novel octapeptide (ADP400) was designed that counteracted 10-1000 nM ADP355- and ADP399-mediated effects on CML and BC cell growth at nanomolar concentrations. ADP400 induced mitogenic effects in MCF-7 BC cells perhaps due to antagonizing endogenous adiponectin actions or acting as an inverse agonist. While the linear dimer agonist ADP399 meets pharmacological criteria of a contemporary peptide drug lead, the peptide showing antagonist activity (ADP400) at similar concentrations will be an important target validation tool to study adiponectin functions.

  3. Development of second generation peptides modulating cellular adiponectin receptor responses

    Directory of Open Access Journals (Sweden)

    Laszlo eOtvos

    2014-10-01

    Full Text Available The adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active adipokines, including adiponectin. Recently we developed and characterized a first-in-class peptide-based adiponectin receptor agonist by using in vitro and in vivo models of glioblastoma and breast cancer (BC. In the current study, we further explored the effects of peptide ADP355 in additional cellular models and found that ADP355 inhibited chronic myeloid leukemia (CML cell proliferation and renal myofibroblast differentiation with mid-nanomolar IC50 values. According to molecular modeling calculations, ADP355 was remarkably flexible in the global minimum with a turn present in the middle of the peptide. Considering these structural features of ADP355 and the fact that adiponectin normally circulates as multimeric complexes, we developed and tested the activity of a linear branched dimer (ADP399. The dimer exhibited approximately 20-fold improved cellular activity inhibiting K562 CML and MCF-7 cell growth with high pM - low nM relative IC50 values. Biodistribution studies suggested superior tissue dissemination of both peptides after subcutaneous administration relative to intraperitoneal inoculation. After screening of a 397-member adiponectin active site library, a novel octapeptide (ADP400 was designed that counteracted 10-1000 nM ADP355- and ADP399-mediated effects on CML and BC cell growth at nanomolar concentrations. ADP400 induced mitogenic effects in MCF-7 BC cells perhaps due to antagonizing endogenous adiponectin actions or acting as an inverse agonist. While the linear dimer agonist ADP399 meets pharmacological criteria of a contemporary peptide drug lead, the peptide showing antagonist activity (ADP400 at similar concentrations will be an important target validation tool to study adiponectin functions.

  4. Cellular renewal and improvement of local cell effector activity in peritoneal cavity in response to infectious stimuli.

    Directory of Open Access Journals (Sweden)

    Alexandra dos Anjos Cassado

    Full Text Available The peritoneal cavity (PerC is a singular compartment where many cell populations reside and interact. Despite the widely adopted experimental approach of intraperitoneal (i.p. inoculation, little is known about the behavior of the different cell populations within the PerC. To evaluate the dynamics of peritoneal macrophage (MØ subsets, namely small peritoneal MØ (SPM and large peritoneal MØ (LPM, in response to infectious stimuli, C57BL/6 mice were injected i.p. with zymosan or Trypanosoma cruzi. These conditions resulted in the marked modification of the PerC myelo-monocytic compartment characterized by the disappearance of LPM and the accumulation of SPM and monocytes. In parallel, adherent cells isolated from stimulated PerC displayed reduced staining for β-galactosidase, a biomarker for senescence. Further, the adherent cells showed increased nitric oxide (NO and higher frequency of IL-12-producing cells in response to subsequent LPS and IFN-γ stimulation. Among myelo-monocytic cells, SPM rather than LPM or monocytes, appear to be the central effectors of the activated PerC; they display higher phagocytic activity and are the main source of IL-12. Thus, our data provide a first demonstration of the consequences of the dynamics between peritoneal MØ subpopulations by showing that substitution of LPM by a robust SPM and monocytes in response to infectious stimuli greatly improves PerC effector activity.

  5. Multi-parametric cytometry from a complex cellular sample: Improvements and limits of manual versus computational-based interactive analyses.

    Science.gov (United States)

    Gondois-Rey, F; Granjeaud, S; Rouillier, P; Rioualen, C; Bidaut, G; Olive, D

    2016-05-01

    The wide possibilities opened by the developments of multi-parametric cytometry are limited by the inadequacy of the classical methods of analysis to the multi-dimensional characteristics of the data. While new computational tools seemed ideally adapted and were applied successfully, their adoption is still low among the flow cytometrists. In the purpose to integrate unsupervised computational tools for the management of multi-stained samples, we investigated their advantages and limits by comparison to manual gating on a typical sample analyzed in immunomonitoring routine. A single tube of PBMC, containing 11 populations characterized by different sizes and stained with 9 fluorescent markers, was used. We investigated the impact of the strategy choice on manual gating variability, an undocumented pitfall of the analysis process, and we identified rules to optimize it. While assessing automatic gating as an alternate, we introduced the Multi-Experiment Viewer software (MeV) and validated it for merging clusters and annotating interactively populations. This procedure allowed the finding of both targeted and unexpected populations. However, the careful examination of computed clusters in standard dot plots revealed some heterogeneity, often below 10%, that was overcome by increasing the number of clusters to be computed. MeV facilitated the identification of populations by displaying both the MFI and the marker signature of the dataset simultaneously. The procedure described here appears fully adapted to manage homogeneously high number of multi-stained samples and allows improving multi-parametric analyses in a way close to the classic approach. © 2016 International Society for Advancement of Cytometry.

  6. Improvement in clinical signs and cellular immunity of dogs with visceral leishmaniasis using the immunomodulator P-MAPA.

    Science.gov (United States)

    Santiago, Maria Emília B; Neto, Luiz Silveira; Alexandre, Eduardo Costa; Munari, Danísio Prado; Andrade, Mariana Macedo C; Somenzari, Marcos Arruda; Ciarlini, Paulo César; de Lima, V M F

    2013-09-01

    This study investigated the immunotherapeutic potential of the protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride immuno-modulator (P-MAPA) on canine visceral leishmaniasis. Twenty mongrel dogs presenting clinical symptoms compatible with leishmaniasis and diagnosis confirmed by the detection of anti-leishmania antibodies were studied. Ten dogs received 15 doses of the immunomodulator (2.0 mg/kg) intramuscularly, and 10 received saline as a placebo. Skin and peripheral blood samples were collected following administration of the immunomodulator. The groups were followed to observe for clinical signals of remission; parasite load in the skin biopsies using real-time PCR, the cytokines IL-2, IL-10 and IFN-γ in the supernatant of peripheral blood mononuclear cells stimulated in vitro with either total promastigote antigen or phytohemagglutinin measured by capture ELISA, and changes in CD4⁺ and CD8⁺ T cell subpopulations evaluated by flow cytometry. Comparison between the groups showed that treatment with the immunomodulator promoted improvement in clinical signs and a significant reduction in parasite load in the skin. In peripheral blood mononuclear cell cultures, supernatants showed a decrease in IL-10 levels and an increase in IL-2 and IFN-γ. An increase in CD8⁺ T cells was observed in peripheral blood. In addition, the in vitro leishmanicidal action of P-MAPA was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and no leishmanicidal activity was detected. These findings suggest that P-MAPA has potential as an immunotherapeutic drug in canine visceral leishmaniasis, since it assists in reestablishing partial immunocompetence of infected dogs.

  7. Short-Acting Beta-Agonist Research: A Perspective

    Directory of Open Access Journals (Sweden)

    Malcolm R Sears

    2001-01-01

    Full Text Available Asthma mortality increased sharply in New Zealand in 1977, prompting a national investigation into circumstances of asthma deaths. Subsequent observations of improved asthma control in subjects withdrawn from regular beta2-agonist treatment raised the question of whether asthma severity and, therefore, mortality could relate to frequent beta-agonist use. A randomized controlled trial of regular inhaled fenoterol versus as-needed bronchodilator use showed worsened asthma control during regular treatment despite concomitant use of inhaled corticosteroids. Assessment of these findings led to delay in the publishing of the American Asthma Guidelines, which were modified to suggest caution in using beta2-agonist treatments. Simultaneously, case control studies in New Zealand suggested that prescription of fenoterol was a substantial risk factor for asthma mortality. The causal association was hotly debated, but increasing evidence pointed to an adverse effect of fenoterol on asthma severity and, hence, mortality. This was supported by dramatic decreases in both morbidity and mortality when fenoterol was effectively withdrawn from use in New Zealand. The link between worsening asthma morbidity and mortality, and the use of potent short-acting beta2-agonists fulfills the Bradford Hill criteria for attributing causality. Application of evidence from randomized, controlled trials of short-acting beta-agonist use has led to a major shift in therapy in asthma to the recommendation of as-needed use only of short-acting beta-agonists and decreased patient reliance on regular bronchodilator therapy.

  8. Pharmacogenetics of β2-Agonists

    Directory of Open Access Journals (Sweden)

    Nobuyuki Hizawa

    2011-01-01

    Full Text Available Short-acting β2-agonists (SABAs and long-acting β2-agonists (LABAs are both important for treatment of asthma and chronic obstructive pulmonary disease (COPD because of their bronchodilator and bronchoprotective effects. However, the use of these agonists, at least for asthma, has generated some controversy because of their association with increased mortality. Pharmacogenetics is the study of genetically determined variation in response to medications, which might prove useful for target therapies in highly responsive patients, especially for more expensive therapies or those with increased risk of side effects. Variation in response to both SABAs and LABAs has been observed in patients with polymorphisms in the β2 adrenoceptor gene (ADRB2. This review summarizes results from various studies on the possible relationship between ADRB2 polymorphisms and the bronchodilator or bronchoprotective effects of inhaled β2-agonists. By assessing the ADRB2 genotype, the hope is that it will be possible to predict the responsiveness to chronic administration of β2-agonists. Genetic testing, however, is of limited usefulness at this stage for ADRB2 because the common variants identified thus far account for only a small proportion of the variation observed for given responses. Carefully performed and adequately powered clinical trials continue to be important for achieving the goal of pharmacogenetic approaches to therapy.

  9. Cellular Telephone

    Institute of Scientific and Technical Information of China (English)

    杨周

    1996-01-01

    Cellular phones, used in automobiles, airliners, and passenger trains, are basically low-power radiotelephones. Calls go through radio transmitters that are located within small geographical units called cells. Because each cell’s signals are too weak to interfere with those of other cells operating on the same fre-

  10. Novel retinoic acid receptor alpha agonists for treatment of kidney disease.

    Directory of Open Access Journals (Sweden)

    Yifei Zhong

    Full Text Available Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs: RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1 in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN. Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN.

  11. Novel retinoic acid receptor alpha agonists for treatment of kidney disease.

    Science.gov (United States)

    Zhong, Yifei; Wu, Yingwei; Liu, Ruijie; Li, Zhengzhe; Chen, Yibang; Evans, Todd; Chuang, Peter; Das, Bhaskar; He, John Cijiang

    2011-01-01

    Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN.

  12. Mussel-inspired bioceramics with self-assembled Ca-P/polydopamine composite nanolayer: preparation, formation mechanism, improved cellular bioactivity and osteogenic differentiation of bone marrow stromal cells.

    Science.gov (United States)

    Wu, Chengtie; Han, Pingping; Liu, Xiaoguo; Xu, Mengchi; Tian, Tian; Chang, Jiang; Xiao, Yin

    2014-01-01

    The nanostructured surface of biomaterials plays an important role in improving their in vitro cellular bioactivity as well as stimulating in vivo tissue regeneration. Inspired by the mussel's adhesive versatility, which is thought to be due to the plaque-substrate interface being rich in 3,4-dihydroxy-l-phenylalamine (DOPA) and lysine amino acids, in this study we developed a self-assembly method to prepare a uniform calcium phosphate (Ca-P)/polydopamine composite nanolayer on the surface of β-tricalcium phosphate (β-TCP) bioceramics by soaking β-TCP bioceramics in Tris-dopamine solution. It was found that the addition of dopamine, reaction temperature and reaction time are three key factors inducing the formation of a uniform Ca-P/polydopamine composite nanolayer. The formation mechanism of a Ca-P/polydopamine composite nanolayer involved two important steps: (i) the addition of dopamine to Tris-HCl solution decreases the pH value and accelerates Ca and P ionic dissolution from the crystal boundaries of β-TCP ceramics; (ii) dopamine is polymerized to form self-assembled polydopamine film and, at the same time, nanosized Ca-P particles are mineralized with the assistance of polydopamine, in which the formation of polydopamine occurs simultaneously with Ca-P mineralization (formation of nanosized microparticles composed of calcium phosphate-based materials), and finally a self-assembled Ca-P/polydopamine composite nanolayer forms on the surface of the β-TCP ceramics. Furthermore, the formed self-assembled Ca-P/polydopamine composite nanolayer significantly enhances the surface roughness and hydrophilicity of β-TCP ceramics, and stimulates the attachment, proliferation, alkaline phosphate (ALP) activity and bone-related gene expression (ALP, OCN, COL1 and Runx2) of human bone marrow stromal cells. Our results suggest that the preparation of self-assembled Ca-P/polydopamine composite nanolayers is a viable method to modify the surface of biomaterials by

  13. Metabolic effects of beta2-agonists in relation to exercise performance

    DEFF Research Database (Denmark)

    Kalsen, Anders

    2015-01-01

    Beta2-agonists are frequently used in the treatment of asthma and exercise-induced bronchoconstriction in elite athletes. However, aside from a bronchodilatory effect, beta2-agonists have also been shown to improve exercise performance, which makes these substances subjected to misuse by elite...

  14. 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.

  15. 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.``

  16. Improving the voding disfunction by a 5-HT7 receptor agonist in rats with chronic spinal cord injury%5-HT7受体激动剂改善脊髓损伤大鼠排尿障碍

    Institute of Scientific and Technical Information of China (English)

    吴刚; 曹海兵; 程曙杰; 陈加生; 谷宝军

    2012-01-01

    Objective:To investigate the effect of 5-hydroxytryptamine serotonin 7 receptor agonists on micturition dysfunction in rats with chronic spinal cord injury (SCI). Method: Intact rats and SCI rats were catheterized through the bladder dome for saline-filling cystometry. Dose-response curves for i. v. LP44 were followed each by SB269970. The capacity, residual volume, micturition volume, and voiding pressure were measured. Result; Intact rats showed few significant changes in cystometric variable. SCI rats responded to LP44 with dose-dependent increase in micturition volume and decrease in capacity, residual volume and voiding pressure, resulting in improvement in voiding efficiency. Effects of LP44 were reversed by SB269970. Conclusion: LP44 is of some help to improvement in voiding efficiency through induced emergence of phasic EUS relaxation.%目的:研究五羟色胺-7受体激动剂对慢性脊髓损伤(spinal cord injury,SCI大鼠排尿障碍的改善作用.方法:体重175~200 g之间的SD雌性大鼠,脊髓损伤模型7只,正常对照8只.乌拉坦麻醉下,在正常大鼠和脊髓损伤的模型的大鼠颈静脉和膀胱内置管,连接压力感受器,记录膀胱最大容量、剩余尿量、排尿量和尿道外括约肌的肌电活动.静脉注入5-HT7受体激动剂LP44(3~300 μg/kg)得到剂量-效应曲线随后再给予5-HT7受体抑制剂SB269970(100 μg/kg).结果:LP44剂量依赖性的降低SCI大鼠膀胱最大容量,并且增加排尿量、减少剩余尿量从而增加排尿效率.但是不能引起脊髓完好的大鼠排尿的改变.SB269970注入后可以逆转LP44的作用.同时LP44引起脊髓损伤大鼠尿道外括约肌强直收缩中出现阶段性的松弛,而对于脊髓完好的大鼠作用无明显改变.结论:LP44可以剂量依赖性地部分恢复SCI大鼠的尿道外括约肌协调性松弛,从而降低膀胱容量,增加排尿量,减少剩余尿量,结果增加排尿效率,改善排尿障碍.

  17. Epimedium polysaccharide and propolis flavone can synergistically inhibit the cellular infectivity of NDV and improve the curative effect of ND in chicken.

    Science.gov (United States)

    Fan, Yunpeng; Liu, Jiaguo; Wang, Deyun; Hu, Yuanliang; Yang, Shujuan; Wang, Junmin; Guo, Liwei; Zhao, Xiaona; Wang, Huali; Jiang, Yu

    2011-04-01

    possessed synergistical action, EP-PF prescription could significantly inhibit the cellular infectivity of NDV, improve the curative effect of ND in chicken and would be expected to exploit into a new-type antiviral drug.

  18. 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.

  19. Use of ß-adrenergic agonists in hybrid catfish

    Science.gov (United States)

    Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

  20. 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 metaboli...

  1. Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?

    DEFF Research Database (Denmark)

    Schwartz, Thue W; Holst, Birgitte

    2007-01-01

    Many small-molecule agonists also display allosteric properties. Such ago-allosteric modulators act as co-agonists, providing additive efficacy--instead of partial antagonism--and they can affect--and often improve--the potency of the endogenous agonist. Surprisingly, the apparent binding sites...... different binding modes. In another, dimeric, receptor scenario, the endogenous agonist binds to one protomer while the ago-allosteric modulator binds to the other, 'allosteric' protomer. It is suggested that testing for ago-allosteric properties should be an integral part of the agonist drug discovery...... process because a compound that acts with--rather than against--the endogenous agonist could be an optimal agonist drug....

  2. 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...

  3. EFFECT OF DESTRUCTION OF NTS AND PVN ON NEIGUAN (PC 6)ELECTROACUPUNCTURE-INDUCED IMPROVEMENT OF ISCHEMIC MYOCARDIAL CELLULAR MEMBRANE POTENTIALS IN RABBITS

    Institute of Scientific and Technical Information of China (English)

    CHEN Ze-bin; WANG Shu-ju; WANG Ya-wen; WU Xu-ping; WANG Hua

    2005-01-01

    Objective:To observe the influence of electrolytic destruction of nucleus solitary tract (NTS) and hypothalamic paraventricular nucleus (PVN) on the effect of electroacupuncture (EA) in improving ischemic myocardia cellular transmembrane action potential (TMAP). Methods: 38 Japanese breed big-ear white rabbits (anesthetized with 20% Urethane, 4mL/kg) were randomly divided into acute myocardial ischemia (AMI) group (n=8), PVN destruction group (n=12) and PVN+NTS destruction group (n=18). AMI model was established by occlusion of the descending anterior branch (DAB) of the coronary artery. TMAP of myocytes was recorded by using a glass microelectrode which was fixed to a suspending spring silver wire. Bilateral "Neiguan"(PC 6) in all the 3 groups were punctured and stimulated electrically by using parameters of continuous waves, frequency ECG-ST elevated significantly while APA lowered, APD50 and APD90 shortened of 7 Hz, intensity of 6 mA and duration of 30 minutes. Results: After AMI,clearly in comparison with those of pre-AMI in the 3 groups. Compared with AMI group, ECG-ST values of PVN destruction group and PVN+NTS destruction group were significantly higher (P<0.05~0.01), while APA, APD50 and APD90 all significantly lower in all the recording time courses(P<0.05). The facts displayed that electrolytic destruction of PVN and PVN+NTS could produce ischemic myocardial injury and reduce the protective effect of EA on ischemic myocardial cells. Comparison between PVN destruction and PVN+NTS groups showed that all the 4 indexes of the later group were evidently worse than those of the former group (P<0.05), suggesting after destruction of these two nuclei, the effect of EA was worsened further. Conclusion: Electrolytic destruction of PVN and NTS weakens the protective effect of EA on ischemic myocardial cells, both NTS and PVN take part in the effect of EA of "Neiguan"(PC 6) Point in improving ischemic myocardium.

  4. Regulation of membrane cholecystokinin-2 receptor by agonists enables classification of partial agonists as biased agonists.

    Science.gov (United States)

    Magnan, Rémi; Masri, Bernard; Escrieut, Chantal; Foucaud, Magali; Cordelier, Pierre; Fourmy, Daniel

    2011-02-25

    Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of β-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or β-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and β-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser(437)-Xaa(438)-Thr(439)-Thr(440)-Xaa(441)-Ser(442)-Thr(443)) were critical for β-arrestin recruitment. However, this region and β-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R·β-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.

  5. Cyclophilin A as a potential genetic adjuvant to improve HIV-1 Gag DNA vaccine immunogenicity by eliciting broad and long-term Gag-specific cellular immunity in mice

    Science.gov (United States)

    Hou, Jue; Zhang, Qicheng; Liu, Zheng; Wang, Shuhui; Li, Dan; Liu, Chang; Liu, Ying; Shao, Yiming

    2016-01-01

    Previous research has shown that host Cyclophilin A (CyPA) can promote dendritic cell maturation and the subsequent innate immune response when incorporated into an HIV-1 Gag protein to circumvent the resistance of dendritic cells to HIV-1 infection. This led us to hypothesize that CyPA may improve HIV-1 Gag-specific vaccine immunogenicity via binding with Gag antigen. The adjuvant effect of CyPA was evaluated using a DNA vaccine with single or dual expression cassettes. Mouse studies indicated that CyPA specifically and markedly promoted HIV-1 Gag-specific cellular immunity but not an HIV-1 Env-specific cellular response. The Gag/CyPA dual expression cassettes stimulated a greater Gag-specific cellular immune response, than Gag immunization alone. Furthermore, CyPA induced a broad Gag-specific T cell response and strong cellular immunity that lasted up to 5 months. In addition, CyPA skewed to cellular rather than humoral immunity. To investigate the mechanisms of the adjuvant effect, site-directed mutagenesis in CyPA, including active site residues H54Q and F60A resulted in mutants that were co-expressed with Gag in dual cassettes. The immune response to this vaccine was analyzed in vivo. Interestingly, the wild type CyPA markedly increased Gag cellular immunity, but the H54Q and F60A mutants drastically reduced CyPA adjuvant activation. Therefore, we suggest that the adjuvant effect of CyPA was based on Gag-CyPA-specific interactions. Herein, we report that Cyclophilin A can augment HIV-1 Gag-specific cellular immunity as a genetic adjuvant in multiplex DNA immunization strategies, and that activity of this adjuvant is specific, broad, long-term, and based on Gag-CyPA interaction. PMID:26305669

  6. Melatonin agonists for treatment of sleep and depressive disorders

    Directory of Open Access Journals (Sweden)

    Seithikurippu R. Pandi-Perumal

    2011-06-01

    Full Text Available 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 promoting properties have been introduced in clinical practice. Ramelteon, the MT1/ MT2 melatonergic agonist, has been used in a large number of clinical trials involving chronic insomniacs and has been found effective in improving the total sleep time and sleep efficiency of insomniacs and has not manifested serious adverse effects. The development of another MT1/MT2 melatonergic agonist agomelatine with antagonsim to 5-HT2c serotonin receptors has been found useful not only in treating sleep problems of patients but also as a first line antidepressant with earlier onset of actions in patients with major depressive disorder. An agonist for MT3 melatonin receptor has also been found effective in animal models of depression. [J Exp Integr Med 2011; 1(3.000: 149-158

  7. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

    Full Text Available A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes. Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

  8. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment.

    Science.gov (United States)

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T; Abbruscato, Thomas J

    2015-06-03

    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype.

  9. The GLP-1 receptor agonist liraglutide reduces pathology-specific tau phosphorylation and improves motor function in a transgenic hTauP301L mouse model of tauopathy.

    Science.gov (United States)

    Hansen, Henrik H; Barkholt, Pernille; Fabricius, Katrine; Jelsing, Jacob; Terwel, Dick; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-03-01

    In addition to a prominent role in glycemic control, glucagon-like peptide 1 (GLP-1) receptor agonists exhibit neuroprotective properties. There is mounting experimental evidence that GLP-1 receptor agonists, including liraglutide, may enhance synaptic plasticity, counteract cognitive deficits and ameliorate neurodegenerative features in preclinical models of Alzheimer's disease (AD), predominantly in the context of β-amyloid toxicity. Here we characterized the effects of liraglutide in a transgenic mutant tau (hTauP301L) mouse tauopathy model, which develops age-dependent pathology-specific neuronal tau phosphorylation and neurofibrillary tangle formation with progressively compromised motor function (limb clasping). Liraglutide (500 µg/kg/day, s.c., q.d., n=18) or vehicle (n=18) was administered to hTauP301L mice for 6 months from the age of three months. Vehicle-dosed wild-type FVB/N mice served as normal control (n=17). The onset and severity of hind limb clasping was markedly different in liraglutide and vehicle-dosed transgenic mice. Clasping behavior was observed in 61% of vehicle-dosed hTauP301L mice with a 55% survival rate in 9-month old transgenic mice. In contrast, liraglutide treatment reduced the clasping rate to 39% of hTauP301L mice, and fully prevented clasping-associated lethality resulting in a survival rate of 89%. Stereological analyses demonstrated that hTauP301L mice exhibited hindbrain-dominant neuronal accumulation of phosphorylated tau closely correlated to the severity of clasping behavior. In correspondence, liraglutide treatment significantly reduced neuronal phospho-tau load by 61.9±10.2% (p<0.001) in hTauP301L mice, as compared to vehicle-dosed controls. In conclusion, liraglutide significantly reduced tau pathology in a transgenic mouse tauopathy model.

  10. Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy.

    Science.gov (United States)

    Trotter, B Wesley; Nanda, Kausik K; Burgey, Christopher S; Potteiger, Craig M; Deng, James Z; Green, Ahren I; Hartnett, John C; Kett, Nathan R; Wu, Zhicai; Henze, Darrell A; Della Penna, Kimberly; Desai, Reshma; Leitl, Michael D; Lemaire, Wei; White, Rebecca B; Yeh, Suzie; Urban, Mark O; Kane, Stefanie A; Hartman, George D; Bilodeau, Mark T

    2011-04-15

    A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.

  11. AGONISTIC BEHAVIOR OF LABORATORY MICE

    Directory of Open Access Journals (Sweden)

    D. Cinghiţă

    2005-01-01

    Full Text Available 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 individuals. Each member of a group has its own place on the ierarchical scale depending on resultes of fhights – it can be leader or it can be subsurvient, depending on if it wines or looses the fight. Once hierarchical scale made, every animal will adjust its behavior. After analyzing the obtained data we have enough reasons to believe that after fights the winner, usually, is the massive mouse, but it is also very important the sexual ripeness, so the immature male will be beaten. The leader male had a big exploring area and it checks up all territory.The females can be more aggressive, its fights are more brutal, than male fights are, when they fight for supremacy, but in this case fights are not as frequent as in the case of males. Always the superior female, on hierarchical scale, shows males its own statute, so the strongest genes will be perpetuated.

  12. Cellular systems biology profiling applied to cellular models of disease.

    Science.gov (United States)

    Giuliano, Kenneth A; Premkumar, Daniel R; Strock, Christopher J; Johnston, Patricia; Taylor, Lansing

    2009-11-01

    Building cellular models of disease based on the approach of Cellular Systems Biology (CSB) has the potential to improve the process of creating drugs as part of the continuum from early drug discovery through drug development and clinical trials and diagnostics. This paper focuses on the application of CSB to early drug discovery. We discuss the integration of protein-protein interaction biosensors with other multiplexed, functional biomarkers as an example in using CSB to optimize the identification of quality lead series compounds.

  13. Optimized Cellular Core for Rotorcraft Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Patz Materials and Technologies proposes to develop a unique structural cellular core material to improve mechanical performance, reduce platform weight and lower...

  14. 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...

  15. Melatonin receptor agonists: new options for insomnia and depression treatment.

    Science.gov (United States)

    Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco

    2011-12-01

    The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT₁ or MT₂ subtype-selective compounds are available up to now. Administration of the MT₂-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT₂ receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT₁ or MT₂ receptors are expected in coming years.

  16. LHRH Agonists for the Treatment of Prostate Cancer: 2012.

    Science.gov (United States)

    Lepor, Herbert; Shore, Neal D

    2012-01-01

    The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge ("clinical flare") and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT.

  17. The Effects of Inhaled β-Adrenergic Agonists in Transient Tachypnea of the Newborn

    Directory of Open Access Journals (Sweden)

    Esengul Keleş MD

    2016-05-01

    Full Text Available Aim. To investigate the efficacy of an inhaled β-adrenergic agonists in transient tachypnea of the newborn (TTN. Method. We retrospectively analyzed a cohort of 51 term infants (Group 1 and 37 term infants (Group 2 monitored in the newborn intensive care unit diagnosed with TTN. Infants in Group 1 received humidified oxygen alone, and infants in Group 2 were administered the inhaled β-2 agonist plus humidified oxygen. Results. TTN clinical respiratory assessment, respiratory rate, oxygen saturation values, need for supplemental oxygen therapy, blood gas PH, PO2, and duration of hospitalization were significantly improved in infants in Group 2 as compared with infants in Group 1 (P .05. Conclusion. Inhaled β-adrenergic agonist added to humidified oxygen was found to improve clinical and laboratory parameters. We believe that further studies should be conducted with larger groups to demonstrate the efficacy of β-2 agonists in TTN patients.

  18. Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

    OpenAIRE

    Maslov, Leonid N; Khaliulin, Igor; Oeltgen, Peter R; Naryzhnaya, Natalia V.; Pei, Jian‐Ming; Brown, Stephen A; Lishmanov, Yury B.; Downey, James M

    2016-01-01

    Abstract It has now been demonstrated that the μ, δ1, δ2, and κ1 opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct‐reducing effect with prophylactic administration and prevent reperfusi...

  19. Impact of efficacy at the μ-opioid receptor on antinociceptive effects of combinations of μ-opioid receptor agonists and cannabinoid receptor agonists.

    Science.gov (United States)

    Maguire, David R; France, Charles P

    2014-11-01

    Cannabinoid receptor agonists, such as Δ(9)-tetrahydrocannabinol (Δ(9)-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ(9)-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ(9)-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ(9)-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ(9)-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain.

  20. Biased signaling by peptide agonists of protease activated receptor 2.

    Science.gov (United States)

    Jiang, Yuhong; Yau, Mei-Kwan; Kok, W Mei; Lim, Junxian; Wu, Kai-Chen; Liu, Ligong; Hill, Timothy A; Suen, Jacky Y; Fairlie, David P

    2017-02-07

    Protease activated receptor 2 (PAR2) is associated with metabolism, obesity, inflammatory, respiratory and gastrointestinal disorders, pain, cancer and other diseases. The extracellular N-terminus of PAR2 is a common target for multiple proteases, which cleave it at different sites to generate different N-termini that activate different PAR2-mediated intracellular signaling pathways. There are no synthetic PAR2 ligands that reproduce the same signaling profiles and potencies as proteases. Structure-activity relationships here for 26 compounds spanned a signaling bias over 3 log units, culminating in three small ligands as biased agonist tools for interrogating PAR2 functions. DF253 (2f-LAAAAI-NH2) triggered PAR2-mediated calcium release (EC50 2 μM) but not ERK1/2 phosphorylation (EC50 > 100 μM) in CHO cells transfected with hPAR2. AY77 (Isox-Cha-Chg-NH2) was a more potent calcium-biased agonist (EC50 40 nM, Ca2+; EC50 2 μM, ERK1/2), while its analogue AY254 (Isox-Cha-Chg-A-R-NH2) was an ERK-biased agonist (EC50 2 nM, ERK1/2; EC50 80 nM, Ca2+). Signaling bias led to different functional responses in human colorectal carcinoma cells (HT29). AY254, but not AY77 or DF253, attenuated cytokine-induced caspase 3/8 activation, promoted scratch-wound healing and induced IL-8 secretion, all via PAR2-ERK1/2 signaling. Different ligand components were responsible for different PAR2 signaling and functions, clues that can potentially lead to drugs that modulate different pathway-selective cellular and physiological responses.

  1. [Pramipexol: a new dopaminergic agonist for the treatment of Parkinson disease].

    Science.gov (United States)

    Grandas, F; Galiano, M L

    1999-05-01

    Pramipexol is a novel nonergot dopamine agonist which has high selectivity for intereacting with dopamine D2 receptors (especially with D3 receptor subtype). It has been effective in early Parkinson's disease as monotherapy and as adjunctive therapy with L-dopa in advanced stages of the disease. Clinical improvement can be observed after 3 or 4 weeks of treatment. The adverse events profile of pramipexol is similar, in general, to that of other dopamine receptor agonists, although it can be foreseen that pramipexol should not induce side effects related to the ergot chemical structure such as eritromelalgia, distal vasospasm, retroperitoneal fibrosis or pleural effusions. Nevertheless, the potential advantages of this promising dopamine agonist should be tested in well-designed prospective comparative studies with other available ergot and nonergot dopamine agonists.

  2. Receptor discrimination and control of agonist-antagonist binding.

    Science.gov (United States)

    Tallarida, R J

    1995-08-01

    The law of mass action is the common model for the interaction of agonist and antagonist compounds with cellular receptors. Parameters of the interaction, obtained from functional and radioligand-binding studies, allow discrimination and subtyping of receptors and aid in understanding specific mechanisms. This article reviews the theory and associated mathematical models and graphical transformations of data that underlie the determination of receptor parameters. The main theory assumes that agonist and antagonist compounds bind to cells that have a fixed number of receptors and provides the framework for obtaining drug-receptor parameters from data and their graphical transformations. Conditions that produce a change in receptor number, a newer concept in pharmacology, can have an important effect on the parameter values derived in the usual way. This review concludes with a discussion of the quantitative study of receptor-mediated feedback control of endogenous ligands, a very new topic with potentially important implications for understanding antagonist effectiveness, loss of control, and chaos in regulated mass action binding.

  3. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

    Science.gov (United States)

    Xia, Yang; Kellems, Rodney E

    2013-06-21

    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These

  4. Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor

    Directory of Open Access Journals (Sweden)

    Ling Yang

    2011-12-01

    Full Text Available The nociceptin/orphanin FQ (NOP receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure–activity relationship (3D-QSAR studies were carried out using comparative molecular field analysis (CoMFA and comparative molecular similarity indices analysis (CoMSIA techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q2 of 0.501, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity.

  5. An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists

    Directory of Open Access Journals (Sweden)

    Xia Chen

    2012-01-01

    Full Text Available Various 2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several 2,3 subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2 mg was the comparator in three studies. Three 2,3-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498, one 1-selective GABAA agonists (zolpidem, and another full agonist (alprazolam were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV- relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD. SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the 2,3 selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the 2,3-selective GABA-A agonists, implying an improved therapeutic window.

  6. Flat Cellular (UMTS) Networks

    NARCIS (Netherlands)

    Bosch, H.G.P.; Samuel, L.G.; Mullender, S.J.; Polakos, P.; Rittenhouse, G.

    2007-01-01

    Traditionally, cellular systems have been built in a hierarchical manner: many specialized cellular access network elements that collectively form a hierarchical cellular system. When 2G and later 3G systems were designed there was a good reason to make system hierarchical: from a cost-perspective i

  7. 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

  8. Conicasterol E, a Small Heterodimer Partner Sparing Farnesoid X Receptor Modulator Endowed with a Pregnane X Receptor Agonistic Activity, from the Marine Sponge Theonella swinhoei

    OpenAIRE

    V. Sepe; Ummarino, R.; D'Auria, M. V.; M. G. Chini; Bifulco, G.; Renga, B; D'Amore, C.; Debitus, Cécile; Fiorucci, S.; Zampella, A.

    2012-01-01

    We report the isolation and pharmacological characterization of conicasterol E isolated from the marine sponge Theonella swinhoei. Pharmacological characterization of this steroid in comparison to CDCA, a natural FXR ligand, and 6-ECDCA, a synthetic FXR agonist generated by an improved synthetic strategy, and rifaximin, a potent PXR agonist, demonstrated that conicasterol E is an FXR modulator endowed with PXR agonistic activity. Conicasterol E induces the expression of genes involved in bile...

  9. Gold Nanoparticles Functionalized with Peptides for Specific Affinity Aggregation Assays of Estrogen Receptors and Their Agonists

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Takatsuji

    2012-04-01

    Full Text Available Nuclear receptors regulate the transcription of genes and various functions such as development, differentiation, homeostasis, and behavior by formation of complexes with ligand and co-activator. Recent findings have shown that agonists of a ligand may have a toxic effect on cellular/tissular function through improper activation of nuclear receptors. In this study, a simple assay system of hetero-complexes of three different molecules (estrogen receptor, ligand, and co-activator peptide has been developed. This assay system employs functionalized gold nanoparticles (GNPs: 15 nm in diameter. The surfaces of the GNPs were modified by a 12- or 20-amino-acid peptide that contains the sequence of co-activator for activating nuclear receptor by an agonist ligand. Owing to the affinity of the peptide, the functionalized GNPs aggregate faster when the nuclear receptor and the agonist ligand are also present. The aggregation of GNPs can be identified by shifts in adsorption spectrum, which give information about the specificity of agonist ligands. Similarly, this spectrum shift can measure concentration of known agonist ligand. This simple agonist screening will be employed as high through-put analysis (HTA in the discovery of drugs that act through nuclear receptors.

  10. Pre-oxidation with KMnO4 changes extra-cellular organic matter's secretion characteristics to improve algal removal by coagulation with a low dosage of polyaluminium chloride

    Institute of Scientific and Technical Information of China (English)

    Lei Wang; Junlian Qiao; Yinghui Hu; Lei Wang; Long Zhang; Qiaoli Zhou; Naiyun Gao

    2013-01-01

    Microcystis aeruginosa was used to study the effect of KMnO4 pre-oxidation on algal removal through coagulation with polyalurninium chloride (PAC).KMnO4 pre-oxidation improved the coagulation efficiency of algal at a low dosage of PAC.The optimal KMnO4 feeding period was in the stationary growth phase of Microcystis aeruginosa.KMnO4 traumatized the algal cells and stimulated cellular release of organic matter,contributing to the pool of extra-cellular organic matter (EOM).KMnO4 also decomposed EOM,especially small molecular weight EOM.Lower concentrations of KMnO4,such as 2 mg/L,induced algae cells to produce moderate amounts of new EOM with molecular weights of 11,280,and 1500 kDa.These relatively large molecules combined easily with PAC,promoting coagulation and removal of algae.High concentrations of KMnO4 1ysed algae cells and produced much high-molecular-weight EOM that did not enhance flocculation by PAC at lower dosages.

  11. Muscimol as an ionotropic GABA receptor agonist.

    Science.gov (United States)

    Johnston, Graham A R

    2014-10-01

    Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol(®)) and 4-PIOL.

  12. Dopamine D1 receptor-agonist interactions: A mutagenesis and homology modeling study.

    Science.gov (United States)

    Mente, Scot; Guilmette, Edward; Salafia, Michelle; Gray, David

    2015-01-01

    The dopamine D1 receptor is a G protein-coupled receptor that regulates intracellular signaling via agonist activation. Although the number of solved GPCR X-ray structures has been steadily increasing, still no structure of the D1 receptor exists. We have used site-directed mutagenesis of 12 orthosteric vicinity residues of possible importance to G protein-coupled activation to examine the function of prototypical orthosteric D1 agonists and partial agonists. We find that residues from four different regions of the D1 receptor make significant contributions to agonist function. All compounds studied, which are catechol-amines, are found to interact with the previously identified residues: the conserved D103(3.32), as well as the trans-membrane V serine residues. Additional key interactions are found for trans-membrane VI residues F288(6.51), F289(6.52) and N292(6.55), as well as the extra-cellular loop residue L190(ECL2). Molecular dynamics simulations of a D1 homology model have been used to help put the ligand-residue interactions into context. Finally, we considered the rescaling of fold-shift data as a method to account for the change in the size of the mutated side-chain and found that this rescaling helps to relate the calculated ligand-residue energies with observed experimental fold-shifts.

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

    Directory of Open Access Journals (Sweden)

    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

  14. 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.

  15. 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.

  16. Optimal Band Allocation for Cognitive Cellular Networks

    CERN Document Server

    Liu, Tingting

    2011-01-01

    FCC new regulation for cognitive use of the TV white space spectrum provides a new means for improving traditional cellular network performance. But it also introduces a number of technical challenges. This letter studies one of the challenges, that is, given the significant differences in the propagation property and the transmit power limitations between the cellular band and the TV white space, how to jointly utilize both bands such that the benefit from the TV white space for improving cellular network performance is maximized. Both analytical and simulation results are provided.

  17. 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.

  18. 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.

  19. The peroxisome proliferator-activated receptor-α(PPAR-α) agonist,AVE8134,attenuates the progression of heart failure and increases survival in rats

    Institute of Scientific and Technical Information of China (English)

    Wolfgang LINZ; Paulus WOHLFART; Manuel BAADER; Kristin BREITSCHOPF; Eugen FALK; Hans-Ludwig SCH(A)FER; Martin GERL; Wemer KRAMER; Hartmut R(U)TTEN

    2009-01-01

    Aim:To investigate the efficacy of the peroxisome proliferator-aotivated receptor-α (PPARα) agonist,AVE8134,in cellular and experimental models of cardiac dysfunction and heart failure.Methods:In Sprague Dawley rats with permanent ligation of the left coronary artery (post-MI),AVE8134 was compared to the PPARy agonist rosiglitazone and in a second study to the ACE inhibitor ramipril.In DOCA-salt sensitive rats,efficacy of AVE8134 on cardiac hypertrophy and fibrosis was investigated.Finally,AVE8134 was administered to old spontaneously hypertensive rats (SHR) at a nonblood pressure lowering dose with survival as endpoint.In cellular models,we studied AVE8134 on hypertrophy in rat cardiomyocytes,nitric oxide signaling in human endothelial cells (HUVEC) and LDL-uptake in human MonoMac-6 cells.Results:In post-MI rats,AVE8134 dose-dependently improved cardiac output,myocardial contractility and relaxation and reduced lung and left ventdcular weight and fibrosis.In contrast,rosiglitazone exacerbated cardiac dysfunction.Treatment at AVE8134 decreased plasma proBNP and arginine and increased plasma citrulline and urinary NOx/creatinine ratio.In DOCA rats,AVE8134 prevented development of high blood pressure,myocardial hypertrophy and cardiac fibrosis,and ameliorated endothelial dysfunction.Compound treatment increased cardiac protein expression and phosphorylation of eNOS.In old SHR,treatment with a low dose of AVE8134 improved cardiac and vascular function and increased life expectancy without lowering blood pressure.AVE8134 reduced phenylephrine-induced hypertrophy in adult rat cardiomyocytes.In HUVEC,Ser-1177-eNOS phosphorylation but not eNOS expression was increased.In monocytes,AVE8134 increased the expression of CD36 and the macrophage scavenger receptor 1,resulting in enhanced uptake of oxidized LDL.Conclusion:The PPARα agonist AVES134 prevents post-MI myocardial hypertrophy,fibrosis and cardiac dysfunction.AVES134 has beneficial effects against hypertension

  20. Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders.

    Science.gov (United States)

    Geoffroy, Pierre Alexis; Etain, Bruno; Franchi, Jean-Arthur Micoulaud; Bellivier, Frank; Ritter, Philipp

    2015-01-01

    Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD.

  1. The Melatonin Receptor Agonist Ramelteon Effectively Treats Insomnia and Behavioral Symptoms in Autistic Disorder

    OpenAIRE

    Kentaro Kawabe; Fumie Horiuchi; Yasunori Oka; Shu-ichi Ueno

    2014-01-01

    Children with autism spectrum disorders (ASD), including autistic disorder, frequently suffer from comorbid sleep problems. An altered melatonin rhythm is considered to underlie the impairment in sleep onset and maintenance in ASD. We report three cases with autistic disorder in whom nocturnal symptoms improved with ramelteon, a selective melatonin receptor agonist. Insomnia and behavior, assessed using the Clinical Global Impression-Improvement Scale, improved in two cases with 2 mg ramelteo...

  2. Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Pickering, Darryl S; Greenwood, Jeremy R;

    2010-01-01

    We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at A...

  3. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

    NARCIS (Netherlands)

    Ellenbroek, J.H.; Tons, H.A.; Westerouen van Meeteren, M.J.; de Graaf, N.; Hanegraaf, M.A.; Rabelink, T.J.; Carlotti, F.; de Koning, E.J.

    2013-01-01

    AIMS/HYPOTHESIS: Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in non-diabetic individuals with obesity and cardiovascular di

  4. Peroxisome Proliferator-Activated Receptor Agonists: Do They Increase Cardiovascular Risk?

    Directory of Open Access Journals (Sweden)

    Ahmad Aljada

    2009-01-01

    agonists, and their primary benefit appears to be the prevention of diabetic complications by improving glycemic control and lipid profile. Recently, the cardiovascular safety of rosiglitazone was brought to center stage following meta analyses and the interim analysis of the RECORD trial. Current evidence points to rosiglitazone having a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas. This review article discusses the mechanism of action of PPAR agonists and correlates it with clinical and laboratory outcomes in the published literature. In addition, this review article attempts to discuss some of the molecular mechanisms regarding the association between TZDs therapy and the nontraditional cardiovascular risks.

  5. Reversible quantum cellular automata

    CERN Document Server

    Schumacher, B

    2004-01-01

    We define quantum cellular automata as infinite quantum lattice systems with discrete time dynamics, such that the time step commutes with lattice translations and has strictly finite propagation speed. In contrast to earlier definitions this allows us to give an explicit characterization of all local rules generating such automata. The same local rules also generate the global time step for automata with periodic boundary conditions. Our main structure theorem asserts that any quantum cellular automaton is structurally reversible, i.e., that it can be obtained by applying two blockwise unitary operations in a generalized Margolus partitioning scheme. This implies that, in contrast to the classical case, the inverse of a nearest neighbor quantum cellular automaton is again a nearest neighbor automaton. We present several construction methods for quantum cellular automata, based on unitaries commuting with their translates, on the quantization of (arbitrary) reversible classical cellular automata, on quantum c...

  6. Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats.

    Science.gov (United States)

    Frank, J A; Wang, Y; Osorio, O; Matthay, M A

    2000-10-01

    To determine whether beta-adrenergic agonist therapy increases alveolar liquid clearance during the resolution phase of hydrostatic pulmonary edema, we studied alveolar and lung liquid clearance in two animal models of hydrostatic pulmonary edema. Hydrostatic pulmonary edema was induced in sheep by acutely elevating left atrial pressure to 25 cmH(2)O and instilling 6 ml/kg body wt isotonic 5% albumin (prepared from bovine albumin) in normal saline into the distal air spaces of each lung. After 1 h, sheep were treated with a nebulized beta-agonist (salmeterol) or nebulized saline (controls), and left atrial pressure was then returned to normal. beta-Agonist therapy resulted in a 60% increase in alveolar liquid clearance over 3 h (P Ringer lactate). beta-Agonist therapy resulted in a significant decrease in excess lung water (P < 0.01) and significant improvement in arterial blood gases by 2 h (P < 0.03). These preclinical experimental studies support the need for controlled clinical trials to determine whether beta-adrenergic agonist therapy would be of value in accelerating the resolution of hydrostatic pulmonary edema in patients.

  7. Xamoterol, a new selective beta-1-adrenoceptor partial agonist, in the treatment of postural hypotension

    DEFF Research Database (Denmark)

    Mehlsen, J; Trap-Jensen, J

    1986-01-01

    Three patients severely disabled from postural hypotension were treated with xamoterol, a selective beta-1-adrenoceptor antagonist with a high degree of partial agonist activity. Oral treatment (200 mg b.i.d.) was chosen on the basis of the effects of acute intravenous administration of xamoterol...... and pindolol, a non-selective beta-adrenoceptor antagonist with partial agonist activity. In these patients pindolol had a predominantly antagonist effect, whereas xamoterol had a predominantly agonist effect after intravenous administration. Oral treatment was carried out with placebo control in a single......, supine). During the placebo period (2 weeks) heart rate decreased to pretreatment levels and mean blood pressure was reduced by only 14 mmHg. The patients reported substantial improvement in their condition during active medication. Xamoterol seems to be a useful alternative in the treatment of postural...

  8. Pituitary binding and internalization of radioiodinated gonadotropin-releasing hormone agonist and antagonist ligands in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wynn, P.C.; Suarez-Quian, C.A.; Childs, G.V.; Catt, K.J.

    1986-10-01

    In rat pituitary gonadotrophs, the rates of binding and endocytosis of two GnRH superagonist analogs, (D-Ala6,Pro9-NEt)GnRH and (D-Lys6,Pro9-NEt)GnRH, were compared with those of the potent antagonist analog (N-acetyl-D-pCl-Phe1,2,D-Trp3,D-Lys6,D-Ala10)GnRH by quantitative electron microscopic autoradiography. In dispersed pituitary cells, the two agonist analogs showed similar binding kinetics and comparable degrees of sequestration, as measured by their resistance to dissociation by low pH buffer. However, quantification of silver grain localization suggested that cellular internalization of the (D-Ala6)GnRH agonist increased more rapidly than that of the (D-Lys6)GnRH analog. These discrepancies, and the finding that a larger amount of the specifically bound /sup 125/I-(D-Ala6)GnRH agonist was removed during glutaraldehyde fixation, indicated that the proportional internalization of this analog was over estimated by quantitative autoradiography owing to loss of cell surface-bound radioligand. We, therefore, employed radioiodinated D-Lys6-substituted analogs to analyze the receptor binding and cellular uptake of GnRH agonist and antagonist derivatives in vivo. After iv injection, a high proportion of the /sup 125/I-(D-Lys6)GnRH agonist was translocated into pituitary gonadotrophs within 60 min, whereas the D-Lys6 antagonist was predominantly associated with the plasma membrane during that time. Four hours after injection of the antagonist, an appreciable proportion of silver grains was associated with intracellular organelles, and this trend increased progressively at later time points. The relatively prolonged cellular processing of the GnRH antagonist is consistent with in vivo binding kinetics, and its slower internalization may reflect the basal rate of GnRH receptor turnover in the cell membrane.

  9. A Meta-Analysis of the Therapeutic Effects of Glucagon-Like Peptide-1 Agonist in Heart Failure

    Directory of Open Access Journals (Sweden)

    Mohammed Munaf

    2012-01-01

    Full Text Available We conducted a meta-analysis of the existing literature of the therapeutic effects of using GLP-1 agonists to improve the metabolism of the failing heart. Animal studies showed significant improvement in markers of cardiac function, such as left ventricular ejection fraction (LVEF, with regular GLP-1 agonist infusions. In clinical trials, the potential effects of GLP-1 agonists in improving cardiac function were modest: LVEF improved by 4.4% compared to placebo (95% C.I 1.36–7.44, =0.005. However, BNP levels were not significantly altered by GLP-1 agonists in heart failure. In two trials, a modest increase in heart rate by up to 7 beats per minute was noted, but meta-analysis demonstrated this was not significant statistically. The small number of studies plus variation in the concentration and length of the regime between the trials would limit our conclusions, even though statistically, heterogeneity chi-squared tests did not reveal any significant heterogeneity in the endpoints tested. Moreover, studies in non-diabetics with heart failure yielded conflicting results. In conclusion, the use of GLP-1 agonists has at best a modest effect on ejection fraction improvement in heart failure, but there was no significant improvement in BNP levels in the meta-analysis.

  10. Recent advances in the discovery of alpha1-adrenoceptor agonists.

    Science.gov (United States)

    Bishop, Michael J

    2007-01-01

    The alpha(1) adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the alpha(1) adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known alpha(1) adrenoceptor agonists are alpha(1A) selective, but the discovery of highly selective alpha(1B) and alpha(1D) adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific alpha(1) agonists as well as contributions to our understanding of agonist-receptor interactions.

  11. Addition of gonadotropin releasing hormone agonist for luteal phase support in in-vitro fertilization: an analysis of 2739 cycles

    Science.gov (United States)

    Şimşek, Erhan; Kılıçdağ, Esra Bulgan; Aytaç, Pınar Çağlar; Çoban, Gonca; Şimşek, Seda Yüksel; Çok, Tayfun; Haydardedeoğlu, Bülent

    2015-01-01

    Objective Luteal phase is defective in in vitro fertilization (IVF) cycles, and many regimens were tried for the very best luteal phase support (LPS). Gonadotropin releasing hormone (GnRH) agonist use, which was administered as an adjunct to the luteal phase support in IVF cycles, was suggested to improve pregnancy outcome measures in certain randomized studies. We analyzed the effects of addition of GnRH agonist to standard progesterone luteal support on pregnancy outcome measures, particularly the live birth rates. Material and Methods This is a retrospective cohort study, including 2739 IVF cycles. Long GnRH agonist and antagonist stimulation IVF cycles with cleavage-stage embryo transfer were included. Cycles were divided into two groups: Group A included cycles with single-dose GnRH agonist plus progesterone LPS and Group B included progesterone only LPS. Live birth rates were the primary outcome measures of the analysis. Miscarriage rates and multiple pregnancy rates were the secondary outcome measures. Results Live birth rates were not statistically different in GnRH agonist plus progesterone (Group A) and progesterone only (Group B) groups in both the long agonist and antagonist stimulation arms (40.8%/41.2% and 32.8%/34.4%, p<0.05 respectively). Moreover, pregnancy rates, implantation rates, and miscarriage rates were found to be similar between groups. Multiple pregnancy rates in antagonist cycles were significantly higher in Group A than those in Group B (12.0% and 6.9%, respectively). Conclusion A beneficial effect of a single dose of GnRH agonist administration as a luteal phase supporting agent is yet to be determined because of the wide heterogeneity of data present in literature. Well-designed randomized clinical studies are required to clarify any effect of luteal GnRH agonist addition on pregnancy outcome measures with different doses, timing, and administration routes of GnRH agonists. PMID:26097392

  12. PPAR agonists for the treatment of cardiovascular disease in patients with diabetes.

    Science.gov (United States)

    Wilding, J P H

    2012-11-01

    Diabetes is a complex disease defined by hyperglycaemia; however, strong associations with abdominal obesity, hypertension and dyslipidaemia contribute to the high risk of cardiovascular disease. Although aggressive glycaemic control reduces microvascular complications, the evidence for macrovascular complications is less certain. The theoretical benefits of the mode of action of peroxisome proliferator-activated receptor (PPAR) agonists are clear. In clinical practice, PPAR-α agonists such as fibrates improve dyslipidaemia, while PPAR-γ agonists such as thiazolidinediones improve insulin resistance and diabetes control. However, although these agents are traditionally classed according to their target, they have different and sometimes conflicting clinical benefit and adverse event profiles. It is speculated that this is because of differing properties and specificities for the PPAR receptors (each of which targets specific genes). This is most obvious in the impact on cardiovascular outcomes--in clinical trials pioglitazone appeared to reduce cardiovascular events, whereas rosiglitazone potentially increased the risk of myocardial infarction. The development of a dual PPAR-α/γ agonist may prove beneficial in effectively managing glycaemic control and improving dyslipidaemia in patients with type 2 diabetes. Yet, development of agents such as muraglitazar and tesaglitazar has been hindered by various serious adverse events. Aleglitazar, a balanced dual PPAR-α/γ agonist, is currently the most advanced in clinical development and has shown promising results in phase II clinical trials with beneficial effects on glucose and lipid variables. A phase III study, ALECARDIO, is ongoing and will establish whether improvements in laboratory test profiles translate into an improvement in cardiovascular outcomes.

  13. 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 (m......GluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists...

  14. Agonistic and reproductive interactions in Betta splendens.

    Science.gov (United States)

    Bronstein, P M

    1984-12-01

    Reproductive and agonistic behaviors in Siamese fighting fish were investigated in eight experiments, and some consequences and determinants of these sequences were isolated. First, fights and the formation of dominance-subordinancy relations were studied. Second, it was determined that large body size as well as males' prior residency in a tank produced an agonistic advantage; the magnitude of this advantage was positively related to the duration of residency. Third, the prior-residency effect in Bettas was determined by males' familiarity with visual and/or tactile cues in their home tanks. Fourth, dominant males had greater access to living space and were more likely to display at a mirror, build nests, and approach females than were subordinates. Finally, it was discovered that chemical cues associated with presumedly inert plastic tank dividers influence Bettas' social behavior.

  15. [Pathophysiological relevance of peroxisome proliferators activated receptors (PPAR) to joint diseases - the pro and con of agonists].

    Science.gov (United States)

    Jouzeau, Jean-Yves; Moulin, David; Koufany, Meriem; Sebillaud, Sylvie; Bianchi, Arnaud; Netter, Patrick

    2008-01-01

    hyperlipidemic patients treated for long periods of time with glitazones or fibrates. Additionally, cellular and animal studies are required to assess whether partial agonists of PPAR (SPPARMs) may preserve therapeutical properties with potentially less safety concern.

  16. Cell proliferation and modulation of interaction of estrogen receptors with coregulators induced by ERα and ERβ agonists.

    Science.gov (United States)

    Evers, Nynke M; van den Berg, Johannes H J; Wang, Si; Melchers, Diana; Houtman, René; de Haan, Laura H J; Ederveen, Antwan G H; Groten, John P; Rietjens, Ivonne M C M

    2014-09-01

    The aim of the present study was to investigate modulation of the interaction of the ERα and ERβ with coregulators in the ligand responses induced by estrogenic compounds. To this end, selective ERα and ERβ agonists were characterized for intrinsic relative potency reflected by EC50 and maximal efficacy towards ERα and ERβ mediated response in ER selective reporter gene assays, and subsequently tested for induction of cell proliferation in T47D-ERβ cells with variable ERα/ERβ ratio, and finally for ligand dependent modulation of the interaction of ERα and ERβ with coregulators using the MARCoNI assay, with 154 unique nuclear receptor coregulator peptides derived from 66 different coregulators. Results obtained reveal an important influence of the ERα/ERβ ratio and receptor selectivity of the compounds tested on induction of cell proliferation. ERα agonists activate cell proliferation whereas ERβ suppresses ERα mediated cell proliferation. The responses in the MARCoNI assay reveal that upon ERα or ERβ activation by a specific agonist, the modulation of the interaction of the ERs with coregulators is very similar indicating only a limited number of differences upon ERα or ERβ activation by a specific ligand. Differences in the modulation of the interaction of the ERs with coregulators between the different agonists were more pronounced. Based on ligand dependent differences in the modulation of the interaction of the ERs with coregulators, the MARCoNI assay was shown to be able to classify the ER agonists discriminating between different agonists for the same receptor, a characteristic not defined by the ER selective reporter gene or proliferation assays. It is concluded that the ultimate effect of the model compounds on proliferation of estrogen responsive cells depends on the intrinsic relative potency of the agonist towards ERα and ERβ and the cellular ERα/ERβ ratio whereas differences in the modulation of the interaction of the ERα and

  17. Heterogeneous cellular networks

    CERN Document Server

    Hu, Rose Qingyang

    2013-01-01

    A timely publication providing coverage of radio resource management, mobility management and standardization in heterogeneous cellular networks The topic of heterogeneous cellular networks has gained momentum in industry and the research community, attracting the attention of standardization bodies such as 3GPP LTE and IEEE 802.16j, whose objectives are looking into increasing the capacity and coverage of the cellular networks. This book focuses on recent progresses,  covering the related topics including scenarios of heterogeneous network deployment, interference management i

  18. A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells.

    Science.gov (United States)

    Cheadle, E J; Lipowska-Bhalla, G; Dovedi, S J; Fagnano, E; Klein, C; Honeychurch, J; Illidge, T M

    2017-01-03

    Anti-CD20 monoclonal antibodies (mAb) such as rituximab have been proven to be highly effective at improving outcome in B-cell malignancies. However, many patients ultimately relapse and become refractory to treatment. The glycoengineered anti-CD20 mAb obinutuzumab was developed to induce enhanced antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis and direct cell death and was shown to lead to improved outcomes in a randomized study in B-CLL. We hypothesized that immune stimulation through Toll-like receptor 7 (TLR7) agonism in combination with obinutuzumab would further enhance lymphoma clearance and the generation of long-term antitumor immune responses. Here we demonstrate, in syngeneic human CD20 (hCD20)-expressing models of lymphoma, that systemic administration of a TLR7 agonist (R848) increases responses when administered in combination with obinutuzumab and protects against disease recurrence. Depletion studies demonstrate that primary antitumor activity is dependent on both NK cells and CD4(+) T cells but not on CD8(+) T cells. However, both CD4(+) and CD8(+) T cells appear necessary for the generation of protective immunological memory. Importantly, increased tumor-free survival post obinutuzumab and R848 combination therapy was seen in hCD20 transgenic mice, which express hCD20 on normal B cells. These findings provide a rationale for clinical testing of obinutuzumab in combination with systemically administered TLR7 agonists to further improve outcome.Leukemia advance online publication, 3 January 2017; doi:10.1038/leu.2016.352.

  19. Signal Use by Octopuses in Agonistic Interactions.

    Science.gov (United States)

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

    2016-02-08

    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.

  20. Nanostructured cellular networks.

    Science.gov (United States)

    Moriarty, P; Taylor, M D R; Brust, M

    2002-12-01

    Au nanocrystals spin-coated onto silicon from toluene form cellular networks. A quantitative statistical crystallography analysis shows that intercellular correlations drive the networks far from statistical equilibrium. Spin-coating from hexane does not produce cellular structure, yet a strong correlation is retained in the positions of nanocrystal aggregates. Mechanisms based on Marangoni convection alone cannot account for the variety of patterns observed, and we argue that spinodal decomposition plays an important role in foam formation.

  1. Definition of the Cellular Mechanisms Which Distinguish Between Estrogen Receptor Agonists and Antagonists

    Science.gov (United States)

    2002-07-01

    the amino- and carboxyl-termini of AR can interact with each other (8-10). He et al has recently discovered a FXXLF motif (F: phenylalanine , X: any...Treatment Guidelines for patients. National Comprehensive Cancer desmolase and steroid 17a- hydroxylase , enzymes involved in the Network and American...S., Manyak, M. J., inhibits 1 -3 hydroxylase (37), leading to increased plasma levels of O’Leary, M. P., and Painter, M. R. Practice trends in the

  2. Cellular Cell Bifurcation of Cylindrical Detonations

    Institute of Scientific and Technical Information of China (English)

    HAN Gui-Lai; JIANG Zong-Lin; WANG Chun; ZHANG Fan

    2008-01-01

    Cellular cell pattern evolution of cylindrically-diverging detonations is numerically simulated successfully by solving two-dimensional Euler equations implemented with an improved two-step chemical kinetic model. From the simulation, three cell bifurcation modes are observed during the evolution and referred to as concave front focusing, kinked and wrinkled wave front instability, and self-merging of cellular cells. Numerical research demonstrates that the wave front expansion resulted from detonation front diverging plays a major role in the cellular cell bifurcation, which can disturb the nonlinearly self-sustained mechanism of detonations and finally lead to cell bifurcations.

  3. Cryptographic primitives based on cellular transformations

    Directory of Open Access Journals (Sweden)

    B.V. Izotov

    2003-11-01

    Full Text Available Design of cryptographic primitives based on the concept of cellular automata (CA is likely to be a promising trend in cryptography. In this paper, the improved method performing data transformations by using invertible cyclic CAs (CCA is considered. Besides, the cellular operations (CO as a novel CAs application in the block ciphers are introduced. Proposed CCAs and COs, integrated under the name of cellular transformations (CT, suit well to be used in cryptographic algorithms oriented to fast software and cheap hardware implementation.

  4. TLR9 agonist protects mice from radiation-induced gastrointestinal syndrome.

    Directory of Open Access Journals (Sweden)

    Subhrajit Saha

    Full Text Available PURPOSE: Radiation-induced gastrointestinal syndrome (RIGS is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9. METHODS AND MATERIALS: Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI (8.4-10.4 Gy, TLR9 agonist (1 mg/kg s.c., 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88. Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR for tumor growth study. RESULTS: Mice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03, 9.4 Gy (p<0.008 and 8.4 Gy (p<0.002 of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01. Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008 with significant reduction of tumor growth (p<0.0001. CONCLUSIONS: TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies.

  5. Inactivated vaccine with adjuvants consisting of pattern recognition receptor agonists confers protection against avian influenza viruses in chickens.

    Science.gov (United States)

    Tang, Yinghua; Lu, Jihu; Wu, Peipei; Liu, Zhenxing; Tian, Zhen; Zha, Guofei; Chen, Hui; Wang, Qiaochu; Wang, Qiaoxiu; Hou, Fengxiang; Kang, Sang-Moo; Hou, Jibo

    2014-08-01

    Use of adjuvant containing pathogen pattern recognition receptor agonists is one of the effective strategies to enhance the efficacy of licensed vaccines. In this study, we investigated the efficacy of avian influenza vaccines containing an adjuvant (CVCVA5) which was composed of polyriboinosinic polyribocytidylic, resiquimod, imiquimod, muramyl dipeptide and levomisole. Avian influenza vaccines adjuvanted with CVCVA5 were found to induce significantly higher titers of hemagglutiniton inhibition antibodies (P≤0.01) than those of commercial vaccines at 2-, 3- and 4-week post vaccination in both specific pathogen free (SPF) chickens and field application. Furthermore, virus shedding was reduced in SPF chickens immunized with H9-CVCVA5 vaccine after H9 subtype heterologous virus challenge. The ratios of both CD3(+)CD4(+) and CD3(+)CD8(+) lymphocytes were slowly elevated in chickens immunized with H9-CVCVA5 vaccine. Lymphocytes adoptive transfer study indicates that CD8(+) T lymphocyte subpopulation might have contributed to improved protection against heterologous virus challenge. Results of this study suggest that the adjuvant CVCVA5 was capable of enhancing the potency of existing avian influenza vaccines by increasing humoral and cellular immune response.

  6. Time-Dependent Protection of CB2 Receptor Agonist in Stroke.

    Directory of Open Access Journals (Sweden)

    Seong-Jin Yu

    Full Text Available Recent studies have indicated that type 2 cannabinoid receptor (CB2R agonists reduce neurodegeneration after brain injury through anti-inflammatory activity. The purpose of this study was to examine the time-dependent interaction of CB2R and inflammation in stroke brain. Adult male rats were subjected to right middle cerebral artery occlusion (MCAo. CB2R mRNA expression was significantly elevated >20 fold on day 2, peaked >40-fold on day 5, and normalized on day 10 post-stroke. Inflammatory markers IBA1 and TLR4 were significantly upregulated 15 fold until day 5 after MCAo. Because of the delayed upregulation of CB2R and IBA1, we next treated animals daily with CB2R agonist AM1241 or anti-inflammatory PPAR-γ agonist pioglitazone from 2 to 5 days after MCAo. Delayed treatment with pioglitazone significantly reduced abnormal neurological scores and body asymmetry as well as brain infarction in stroke animals. No behavioral improvement or reduction in brain infarction was found in animals receiving AM1241. Pioglitazone, but not AM1241, significantly reduced IBA1 expression in the stroke cortex, suggesting that delayed treatment with AM1241 failed to alter ischemia-mediated IBA-1 upregulation. In contrast, pretreatment with AM1241 significantly reduced brain infarction and neurological deficits. In conclusion, our data support a time-dependent neuroprotection of CB2 agonist in an animal model of stroke. Delayed post- treatment with PPAR-γ agonist induced behavioral recovery and microglial suppression; early treatment with CB2R agonist suppressed neurodegeneration in stroke animals.

  7. [Cardiovascular effects of GLP-1 receptor agonist treatment: focus on liraglutide].

    Science.gov (United States)

    Haluzík, Martin; Trachta, Pavel; Mráz, Miloš

    2015-01-01

    Cardiovascular risk reduction is the major aim of type 2 diabetes mellitus treatment. The effects of various antidiabetics on the cardiovascular complications are currently under careful scrutiny. Incretin-based therapy that utilizes the effects of glucagon-like peptide 1 (GLP-1) or stimulation of its receptor by GLP-1 receptor agonists represents one of the most promising approaches from the potential cardiovascular risk reduction point of view. Experimental studies have shown that the GLP-1 and GLP-1 agonists treatment improves endothelial function, decrease blood pressure and protects myocardium during experimentally-induced ischemia. Clinical studies with GLP-1 receptor agonists consistently show that, in addition to good antidiabetic efficacy, its long-term administration decreases blood pressure, body weight and improves circulating lipid levels while slightly increasing heart rate. In this paper, we focus on the cardiovascular effects of GLP-1 receptor agonist liraglutide. Preliminary analyses of cardiovascular complications in phase III trials with liraglutide indicate its good cardiovascular safety. A possibility of cardioprotective effects of liraglutide remains still open and is currently studied within a prospective cardiovascular trial LEADER.

  8. Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents.

    Directory of Open Access Journals (Sweden)

    Ola Fjellström

    Full Text Available Type 2 diabetes (T2D occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.

  9. Agonist trigger: what is the best approach? Agonist trigger and low dose hCG

    DEFF Research Database (Denmark)

    Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2012-01-01

    Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)......Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)...

  10. Improved glowworm swarm optimization based on cellular automata and its application in Wiener model identification%元胞萤火虫算法在Wiener模型辨识中的应用

    Institute of Scientific and Technical Information of China (English)

    李远梅; 张宏立

    2016-01-01

    Basic glowworm swarm optimization possesses slow convergence speed,poor local search ability and easiness to fall in local peak.To overcome these problems,an adaptive step algorithm integrating the mechanism of cellular automata was pro-posed,namely applying the evolutionary rule and domain rule to glowworm swarm optimization.Neighborhood was selected via domain model and ierative refinement was proceeded by means of evolutionary rule coalesced with game of life and survival of the fittest within the domain structure.Typical test functions were simulated and tested,the results of which reveal the proposed al-gorithm has better global searching ability,convergence speed and precision.Because Wiener model of the nonlinear system pos-sesses nonlinear drag casing to identify difficultly,the improved cellular glowworm swarm optimization was put forward for model parameter identification.Parameter identification problem was converted to function optimization problem and solved using cel-lular glowworm swarm optimization.It is verified to be effective and feasible in identification problem with numerical simulation.%基本萤火虫算法存在陷入局部最优、后期收敛慢等固有缺点,为此将元胞自动机机理融入自适应步长萤火虫算法,即将邻域规则和演化规则融合在萤火虫算法中。通过其邻域模型选择邻域集合,在其邻域结构内通过一种融合生命游戏与优胜劣汰的演化规则进行迭代寻优。对4种典型的测试函数进行实验,实验结果表明,该算法能跳出局部最优,有较强的收敛速度和精度,可应用于非线性系统中 Wiener 模型的参数辨识。因 Wiener 模型含有非线性部分,导致不易辨识,采用改进的元胞萤火虫算法将该参数辨识问题转变为优化函数问题,利用元胞萤火虫算法进行函数寻优。数值仿真验证了改进算法能够有效地进行非线性系统参数辨识。

  11. CB1 receptor agonist WIN55212-2 improves motor complications in Parkinson's disease%CB1受体激动剂WIN55212-2改善帕金森病运动并发症的实验研究

    Institute of Scientific and Technical Information of China (English)

    马雅萍; 宋璐; 刘振国; 巴茂文; 卞雷斯

    2011-01-01

    目的 探讨CB1受体激动剂WIN55212-2对左旋多巴诱发的运动并发症的行为学及细胞学作用.方法通过6-OHDA立体定向注射至大鼠右侧前脑内侧束建立PD动物模型,成功的PD大鼠模型分别接受左旋多巴/苄丝肼(50mg/kg加12.5mg/kg苄丝肼,每天2次)+溶剂、左旋多巴/苄丝肼+WIN55212-2(1 mg/kg)腹腔注射,共持续21d.评估用药后大鼠的旋转反应时间、剂峰旋转圈数变化和关期发生率;采用Western blot方法检测纹状体信号转导蛋白DARPP-32(Thr75)和ERK1/2 (Thr202/Tyr204)的磷酸化表达.结果长期联合应用WIN55212-2和左旋多巴,缓解了左旋多巴单独用药所致的PD大鼠旋转反应时间缩短、剂峰旋转圈数增加的趋势,并明显降低关期发生频率.WIN55212-2与左旋多巴合用显著降低了纹状体内DARPP-32(Thr75)的磷酸化;但未使ERK1/2磷酸化表达降低至对照组水平.结论激动CB1受体可能有益于预防帕金森病运动并发症.%Objective To investigate cellular and behavioural effects of CB1 receptor agonist WIN55212-2 in a rat model of levodopa-induced motor complications. Methods The hemi-Parkinsonian rat model was produced by stereotaxically injecting 6-OHDA to right medial forebrain bundle( MFB). Animals were intraperitoneally treated with levodopa/ benserazide (50mg/kg levodopa plus 12.5mg/kg benserazide) or WIN55212-2( lmg/kg) + levodopa/benserazide twice a day for 21 days. Rotational duration,peak rotation and the frequency of failures to L-dopa were estimated. After sacrificed,the phosphorylation of dopamine and cAMP- regulated phosphoprotein of Mr 32,000( DARPP-32) at Thr75 site and extracellular signal-regulated kinase (ERK) at Thr202 and Tyr204 site was observed by Western blot. Results W1N55212-2 plus L-dopa treatment prolonged the duration of the motor response and reduced peak turning. WIN55212-2 plus L-dopa also decreased the frequency of failures to L-dopa. The long-term use of L-dopa reduced the

  12. 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.

  13. 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.

  14. Regulation of TNF-alpha secretion by a specific melanocortin-1 receptor peptide agonist.

    Science.gov (United States)

    Ignar, Diane M; Andrews, John L; Jansen, Marilyn; Eilert, Michelle M; Pink, Heather M; Lin, Peiyuan; Sherrill, Ronald G; Szewczyk, Jerzy R; Conway, James G

    2003-05-01

    The lack of specific pharmacological tools has impeded the evaluation of the role of each melanocortin receptor (MCR) subtype in the myriad physiological effects of melanocortins. 154N-5 is an octapeptide (MFRdWFKPV-NH(2)) that was first identified as an MC1R antagonist in Xenopus melanophores [J. Biol. Chem. 269 (1994) 29846]. In this manuscript, we show that 154N-5 is a specific agonist for human and murine MC1R. The peptide has negligible activity at MC3R and MC4R and is 25-fold less potent and a weak agonist at MC5R. 154N-5 was tested in both a cellular and an animal model of tumor necrosis factor-alpha (TNF-alpha) secretion. The inhibitory efficacy of 154N-5 on TNF-alpha secretion in both models was similar to the nonselective agonist NDP-alpha-melanocyte stimulating hormone (NDP-alphaMSH), thus, we conclude that inhibition of TNF-alpha secretion by melanocortin peptides is mediated by MC1R. 154N-5 is a valuable new tool for the evaluation of specific contribution of MC1R agonism to physiological and pathological processes.

  15. Dopamine agonist: pathological gambling and hypersexuality.

    Science.gov (United States)

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication.

  16. Combining GLP-1 receptor agonists with insulin

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Vilsbøll, T

    2013-01-01

    physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose...... potential of GLP-1RA-insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale...

  17. SNC 80 and related delta opioid agonists.

    Science.gov (United States)

    Calderon, S N; Coop, A

    2004-01-01

    The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, was a major advance in the field of delta-opioid ligands. Much research has been performed to uncover the structure-activity relationships (SAR) of this class of ligands and also to compare the diarylmethylpiperazines with the traditional morphinan-based delta opioids. This review focuses on the development of the SAR of this unique series of ligands, and discusses questions which remain unanswered.

  18. Sports doping: emerging designer and therapeutic β2-agonists.

    Science.gov (United States)

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

  19. Transcriptional networks in plasmacytoid dendritic cells stimulated with synthetic TLR 7 agonists

    Directory of Open Access Journals (Sweden)

    Vasilakos John P

    2007-10-01

    Full Text Available Abstract Background Plasmacytoid Dendritic Cells (pDC comprise approximately 0.2 to 0.8% of the blood mononuclear cells and are the primary type 1 interferon (IFN, producing cells, secreting high levels of IFN in response to viral infections. Plasmacytoid dendritic cells express predominantly TLRs 7 & 9, making them responsive to ssRNA and CpG DNA. The objective of this study was to evaluate the molecular and cellular processes altered upon stimulation of pDC with synthetic TLR 7 and TLR 7/8 agonists. To this end, we evaluated changes in global gene expression upon stimulation of 99.9% pure human pDC with the TLR7 selective agonists 3M-852A, and the TLR7/8 agonist 3M-011. Results Global gene expression was evaluated using the Affymetrix U133A GeneChip® and selected genes were confirmed using real time TaqMan® RTPCR. The gene expression profiles of the two agonists were similar indicating that changes in gene expression were solely due to stimulation through TLR7. Type 1 interferons were among the highest induced genes and included IFNB and multiple IFNα subtypes, IFNα2, α5, α6, α8, α1/13, α10, α14, α16, α17, α21. A large number of chemokines and co-stimulatory molecules as well as the chemokine receptor CCR7 were increased in expression indicating maturation and change in the migratory ability of pDC. Induction of an antiviral state was shown by the expression of several IFN-inducible genes with known anti-viral activity. Further analysis of the data using the pathway analysis tool MetaCore gave insight into molecular and cellular processes impacted. The analysis revealed transcription networks that show increased expression of signaling components in TLR7 and TLR3 pathways, and the cytosolic anti-viral pathway regulated by RIG1 and MDA5, suggestive of optimization of an antiviral state targeted towards RNA viruses. The analysis also revealed increased expression of a network of genes important for protein ISGylation as well as an

  20. Differentiation of δ, μ, and κ opioid receptor agonists based on pharmacophore development and computed physicochemical properties

    Science.gov (United States)

    Filizola, Marta; Villar, Hugo O.; Loew, Gilda H.

    2001-04-01

    Compounds that bind with significant affinity to the opioid receptor types, δ, μ, and κ, with different combinations of activation and inhibition at these three receptors could be promising behaviorally selective agents. Working on this hypothesis, the chemical moieties common to three different sets of opioid receptor agonists with significant affinity for each of the three receptor types δ, μ, or κ were identified. Using a distance analysis approach, common geometric arrangements of these chemical moieties were found for selected δ, μ, or κ opioid agonists. The chemical and geometric commonalities among agonists at each opioid receptor type were then compared with a non-specific opioid recognition pharmacophore recently developed. The comparison provided identification of the additional requirements for activation of δ, μ, and κ opioid receptors. The distance analysis approach was able to clearly discriminate κ-agonists, while global molecular properties for all compounds were calculated to identify additional requirements for activation of δ and μ receptors. Comparisons of the combined geometric and physicochemical properties calculated for each of the three sets of agonists allowed the determination of unique requirements for activation of each of the three opioid receptors. These results can be used to improve the activation selectivity of known opioid agonists and as a guide for the identification of novel selective opioid ligands with potential therapeutic usefulness.

  1. Epigenetics and Cellular Metabolism

    Science.gov (United States)

    Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao

    2016-01-01

    Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well. PMID:27695375

  2. Architected Cellular Materials

    Science.gov (United States)

    Schaedler, Tobias A.; Carter, William B.

    2016-07-01

    Additive manufacturing enables fabrication of materials with intricate cellular architecture, whereby progress in 3D printing techniques is increasing the possible configurations of voids and solids ad infinitum. Examples are microlattices with graded porosity and truss structures optimized for specific loading conditions. The cellular architecture determines the mechanical properties and density of these materials and can influence a wide range of other properties, e.g., acoustic, thermal, and biological properties. By combining optimized cellular architectures with high-performance metals and ceramics, several lightweight materials that exhibit strength and stiffness previously unachievable at low densities were recently demonstrated. This review introduces the field of architected materials; summarizes the most common fabrication methods, with an emphasis on additive manufacturing; and discusses recent progress in the development of architected materials. The review also discusses important applications, including lightweight structures, energy absorption, metamaterials, thermal management, and bioscaffolds.

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

    OpenAIRE

    Maharjan Anu S; Pilling Darrell; Gomer Richard H

    2010-01-01

    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 fi...

  4. Cellular blue naevus

    Directory of Open Access Journals (Sweden)

    Mittal R

    2001-01-01

    Full Text Available A 31-year-old man had asymptomatic, stationary, 1.5X2 cm, shiny, smooth, dark blue nodule on dorsum of right hand since 12-14 years. In addition he had developed extensive eruption of yellow to orange papulonodular lesions on extensors of limbs and buttocks since one and half months. Investigations confirmed that yellow papules were xanthomatosis and he had associated diabetes mellitus and hyperlipidaemia. Biopsy of blue nodule confirmed the clinical diagnosis of cellular blue naevus. Cellular blue naevus is rare and its association with xanthomatosis and diabetes mellitus were interesting features of above patients which is being reported for its rarity.

  5. Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist.

    Science.gov (United States)

    Kaminski, Rafal M; Banerjee, Madhumita; Rogawski, Michael A

    2004-06-01

    Although the mechanism of action of topiramate is not fully understood, its anticonvulsant properties may result, at least in part, from an interaction with AMPA/kainate receptors. We have recently shown that topiramate selectively inhibits postsynaptic responses mediated by GluR5 kainate receptors. To determine if this action of topiramate is relevant to the anticonvulsant effects of the drug in vivo, we determined the protective activity of topiramate against seizures induced by intravenous infusion of various ionotropic glutamate receptor agonists in mice. Topiramate (25-100 mg/kg, i.p.) produced a dose-dependent elevation in the threshold for clonic seizures induced by infusion of ATPA, a selective agonist of GluR5 kainate receptors. Topiramate was less effective in protecting against clonic seizures induced by kainate, a mixed agonist of AMPA and kainate receptors. Topiramate did not affect clonic seizures induced by AMPA or NMDA. In contrast, the thresholds for tonic seizures induced by higher doses of these various glutamate receptor agonists were all elevated by topiramate. Unlike topiramate, carbamazepine elevated the threshold for AMPA- but not ATPA-induced clonic seizures. Our results are consistent with the possibility that the effects of topiramate on clonic seizure activity are due to functional blockade of GluR5 kainate receptors. Protection from tonic seizures may be mediated by other actions of the drug. Together with our in vitro cellular electrophysiological results, the present observations strongly support a unique mechanism of action of topiramate, which involves GluR5 kainate receptors.

  6. Experimental study of 5-hydroxytryptamine 1A receptor agonist to improve the voiding dysfunction in diabetic rats%5-羟色胺1A受体激动剂改善糖尿病大鼠排尿功能障碍的实验研究

    Institute of Scientific and Technical Information of China (English)

    陈加生; 吴刚; 谷宝军

    2014-01-01

    目的 研究5-羟色胺1A(5-HT1A)受体激动剂对糖尿病大鼠排尿障碍的改善作用.方法 SD雌性大鼠14只,体质量250~ 275 g.采用随机数字表法随机分成2组:实验组7只腹腔注射链脲霉素65 mg/kg建立糖尿病大鼠模型,对照组7只.8周后乌拉坦1.3 g/kg麻醉下,2组大鼠颈静脉和膀胱内置管,连接压力感受器,记录排尿量、残余尿量、膀胱容量和尿道外括约肌的肌电活动.静脉注入5-HT1A受体激动剂8-羟基-丙胺-四氢萘(8-OH-DPAT,0.003~ 1.000 mg/kg),得到剂量-效应曲线后再给予5-HT1A受体抑制剂WAY-100635(0.300 mg/kg).观察比较2组大鼠用药前后尿动力学指标的变化. 结果 糖尿病大鼠膀胱容量、残余尿量高于对照组大鼠,排尿效率下降.随着8-OH-DPAT(0.003~ 1.000 mg/kg)剂量增加,糖尿病大鼠排尿量从(2.15±0.49) ml增至(2.85±0.21) ml,残余尿量从(3.40±0.74) ml降至(1.82±.0.48) ml,排尿效率从(39.0±9.3)%增至(61.6±6.9)%.对照组大鼠用药前后排尿情况变化差异无统计学意义(P>0.05).肌电图显示8-OH-DPAT能改善糖尿病大鼠受损的尿道外括约肌高频舒张收缩功能,对于对照组大鼠也有增强作用.而WAY-100635能逆转8-OH-DPAT的效应. 结论 糖尿病大鼠尿道外括约肌高频舒张收缩活动减弱,排尿效率下降.5-HT1A受体激动剂8-OH-DPAT可以部分恢复糖尿病大鼠尿道外括约肌协调性松弛,从而提高排尿效率,改善排尿障碍.%Objective To investigate the effect of 5-hydroxytryptamine 1A (5-HT1A) receptor agonists to improve micturition function in rats with diabetes mellitus (DM).Methods Fourteen female SD rats with the weight of 250 to 275 g were used.Seven rats were in the DM model group with intraperitoneal injection streptozotocin (STZ,65 mg/kg).Rats in the control group and DM group were anesthetized with urethane (1.3 g/kg) 8 weeks later.A polyethylene (PE)-50 catheter were placed in the left jugular vein for intravenous

  7. Antidiabetic properties of the histamine H3 receptor protean agonist proxyfan.

    Science.gov (United States)

    Henry, Melanie B; Zheng, Shuqin; Duan, Chenxia; Patel, Bhuneshwari; Vassileva, Galya; Sondey, Christopher; Lachowicz, Jean; Hwa, Joyce J

    2011-03-01

    Proxyfan is a histamine H3 receptor protean agonist that can produce a spectrum of pharmacological effects including agonist, inverse agonist, and antagonist. We have discovered that proxyfan (10 mg/kg orally) significantly improved glucose excursion after an ip glucose tolerance test in either lean or high-fat/cholesterol diet-induced obese mice. It also reduced plasma glucose levels comparable to that of metformin (300 mg/kg orally) in a nongenetic type 2 diabetes mouse model. The dose-dependent decrease in glucose excursion correlated with inhibition of ex vivo H3 receptor binding in the cerebral cortex. In addition, glucose levels were significantly reduced compared with vehicle-treated mice after intracerebroventricular administration of proxyfan, suggesting the involvement of central H3 receptors. Proxyfan-induced reduction of glucose excursion was not observed in the H3 receptor knockout mice, suggesting that proxyfan mediates this effect through H3 receptors. Proxyfan reduced glucose excursion by significantly increasing plasma insulin levels in a glucose-independent manner. However, no difference in insulin sensitivity was observed in proxyfan-treated mice. The H1 receptor antagonist chlorpheniramine and the H2 receptor antagonist zolantidine had modest effects on glucose excursion, and neither inhibited the glucose excursion reduced by proxyfan. The H3 receptor antagonist/inverse agonist, thioperamide, had weaker effects on glucose excursion compared with proxyfan, whereas the H3 receptor agonist imetit did not affect glucose excursion. In conclusion, these findings demonstrate, for the first time, that manipulation of central histamine H3 receptor by proxyfan can significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism.

  8. Cellular rehabilitation of photobiomodulation

    Science.gov (United States)

    Liu, Timon Cheng-Yi; Yuan, Jian-Qin; Wang, Yan-Fang; Xu, Xiao-Yang; Liu, Song-Hao

    2007-05-01

    Homeostasis is a term that refers to constancy in a system. A cell in homeostasis normally functions. There are two kinds of processes in the internal environment and external environment of a cell, the pathogenic processes (PP) which disrupts the old homeostasis (OH), and the sanogenetic processes (SP) which restores OH or establishes a new homeostasis (NH). Photobiomodualtion (PBM), the cell-specific effects of low intensity monochromatic light or low intensity laser irradiation (LIL) on biological systems, is a kind of modulation on PP or SP so that there is no PBM on a cell in homeostasis. There are two kinds of pathways mediating PBM, the membrane endogenetic chromophores mediating pathways which often act through reactive oxygen species, and membrane proteins mediating pathways which often enhance cellular SP so that it might be called cellular rehabilitation. The cellular rehabilitation of PBM will be discussed in this paper. It is concluded that PBM might modulate the disruption of cellular homeostasis induced by pathogenic factors such as toxin until OH has been restored or NH has been established, but can not change homeostatic processes from one to another one.

  9. Cellular Response to Irradiation

    Institute of Scientific and Technical Information of China (English)

    LIU Bo; YAN Shi-Wei

    2011-01-01

    To explore the nonlinear activities of the cellular signaling system composed of one transcriptional arm and one protein-interaction arm, we use an irradiation-response module to study the dynamics of stochastic interactions.It is shown that the oscillatory behavior could be described in a unified way when the radiation-derived signal and noise are incorporated.

  10. PPARγ partial agonist GQ-16 strongly represses a subset of genes in 3T3-L1 adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Milton, Flora Aparecida [Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília (Brazil); Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States); Cvoro, Aleksandra [Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States); Amato, Angelica A. [Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília (Brazil); Sieglaff, Douglas H.; Filgueira, Carly S.; Arumanayagam, Anithachristy Sigamani [Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States); Caro Alves de Lima, Maria do; Rocha Pitta, Ivan [Laboratório de Planejamento e Síntese de Fármacos – LPSF, Universidade Federal de Pernambuco (Brazil); Assis Rocha Neves, Francisco de [Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília (Brazil); Webb, Paul, E-mail: pwebb@HoustonMethodist.org [Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States)

    2015-08-28

    Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists that improve insulin resistance but trigger side effects such as weight gain, edema, congestive heart failure and bone loss. GQ-16 is a PPARγ partial agonist that improves glucose tolerance and insulin sensitivity in mouse models of obesity and diabetes without inducing weight gain or edema. It is not clear whether GQ-16 acts as a partial agonist at all PPARγ target genes, or whether it displays gene-selective actions. To determine how GQ-16 influences PPARγ activity on a gene by gene basis, we compared effects of rosiglitazone (Rosi) and GQ-16 in mature 3T3-L1 adipocytes using microarray and qRT-PCR. Rosi changed expression of 1156 genes in 3T3-L1, but GQ-16 only changed 89 genes. GQ-16 generally showed weak effects upon Rosi induced genes, consistent with partial agonist actions, but a subset of modestly Rosi induced and strongly repressed genes displayed disproportionately strong GQ-16 responses. PPARγ partial agonists MLR24 and SR1664 also exhibit disproportionately strong effects on transcriptional repression. We conclude that GQ-16 displays a continuum of weak partial agonist effects but efficiently represses some negatively regulated PPARγ responsive genes. Strong repressive effects could contribute to physiologic actions of GQ-16. - Highlights: • GQ-16 is an insulin sensitizing PPARγ ligand with reduced harmful side effects. • GQ-16 displays a continuum of weak partial agonist activities at PPARγ-induced genes. • GQ-16 exerts strong repressive effects at a subset of genes. • These inhibitor actions should be evaluated in models of adipose tissue inflammation.

  11. Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer's Disease.

    Science.gov (United States)

    Stachel, Shawn J; Zerbinatti, Celina; Rudd, Michael T; Cosden, Mali; Suon, Sokreine; Nanda, Kausik K; Wessner, Keith; DiMuzio, Jillian; Maxwell, Jill; Wu, Zhenhua; Uslaner, Jason M; Michener, Maria S; Szczerba, Peter; Brnardic, Edward; Rada, Vanessa; Kim, Yuntae; Meissner, Robert; Wuelfing, Peter; Yuan, Yang; Ballard, Jeanine; Holahan, Marie; Klein, Daniel J; Lu, Jun; Fradera, Xavier; Parthasarathy, Gopal; Uebele, Victor N; Chen, Zhongguo; Li, Yingjie; Li, Jian; Cooke, Andrew J; Bennett, D Jonathan; Bilodeau, Mark T; Renger, John

    2016-04-14

    Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.

  12. Clonazepam as Agonist Substitution Treatment for Benzodiazepine Dependence: A Case Report

    Directory of Open Access Journals (Sweden)

    Angelo Giovanni Icro Maremmani

    2013-01-01

    Full Text Available Nowadays, the misuse of benzodiazepines (BZDs is a cause for a serious concern among pharmacologically inexperienced patients, whether treated or untreated, that could lead to significant complications, including tolerance, dependence, and addiction. We present a case report in which an Italian patient affected by anxiety disorder and treated with BZDs presented a severe case of dependence on BZDs. We treated him according to an agonist substitution approach, switching from the abused BZD to a slow-onset, long-acting, high potency agonist (clonazepam, and looking at the methadone treatment model as paradigm. We decided to use clonazepam for its pharmacokinetic properties. The advantage of choosing a slow-onset, long-lasting BZD for the treatment of our patient was that it led us to a remarkable improvement in the clinical situation, including the cessation of craving, absence of withdrawal symptoms, reduced anxiety, improvements in social functioning, and a better cognition level.

  13. Infrared image enhancement using Cellular Automata

    Science.gov (United States)

    Qi, Wei; Han, Jing; Zhang, Yi; Bai, Lian-fa

    2016-05-01

    Image enhancement is a crucial technique for infrared images. The clear image details are important for improving the quality of infrared images in computer vision. In this paper, we propose a new enhancement method based on two priors via Cellular Automata. First, we directly learn the gradient distribution prior from the images via Cellular Automata. Second, considering the importance of image details, we propose a new gradient distribution error to encode the structure information via Cellular Automata. Finally, an iterative method is applied to remap the original image based on two priors, further improving the quality of enhanced image. Our method is simple in implementation, easy to understand, extensible to accommodate other vision tasks, and produces more accurate results. Experiments show that the proposed method performs better than other methods using qualitative and quantitative measures.

  14. 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.

  15. The importance of β2-agonists in myocardial infarction

    DEFF Research Database (Denmark)

    Rørth, Rasmus; Fosbøl, Emil L; Mogensen, Ulrik M;

    2015-01-01

    PURPOSE: β2-Agonists are widely used for relief of respiratory symptoms. Studies so far have reported conflicting results regarding use of β2-agonists and risk of myocardial infarction (MI). Yet, coronary angiographical data and longitudinal outcomes data are sparse and could help explain...

  16. A novel HIV vaccine adjuvanted by IC31 induces robust and persistent humoral and cellular immunity.

    Directory of Open Access Journals (Sweden)

    Laura Pattacini

    Full Text Available The HIV vaccine strategy that, to date, generated immune protection consisted of a prime-boost regimen using a canarypox vector and an HIV envelope protein with alum, as shown in the RV144 trial. Since the efficacy was weak, and previous HIV vaccine trials designed to generate antibody responses failed, we hypothesized that generation of T cell responses would result in improved protection. Thus, we tested the immunogenicity of a similar envelope-based vaccine using a mouse model, with two modifications: a clade C CN54gp140 HIV envelope protein was adjuvanted by the TLR9 agonist IC31®, and the viral vector was the vaccinia strain NYVAC-CN54 expressing HIV envelope gp120. The use of IC31® facilitated immunoglobulin isotype switching, leading to the production of Env-specific IgG2a, as compared to protein with alum alone. Boosting with NYVAC-CN54 resulted in the generation of more robust Th1 T cell responses. Moreover, gp140 prime with IC31® and alum followed by NYVAC-CN54 boost resulted in the formation and persistence of central and effector memory populations in the spleen and an effector memory population in the gut. Our data suggest that this regimen is promising and could improve the protection rate by eliciting strong and long-lasting humoral and cellular immune responses.

  17. Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials

    DEFF Research Database (Denmark)

    Madsbad, Sten; Krarup, Thure; Deacon, Carolyn F;

    2008-01-01

    PURPOSE OF REVIEW: To discuss the virtues and shortcomings of the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes. RECENT FINDINGS: The injectable glucagon-like peptide-1 receptor agonists exenatide significantly improves......-acting glucagon-like peptide-1 receptor agonists liraglutide and exenatide long-acting release reduce haemoglobin A1c by about 1.0-2.0% and have fewer gastrointestinal side-effects. The orally available dipeptidyl peptidase-4 inhibitors, that is sitagliptin and vildagliptin reduce haemoglobin A1c by 0...

  18. Treatment of Type 2 Diabetes by Free Fatty Acid Receptor Agonists

    OpenAIRE

    Kenneth R. Watterson; Hudson, Brian D.; Ulven, Trond; Milligan, Graeme

    2014-01-01

    Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for Free Fatty Acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long chain FFA receptor, FFA1, improved glycaemic control an...

  19. Estrogen receptor beta agonists in neurobehavioral investigations.

    Science.gov (United States)

    Choleris, Elena; Clipperton, Amy E; Phan, Anna; Kavaliers, Martin

    2008-07-01

    Neurobehavioral investigations into the functions of estrogen receptor (ER)alpha and ERbeta have utilized 'knockout' mice, phytoestrogens and, more recently, ER-specific agonists. Feeding, sexual, aggressive and social behavior, anxiety, depression, drug abuse, pain perception, and learning (and associated synaptic plasticity) are affected by ERalpha and ERbeta in a manner that is dependent upon the specific behavior studied, gender and developmental stage. Overall, ERalpha and ERbeta appear to function together to foster sociosexual behavior while inhibiting behaviors that, if occurring at the time of behavioral estrous, may compete with reproduction (eg, feeding). Recently developed pharmacological tools have limited selectivity and availability to the research community at large, as they are not commercially available. The development of highly selective, commercially available ERbeta-specific antagonists would greatly benefit preclinical and applied research.

  20. Molecular and Cellular Signaling

    CERN Document Server

    Beckerman, Martin

    2005-01-01

    A small number of signaling pathways, no more than a dozen or so, form a control layer that is responsible for all signaling in and between cells of the human body. The signaling proteins belonging to the control layer determine what kinds of cells are made during development and how they function during adult life. Malfunctions in the proteins belonging to the control layer are responsible for a host of human diseases ranging from neurological disorders to cancers. Most drugs target components in the control layer, and difficulties in drug design are intimately related to the architecture of the control layer. Molecular and Cellular Signaling provides an introduction to molecular and cellular signaling in biological systems with an emphasis on the underlying physical principles. The text is aimed at upper-level undergraduates, graduate students and individuals in medicine and pharmacology interested in broadening their understanding of how cells regulate and coordinate their core activities and how diseases ...

  1. 蜂窝网中基于分布式约束满足算法的改进信道分配%Distributed Constraint Satisfaction of an Improved Channel Assignment Approach in Cellular Network

    Institute of Scientific and Technical Information of China (English)

    韦沙; 刘威; 陈小慧; 程文青

    2012-01-01

    随着蜂窝网业务需求的不断增长,如何利用有限的信道资源在各小区间进行复用,以便既能避免移动用户之间的干扰,又能满足所有移动用户的话务请求,使蜂窝系统容量大大增加,已成为一项重要研究课题.此类问题属于NP-hard的信道分配问题(Channel Assignment Problem,CAP),将CAP问题形式化为分布式约束满足问题(DCSP),然后提出基于改进现有的信道分配策略,以获得更高的信道利用率、较令人满意的系统服务质量,尽可能满足所有用户的话务请求.将利用尽可能简单、搜寻时间短的算法,并将现有的benchmark问题进行仿真.实验表明,该方案对有效改进信道分配问题,充分利用有限的信道资源,降低系统的阻塞率,有着较好的应用前景.%As demands grow for wireless communication systems and the limited number of channel resources, the channel assignment problem(CAP) becomes increasingly important The goal of channel assignment is to reduce the interferences, and enhance the capacity. CAP is a well-known NP-hard problem. In this paper, we modeled CAP as a Distributed Constraint Satisfaction Problem(DSCP) with fully considerations on all constraints of interferences, then proposed an improve channel assignment approach to minimized more required number of channels in cellular mobile system and minimize the number of blocked hosts. We also provided one kind of complete search algorithms, which outperforms others by providing quasi-optimal solutions at a related lower cost and time. We evaluated the performance of our approach in solving CAP, which is based on the existing benchmark. The simulation result shows that our approach provides optimal solutions and minimizes call failures, which is more feasible and easy to be applied in practical engineering.

  2. Environment Aware Cellular Networks

    KAUST Repository

    Ghazzai, Hakim

    2015-02-01

    The unprecedented rise of mobile user demand over the years have led to an enormous growth of the energy consumption of wireless networks as well as the greenhouse gas emissions which are estimated currently to be around 70 million tons per year. This significant growth of energy consumption impels network companies to pay huge bills which represent around half of their operating expenditures. Therefore, many service providers, including mobile operators, are looking for new and modern green solutions to help reduce their expenses as well as the level of their CO2 emissions. Base stations are the most power greedy element in cellular networks: they drain around 80% of the total network energy consumption even during low traffic periods. Thus, there is a growing need to develop more energy-efficient techniques to enhance the green performance of future 4G/5G cellular networks. Due to the problem of traffic load fluctuations in cellular networks during different periods of the day and between different areas (shopping or business districts and residential areas), the base station sleeping strategy has been one of the main popular research topics in green communications. In this presentation, we present several practical green techniques that provide significant gains for mobile operators. Indeed, combined with the base station sleeping strategy, these techniques achieve not only a minimization of the fossil fuel consumption but also an enhancement of mobile operator profits. We start with an optimized cell planning method that considers varying spatial and temporal user densities. We then use the optimal transport theory in order to define the cell boundaries such that the network total transmit power is reduced. Afterwards, we exploit the features of the modern electrical grid, the smart grid, as a new tool of power management for cellular networks and we optimize the energy procurement from multiple energy retailers characterized by different prices and pollutant

  3. Neuroprotective effect of an angiotensin receptor type 2 agonist following cerebral ischemia in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Lee Seyoung

    2012-08-01

    Full Text Available Abstract Background Intracerebral administration of the angiotensin II type 2 receptor (AT2R agonist, CGP42112, is neuroprotective in a rat model of ischemic stroke. To explore further its possible cellular target(s and therapeutic utility, we firstly examined whether CGP42112 may exert direct protective effects on primary neurons following glucose deprivation in vitro. Secondly, we tested whether CGP42112 is effective when administered systemically in a mouse model of cerebral ischemia. Methods Primary cortical neurons were cultured from E17 C57Bl6 mouse embryos for 9 d, exposed to glucose deprivation for 24 h alone or with drug treatments, and percent cell survival assessed using trypan blue exclusion. Ischemic stroke was induced in adult male C57Bl6 mice by middle cerebral artery occlusion for 30 min, followed by reperfusion for 23.5 h. Neurological assessment was performed and then mice were euthanized and infarct and edema volume were analysed. Results During glucose deprivation, CGP42112 (1x10-8 M and 1x10-7 M reduced cell death by ~30%, an effect that was prevented by the AT2R antagonist, PD123319 (1x10-6 M. Neuroprotection by CGP42112 was lost at a higher concentration (1x10-6 M but was unmasked by co-application with the AT1R antagonist, candesartan (1x10-7 M. By contrast, Compound 21 (1x10-8 M to 1x10-6 M, a second AT2R agonist, had no effect on neuronal survival. Mice treated with CGP42112 (1 mg/kg i.p. after cerebral ischemia had improved functional outcomes over vehicle-treated mice as well as reduced total and cortical infarct volumes. Conclusions These results indicate that CGP42112 can directly protect neurons from ischemia-like injury in vitro via activation of AT2Rs, an effect opposed by AT1R activation at high concentrations. Furthermore, systemic administration of CGP42112 can reduce functional deficits and infarct volume following cerebral ischemia in vivo.

  4. The Melatonin Receptor Agonist Ramelteon Effectively Treats Insomnia and Behavioral Symptoms in Autistic Disorder

    Directory of Open Access Journals (Sweden)

    Kentaro Kawabe

    2014-01-01

    Full Text Available Children with autism spectrum disorders (ASD, including autistic disorder, frequently suffer from comorbid sleep problems. An altered melatonin rhythm is considered to underlie the impairment in sleep onset and maintenance in ASD. We report three cases with autistic disorder in whom nocturnal symptoms improved with ramelteon, a selective melatonin receptor agonist. Insomnia and behavior, assessed using the Clinical Global Impression-Improvement Scale, improved in two cases with 2 mg ramelteon and in the third case with 8 mg ramelteon. Our findings demonstrate that ramelteon is effective not only for insomnia, but for behavioral problems as well, in patients with autistic disorder.

  5. The melatonin receptor agonist ramelteon effectively treats insomnia and behavioral symptoms in autistic disorder.

    Science.gov (United States)

    Kawabe, Kentaro; Horiuchi, Fumie; Oka, Yasunori; Ueno, Shu-Ichi

    2014-01-01

    Children with autism spectrum disorders (ASD), including autistic disorder, frequently suffer from comorbid sleep problems. An altered melatonin rhythm is considered to underlie the impairment in sleep onset and maintenance in ASD. We report three cases with autistic disorder in whom nocturnal symptoms improved with ramelteon, a selective melatonin receptor agonist. Insomnia and behavior, assessed using the Clinical Global Impression-Improvement Scale, improved in two cases with 2 mg ramelteon and in the third case with 8 mg ramelteon. Our findings demonstrate that ramelteon is effective not only for insomnia, but for behavioral problems as well, in patients with autistic disorder.

  6. Improved Case-Based Reasoning Based Cellular Automaton for Simulating Land Cover Change%改进的案例推理CA模型及土地覆盖变化模拟

    Institute of Scientific and Technical Information of China (English)

    张琴; 张友静; 张滔

    2012-01-01

    This paper presents an improved Case-Based Reasoning based Cellular Automata model (CBR-CA) in modeling multiple land covers changes. Currently, various research communities have tried to build and apply mathematic models with CBR or CA as systemic method to study concerning specific geo-scientific problems. However.original CBR-CA model has problems in modeling numerous class changes,especially in modeling land cover changes with large region and long time. In this paper,an improved CBR-CA is designed to calculate conversion probabilities for computing multiple land cover. Firstly, the macro transition probability of each class is added to the objective function, which can express the characteristic of multiple class changes. Then, considering the time weight, which can reflect the space-time changes of land cover, the final probability function is derived by both. In addition, due to variation of land cover types and their spatial relationships in complex geography changes, Monte Carlo is made use of deciding the final transition classes. This model has been applied to simulate the land cover changes of the source of the Yellow River in 1995,2000 and 2006,and has been applied to predict this region in 2012 and 2018 by building the historical case-based database with the land cover data in 1977 and 1985. The simulated and actual patterns are basic consistent in amounts,accounting for 0.002% ,0.012% and 0.005% of the total error,respectively, the space accuracies totally beyond 70%. The result indicates that this model can simulate and predict the land cover changes which are with multiple classes and with long time.%对基于案例推理的元胞自动机模型(CBR-CA)进行改进,将各类别的宏观转移概率添加到目标函数中,体现各类别的转变特征,并增加时间权重来确定转移概率,实现时间尺度上的模拟;由于土地覆盖变化的多样性和空间结构的复杂性,利用Monte Carlo(M-C)法确定土地覆盖的最终转换

  7. Quantum dot-based screening system for discovery of g protein-coupled receptor agonists.

    Science.gov (United States)

    Lee, Junghan; Kwon, Yong-Jun; Choi, Youngseon; Kim, Hi Chul; Kim, Keumhyun; Kim, JinYeop; Park, Sun; Song, Rita

    2012-07-09

    Cellular imaging has emerged as an important tool to unravel biological complexity and to accelerate the drug-discovery process, including cell-based screening, target identification, and mechanism of action studies. Recently, semiconductor nanoparticles known as quantum dots (QDs) have attracted great interest in cellular imaging applications due to their unique photophysical properties such as size, tunable optical property, multiplexing capability, and photostability. Herein, we show that QDs can also be applied to assay development and eventually to high-throughput/content screening (HTS/HCS) for drug discovery. We have synthesized QDs modified with PEG and primary antibodies to be used as fluorescent probes for a cell-based HTS system. The G protein-coupled receptor (GPCR) family is known to be involved in most major diseases. We therefore constructed human osteosarcoma (U2OS) cells that specifically overexpress two types of differently tagged GPCRs: influenza hemagglutinin (HA) peptide-tagged κ-opioid receptors (κ-ORs) and GFP-tagged A3 adenosine receptors (A3AR). In this study, we have demonstrated that 1) anti-HA antibody-conjugated QDs could specifically label HA-tagged κ-ORs, 2) subsequent treatment of QD-tagged GPCR agonists allowed agonist-induced translocation to be monitored in real time, 3) excellent emission spectral properties of QD permitted the simultaneous detection of two GPCRs in one cell, and 4) the robust imaging capabilities of the QD-antibody conjugates could lead to reproducible quantitative data from high-content cellular images. These results suggest that the present QD-based GPCR inhibitor screening system can be a promising platform for further drug screening applications.

  8. Green Cellular Networks: A Survey, Some Research Issues and Challenges

    CERN Document Server

    Hasan, Ziaul; Bhargava, Vijay K

    2011-01-01

    Energy efficiency in cellular networks is a growing concern for cellular operators to not only maintain profitability, but also to reduce the overall environment effects. This emerging trend of achieving energy efficiency in cellular networks is motivating the standardization authorities and network operators to continuously explore future technologies in order to bring improvements in the entire network infrastructure. In this article, we present a brief survey of methods to improve the power efficiency of cellular networks, explore some research issues and challenges and suggest some techniques to enable an energy efficient or "green" cellular network. Since base stations consume a maximum portion of the total energy used in a cellular system, we will first provide a comprehensive survey on techniques to obtain energy savings in base stations. Next, we discuss how heterogenous network deployment based on micro, pico and femto-cells can be used to achieve this goal. Since cognitive radio and cooperative rela...

  9. 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

  10. Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor

    DEFF Research Database (Denmark)

    Stolk, Jan; Stockley, Robert A; Stoel, Berend C

    2012-01-01

    Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-init...

  11. Cellular communication through light.

    Directory of Open Access Journals (Sweden)

    Daniel Fels

    Full Text Available Information transfer is a fundamental of life. A few studies have reported that cells use photons (from an endogenous source as information carriers. This study finds that cells can have an influence on other cells even when separated with a glass barrier, thereby disabling molecule diffusion through the cell-containing medium. As there is still very little known about the potential of photons for intercellular communication this study is designed to test for non-molecule-based triggering of two fundamental properties of life: cell division and energy uptake. The study was performed with a cellular organism, the ciliate Paramecium caudatum. Mutual exposure of cell populations occurred under conditions of darkness and separation with cuvettes (vials allowing photon but not molecule transfer. The cell populations were separated either with glass allowing photon transmission from 340 nm to longer waves, or quartz being transmittable from 150 nm, i.e. from UV-light to longer waves. Even through glass, the cells affected cell division and energy uptake in neighboring cell populations. Depending on the cuvette material and the number of cells involved, these effects were positive or negative. Also, while paired populations with lower growth rates grew uncorrelated, growth of the better growing populations was correlated. As there were significant differences when separating the populations with glass or quartz, it is suggested that the cell populations use two (or more frequencies for cellular information transfer, which influences at least energy uptake, cell division rate and growth correlation. Altogether the study strongly supports a cellular communication system, which is different from a molecule-receptor-based system and hints that photon-triggering is a fine tuning principle in cell chemistry.

  12. Synthesis and evaluation of structurally constrained quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists.

    Science.gov (United States)

    Nagase, Tsuyoshi; Mizutani, Takashi; Sekino, Etsuko; Ishikawa, Shiho; Ito, Sayaka; Mitobe, Yuko; Miyamoto, Yasuhisa; Yoshimoto, Ryo; Tanaka, Takeshi; Ishihara, Akane; Takenaga, Norihiro; Tokita, Shigeru; Sato, Nagaaki

    2008-11-13

    A series of structurally constrained derivatives of the potent H 3 inverse agonist 1 was designed, synthesized, and evaluated as histamine H 3 receptor inverse agonists. As a result, the N-cyclobutylpiperidin-4-yloxy group as in 2f was identified as an optimal surrogate structure for the flexible 1-pyrrolidinopropoxy group of 1. Subsequent optimization of the quinazolinone core of 2f revealed that substitution at the 5-position of the quinazolinone ring influences potency. Representative derivatives 5a and 5s showed improved potency in a histamine release assay in rats and a receptor occupancy assay in mice.

  13. Cellular automata: structures

    OpenAIRE

    Ollinger, Nicolas

    2002-01-01

    Jury : François Blanchard (Rapporteur), Marianne Delorme (Directeur), Jarkko Kari (Président), Jacques Mazoyer (Directeur), Dominique Perrin, Géraud Sénizergues (Rapporteur); Cellular automata provide a uniform framework to study an important problem of "complex systems" theory: how and why do system with a easily understandable -- local -- microscopic behavior can generate a more complicated -- global -- macroscopic behavior? Since its introduction in the 40s, a lot of work has been done to ...

  14. Engineering Cellular Metabolism

    DEFF Research Database (Denmark)

    Nielsen, Jens; Keasling, Jay

    2016-01-01

    Metabolic engineering is the science of rewiring the metabolism of cells to enhance production of native metabolites or to endow cells with the ability to produce new products. The potential applications of such efforts are wide ranging, including the generation of fuels, chemicals, foods, feeds...... of metabolic engineering and will discuss how new technologies can enable metabolic engineering to be scaled up to the industrial level, either by cutting off the lines of control for endogenous metabolism or by infiltrating the system with disruptive, heterologous pathways that overcome cellular regulation....

  15. Failover in cellular automata

    CERN Document Server

    Kumar, Shailesh

    2010-01-01

    A cellular automata (CA) configuration is constructed that exhibits emergent failover. The configuration is based on standard Game of Life rules. Gliders and glider-guns form the core messaging structure in the configuration. The blinker is represented as the basic computational unit, and it is shown how it can be recreated in case of a failure. Stateless failover using primary-backup mechanism is demonstrated. The details of the CA components used in the configuration and its working are described, and a simulation of the complete configuration is also presented.

  16. Vitamin D receptor agonists inhibit pro-inflammatory cytokine production from the respiratory epithelium in cystic fibrosis.

    LENUS (Irish Health Repository)

    McNally, P

    2011-07-22

    BACKGROUND: 1,25-Dihydroxycholecalciferol (1,25(OH)(2)D(3)) has been shown to mitigate epithelial inflammatory responses after antigen exposure. Patients with cystic fibrosis (CF) are at particular risk for vitamin D deficiency. This may contribute to the exaggerated inflammatory response to pulmonary infection in CF. METHODS: CF respiratory epithelial cell lines were exposed to Pseudomonas aeruginosa lipopolysaccharide (LPS) and Pseudomonas conditioned medium (PCM) in the presence or absence of 1,25(OH)(2)D(3) or a range of vitamin D receptor (VDR) agonists. Levels of IL-6 and IL-8 were measured in cell supernatants, and cellular total and phosphorylated IκBα were determined. Levels of human cathelicidin antimicrobial peptide (hCAP18) mRNA and protein were measured in cells after treatment with 1,25(OH)(2)D(3). RESULTS: Pretreatment with 1,25(OH)(2)D(3) was associated with significant reductions in IL-6 and IL-8 protein secretion after antigen exposure, a finding reproduced with a range of low calcaemic VDR agonists. 1,25(OH)(2)D(3) treatment led to a decrease in IκBα phosphorylation and increased total cellular IκBα. Treatment with 1,25(OH)(2)D(3) was associated with an increase in hCAP18\\/LL-37 mRNA and protein levels. CONCLUSIONS: Both 1,25(OH)(2)D(3) and other VDR agonists significantly reduce the pro-inflammatory response to antigen challenge in CF airway epithelial cells. VDR agonists have significant therapeutic potential in CF.

  17. 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.

  18. Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor

    DEFF Research Database (Denmark)

    Holst, Birgitte; Lang, Manja; Brandt, Erik

    2006-01-01

    (TM)-III, TM-VI and TM-VII]. In contrast, the inverse agonist peptides bind in a pocket that extends all the way from the extracellular end of TM-II (AspII:20) across between TM-III and TM-VI/VII to TM-V and TM-IV. The potency of the main inverse agonist could be improved up to 20-fold by a number...... of space-generating mutants located relatively deep in the binding pocket at key positions in TM-III, TM-IV and TM-V. It is proposed that the inverse agonists prevent the spontaneous receptor activation by inserting relatively deeply across the main ligand-binding pocket and sterically blocking...

  19. Methadone-related opioid agonist pharmacotherapy for heroin addiction. History, recent molecular and neurochemical research and future in mainstream medicine.

    Science.gov (United States)

    Kreek, M J

    2000-01-01

    In 1963, Professor Vincent P. Dole at the Rockefeller University formed a small team to develop a pharmacotherapy for the management of heroin addiction. They hypothesized that heroin addiction is a disease of the brain with behavioral manifestations, and not merely a personality disorder or criminal behavior and began to address the specific question of whether a long-acting opioid agonist could be used in the long-term maintenance treatment of heroin addiction. Over the next 35 years, many studies documented the safety, efficacy and effectiveness of methadone pharmacotherapy for heroin addiction, but Federal regulations and stigmatization of heroin addiction prevented implementation of treatment. Finally, in 1999, NIH published a report unequivocally supporting methadone maintenance pharmacotherapy for heroin addiction. Two other effective opioid agonist treatments have been developed: the even longer acting opioid agonist l-alpha-acetylmethadol (LAAM) has been approved for pharmacotherapy for heroin addiction, and still under study is the opioid partial agonist-antagonist buprenorphine-naloxone combination. A variety of studies, both laboratory based and clinical, have revealed the mechanisms of action of long-acting opioid agonists in treatment, including prevention of disruption of molecular, cellular and physiologic events and, in fact, allowing normalization of those functions disrupted by chronic heroin use. Recent molecular biological studies have revealed single nucleotide polymorphisms of the human mu opioid receptor gene; the mu opioid receptor is the site of action of heroin, the major opiate drug of abuse, analgesic agents such as morphine, and the major treatment agents for heroin addiction. These findings support the early hypotheses of our laboratory that addiction may be due to a combination of genetic, drug-induced and environmental (including behavioral) factors and also, that atypical stress responsivity may contribute to the acquisition and

  20. The effects of the 5-HT(6) receptor agonist EMD and the 5-HT(7) receptor agonist AS19 on memory formation.

    Science.gov (United States)

    Meneses, A; Perez-Garcia, G; Liy-Salmeron, G; Flores-Galvez, D; Castillo, C; Castillo, E

    2008-12-16

    Growing evidence indicates that 5-hydrohytryptamine (5-HT) receptors mediate learning and memory. Particularly interesting are 5-HT(6) and 5-HT(7) receptors, which are localized in brain areas involved in memory formation. Interestingly, recently selective 5-HT(6) and 5-HT(7) receptor agonists and antagonists have become available. Previous evidence indicates that 5-HT(6) or 5-HT(7) receptors antagonists had no effects, improved memory formation and/or reversed amnesia. Herein, the effects of EMD (a 5-HT(6) receptor agonist) and AS19 (a 5-HT(7) receptor agonist) in the associative learning task of autoshaping were studied. Post-training systemic administration of EMD (1-10 mg/kg) or AS19 (1-10 mg/kg) were tested in short-term memory (STM) and long-term memory (LTM). Results showed that only EMD 5.0mg/kg impaired both STM and LTM. AS19 at 1-10 mg/kg significantly impaired STM but not LTM. In those groups used to test only LTM, EMD impaired it; while AS19 improved LTM. Moreover, in the interaction experiments, the STM EMD-impairment effect was partially reversed by the selective 5-HT(6) receptor antagonist SB-399885 (10 mg/kg). The STM AS19-impairment effect (5.0 mg/kg) was not altered by the selective 5-HT(1A) antagonist WAY 100635 (0.3 mg/kg) but reversed by the selective 5-HT(7) receptor antagonist SB-269970 (10.0 mg/kg). The AS19-SB-269970 combination impaired LTM. Taken together these data suggest that the stimulation of 5-HT(6) impaired both STM and LTM. 5-HT(7) receptors stimulation impaired STM but improved LTM. And these results are discussed in the context of their possible neural bases.

  1. Treating enhanced GABAergic inhibition in Down syndrome: use of GABA α5-selective inverse agonists.

    Science.gov (United States)

    Martínez-Cué, Carmen; Delatour, Benoît; Potier, Marie-Claude

    2014-10-01

    Excess inhibition in the brain of individuals carrying an extra copy of chromosome 21 could be responsible for cognitive deficits observed throughout their lives. A change in the excitatory/inhibitory balance in adulthood would alter synaptic plasticity, potentially triggering learning and memory deficits. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system and binds to GABAA receptors, opens a chloride channel, and reduces neuronal excitability. In this review we discuss methods to alleviate neuronal inhibition in a mouse model of Down syndrome, the Ts65Dn mouse, using either an antagonist (pentylenetetrazol) or two different inverse agonists selective for the α5-subunit containing receptor. Both inverse agonists, which reduce inhibitory GABAergic transmission, could rescue learning and memory deficits in Ts65Dn mice. We also discuss safety issues since modulation of the excitatory-inhibitory balance to improve cognition without inducing seizures remains particularly difficult when using GABA antagonists.

  2. Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology.

    Science.gov (United States)

    Drucker, D J; Rosen, C F

    2011-11-01

    Type 2 diabetes mellitus is characterised by beta cell failure, which frequently develops in the setting of insulin resistance. Inflammation contributes to the pathophysiology of type 2 diabetes by impairing insulin action in peripheral tissues and via reduction of beta cell function. Inflammation may also play an important role in the development of complications that arise in patients with type 2 diabetes. Hence, the anti-inflammatory actions of commonly used glucose-lowering drugs may contribute, indirectly, to their mechanisms of action and therapeutic benefit. Herein we highlight the anti-inflammatory actions of glucagon-like peptide-1 (GLP-1), which exerts direct and indirect actions on immune function. The observations that GLP-1 receptor agonists exert anti-inflammatory actions in preclinical studies, taken together with case reports linking improvements in psoriasis with GLP-1 receptor agonist therapy, illustrates the emerging clinical implications of non-classical anti-inflammatory actions of incretin-based therapeutics.

  3. Successful treatment of dopamine dysregulation syndrome with dopamine D2 partial agonist antipsychotic drug

    Directory of Open Access Journals (Sweden)

    Mizushima Jin

    2012-07-01

    Full Text Available Abstract Dopamine dysregulation syndrome (DDS consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson’s disease (PD. Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system.

  4. Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

    Science.gov (United States)

    Mosińska, Paula; Zatorski, Hubert; Storr, Martin; Fichna, Jakub

    2017-01-01

    There is an unmet need for effective pharmacological therapies for constipation, a symptom that significantly deteriorates patients’ quality of life and impacts health care. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor and has been shown to exert prokinetic effects on gastrointestinal (GI) motility via the vagus and pelvic nerves. The pharmacological potential of ghrelin is hampered by its short half-life. Ghrelin receptor (GRLN-R) agonists with enhanced pharmacokinetics were thus developed. Centrally penetrant GRLN-R agonists stimulate defecation and improve impaired lower GI transit in animals and humans. This review summarizes the current knowledge on relamorelin, a potent ghrelin mimetic, and other GRLN-R analogs which are in preclinical or clinical stages of development for the management of disorders with underlying GI hypomotility, like constipation. PMID:28238253

  5. Treatment of type 2 diabetes with glucagon-like peptide-1 receptor agonists

    DEFF Research Database (Denmark)

    Hansen, K B; Knop, F K; Holst, Jens Juul;

    2009-01-01

    ongoing decline in pancreatic beta-cell function and, lastly, they have a number of side effects including hypoglycaemia and weight gain. Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of pharmacological agents, which improve glucose homeostasis in a multifaceted way. Their effects...... of hypoglycaemia with GLP-1 receptor agonists is low, the compounds have clinically relevant effects on body weight, and data are suggesting beneficial effects on cardiovascular risk factors. Exenatide was released in 2005 for the treatment of type 2 diabetes and liraglutide is expected to be approved by the Food...... and Drug Administration in US and the European Medical Agency in Europe for use in 2009. In this review, the available data on the two drugs are presented and discussed....

  6. 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

    /13) pathway. The recognition pattern of wFw-Isn-NH(2) with the ghrelin receptor also differed significantly from that of all previously characterized unbiased agonists. Most importantly, wFw-Isn-NH(2) was not dependent on GluIII:09 (Glu3.33), which otherwise is an obligatory TM III anchor point residue...... orientation as compared with, for example, the wFw peptide agonists. It is concluded that the novel peptide-mimetic ligand wFw-Isn-NH(2) is a biased ghrelin receptor agonist and that the selective signaling pattern presumably is due to its unique receptor recognition pattern lacking interaction with key...

  7. Effects of direct- and indirect-acting serotonin receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in rhesus monkeys.

    Science.gov (United States)

    Li, Jun-Xu; Koek, Wouter; Rice, Kenner C; France, Charles P

    2011-04-01

    Serotonergic (5-HT) systems modulate pain, and drugs acting on 5-HT systems are used with opioids to treat pain. This study examined the effects of 5-HT receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in monkeys. Morphine increased tail-withdrawal latency in a dose-related manner; 5-HT receptor agonists alone increased tail-withdrawal latency at 50 °C but not 55 °C water. The antinociceptive effects of morphine occurred with smaller doses when monkeys received an indirect-acting (fenfluramine) or direct acting (8-OH-DPAT, F13714, buspirone, quipazine, DOM, and 2C-T-7) agonist. The role of 5-HT receptor subtypes in these interactions was confirmed with selective 5-HT(1A) (WAY100635) and 5-HT(2A) (MDL100907) receptor antagonists. None of the 5-HT drugs had morphine-like discriminative stimulus effects; however, fenfluramine and 5-HT(2A) receptor agonists attenuated the discriminative stimulus effects of morphine and this attenuation was prevented by MDL100907. The 5-HT(1A) receptor agonists did not alter the discriminative stimulus effects of morphine. Thus, 5-HT receptor agonists increase the potency of morphine in an assay of antinociception, even under conditions where 5-HT agonists are themselves without effect (ie, 55 °C water), without increasing (and in some cases decreasing) the potency of morphine in a drug discrimination assay. Whereas 5-HT(2A) receptor agonists increase the potency of morphine for antinociception at doses that have no effect on the rate of operant responding, 5-HT(1A) receptor agonists increase the potency of morphine only at doses that eliminate operant responding. These data suggest that drugs acting selectively on 5-HT receptor subtypes could help to improve the use of opioids for treating pain.

  8. Nicotine receptor partial agonists for smoking cessation

    Directory of Open Access Journals (Sweden)

    Kate Cahill

    Full Text Available BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist and reducing smoking satisfaction (acting as an antagonist. OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist' in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialized register was in December 2011. We also searched online clinical trials registers. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up. The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs, using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: Two recent cytisine trials (937 people

  9. Characterization of 12 GnRH peptide agonists – a kinetic perspective

    Science.gov (United States)

    Nederpelt, Indira; Georgi, Victoria; Schiele, Felix; Nowak‐Reppel, Katrin; Fernández‐Montalván, Amaury E.; IJzerman, Adriaan P.

    2015-01-01

    Background and Purpose Drug‐target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin‐releasing hormone (GnRH) receptor for the treatment of hormone‐dependent diseases. Surprisingly, the kinetic receptor‐binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor‐binding kinetics of 12 GnRH peptide agonists, including many marketed drugs. Experimental Approach A novel radioligand‐binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabelled peptide agonist, [125I]‐triptorelin. In addition to radioligand‐binding studies, a homogeneous time‐resolved FRET Tag‐lite™ method was developed as an alternative assay for the same purpose. Key Results Two novel competition association assays were successfully developed and applied to determine the kinetic receptor‐binding characteristics of 12 high‐affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). Conclusions and Implications Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor. PMID:26398856

  10. Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors.

    Science.gov (United States)

    Smith, R L; Canton, H; Barrett, R J; Sanders-Bush, E

    1998-11-01

    Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor density and cellular microenvironment, we also examined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native preparation. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT.

  11. Synthetic Toll like receptor-4 (TLR-4 agonist peptides as a novel class of adjuvants.

    Directory of Open Access Journals (Sweden)

    Arulkumaran Shanmugam

    Full Text Available BACKGROUND: Adjuvants serve as catalysts of the innate immune response by initiating a localized site of inflammation that is mitigated by the interactions between antigens and toll like receptor (TLR proteins. Currently, the majority of vaccines are formulated with aluminum based adjuvants, which are associated with various side effects. In an effort to develop a new class of adjuvants, agonists of TLR proteins, such as bacterial products, would be natural candidates. Lipopolysaccharide (LPS, a major structural component of gram negative bacteria cell walls, induces the systemic inflammation observed in septic shock by interacting with TLR-4. The use of synthetic peptides of LPS or TLR-4 agonists, which mimic the interaction between TLR-4 and LPS, can potentially regulate cellular signal transduction pathways such that a localized inflammatory response is achieved similar to that generated by adjuvants. METHODOLOGY/PRINCIPAL FINDINGS: We report the identification and activity of several peptides isolated using phage display combinatorial peptide technology, which functionally mimicked LPS. The activity of the LPS-TLR-4 interaction was assessed by NF-κB nuclear translocation analyses in HEK-BLUE™-4 cells, a cell culture model that expresses only TLR-4, and the murine macrophage cell line, RAW264.7. Furthermore, the LPS peptide mimics were capable of inducing inflammatory cytokine secretion from RAW264.7 cells. Lastly, ELISA analysis of serum from vaccinated BALB/c mice revealed that the LPS peptide mimics act as a functional adjuvant. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the identification of synthetic peptides that mimic LPS by interacting with TLR-4. This LPS mimotope-TLR-4 interaction will allow for the development and use of these peptides as a new class of adjuvants, namely TLR-4 agonists.

  12. 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.

  13. Long acting β2-agonist and corticosteroid restore airway glandular cell function altered by bacterial supernatant

    Directory of Open Access Journals (Sweden)

    Nawrocki-Raby Béatrice

    2010-01-01

    Full Text Available Abstract Background Staphylococcus aureus releases virulence factors (VF that may impair the innate protective functions of airway cells. The aim of this study was to determine whether a long-acting β2 adrenergic receptor agonist (salmeterol hydroxynaphthoate, Sal combined with a corticosteroid (fluticasone propionate, FP was able to regulate ion content and cytokine expression by airway glandular cells after exposure to S. aureus supernatant. Methods A human airway glandular cell line was incubated with S. aureus supernatant for 1 h and then treated with the combination Sal/FP for 4 h. The expression of actin and CFTR proteins was analyzed by immunofluorescence. Videomicroscopy was used to evaluate chloride secretion and X-ray microanalysis to measure the intracellular ion and water content. The pro-inflammatory cytokine expression was assessed by RT-PCR and ELISA. Results When the cells were incubated with S. aureus supernatant and then with Sal/FP, the cellular localisation of CFTR was apical compared to the cytoplasmic localisation in cells incubated with S. aureus supernatant alone. The incubation of airway epithelial cells with S. aureus supernatant reduced by 66% the chloride efflux that was fully restored by Sal/FP treatment. We also observed that Sal/FP treatment induced the restoration of ion (Cl and S and water content within the intracellular secretory granules of airway glandular cells and reduced the bacterial supernatant-dependent increase of pro-inflammatory cytokines IL8 and TNFα. Conclusions Our results demonstrate that treatment with the combination of a corticosteroid and a long-acting β2 adrenergic receptor agonist after bacterial infection restores the airway glandular cell function. Abnormal mucus induced by defective ion transport during pulmonary infection could benefit from treatment with a combination of β2 adrenergic receptor agonist and glucocorticoid.

  14. Basic understanding of gonadotropin-releasing hormone-agonist triggering.

    Science.gov (United States)

    Casper, Robert F

    2015-04-01

    A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle-stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (≥6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles.

  15. Conicasterol E, a small heterodimer partner sparing farnesoid X receptor modulator endowed with a pregnane X receptor agonistic activity, from the marine sponge Theonella swinhoei.

    Science.gov (United States)

    Sepe, Valentina; Ummarino, Raffaella; D'Auria, Maria Valeria; Chini, Maria Giovanna; Bifulco, Giuseppe; Renga, Barbara; D'Amore, Claudio; Debitus, Cécile; Fiorucci, Stefano; Zampella, Angela

    2012-01-12

    We report the isolation and pharmacological characterization of conicasterol E isolated from the marine sponge Theonella swinhoei. Pharmacological characterization of this steroid in comparison to CDCA, a natural FXR ligand, and 6-ECDCA, a synthetic FXR agonist generated by an improved synthetic strategy, and rifaximin, a potent PXR agonist, demonstrated that conicasterol E is an FXR modulator endowed with PXR agonistic activity. Conicasterol E induces the expression of genes involved in bile acids detoxification without effect on the expression of small heterodimer partner (SHP), thus sparing the expression of genes involved in bile acids biosynthesis. The relative positioning in the ligand binding domain of FXR, explored through docking calculations, demonstrated a different spatial arrangement for conicasterol E and pointed to the presence of simultaneous and efficient interactions with the receptor. In summary, conicasterol E represents a FXR modulator and PXR agonist that might hold utility in treatment of liver disorders.

  16. Influence of hydrodynamic conditions on quantitative cellular assays in microfluidic systems.

    Science.gov (United States)

    Yin, Huabing; Zhang, Xunli; Pattrick, Nicola; Klauke, Norbert; Cordingley, Hayley C; Haswell, Stephen J; Cooper, Jonathan M

    2007-09-15

    This study demonstrates the importance of the hydrodynamic environment in microfluidic systems in quantitative cellular assays using live cells. Commonly applied flow conditions used in microfluidics were evaluated using the quantitative intracellular Ca2+ analysis of Chinese hamster ovary (CHO) cells as a model system. Above certain thresholds of shear stress, hydrodynamically induced intracellular Ca2+ fluxes were observed which mimic the responses induced by chemical stimuli, such as the agonist uridine 5'-triphosphate tris salt (UTP). This effect is of significance given the increasing application of microfluidic devices in high-throughput cellular analysis for biophysical applications and pharmacological screening.

  17. MELATONIN DAN MELATONIN RECEPTOR AGONIST SEBAGAI PENANGANAN INSOMNIA PRIMER KRONIS

    Directory of Open Access Journals (Sweden)

    Ni Luh Putu Ayu Maha Iswari

    2013-04-01

    Full Text Available Melatonin is a hormone that has an important role in the mechanism of sleep. Hypnotic effects of melatonin and melatonin receptor agonist are mediated via MT1 and MT2 receptors, especially in circadian rhythm pacemaker, suprachiasmatic nucleus, which is worked on the hypothalamic sleep switch. This mechanism is quite different with the GABAergic drugs such as benzodiazepine. Agonist melatonin triggers the initiation of sleep and normalize circadian rhythms so that makes it easier to maintain sleep. The main disadvantage of melatonin in helping sleep maintenance on primary insomnia is that the half life is very short. The solution to this problem is the use of prolonged-release melatonin and melatonin receptor agonist agents such as ramelteon. Melatoninergic agonist does not cause withdrawal effects, dependence, as well as cognitive and psychomotor disorders as often happens on the use of benzodiazepine.  

  18. Cellular image classification

    CERN Document Server

    Xu, Xiang; Lin, Feng

    2017-01-01

    This book introduces new techniques for cellular image feature extraction, pattern recognition and classification. The authors use the antinuclear antibodies (ANAs) in patient serum as the subjects and the Indirect Immunofluorescence (IIF) technique as the imaging protocol to illustrate the applications of the described methods. Throughout the book, the authors provide evaluations for the proposed methods on two publicly available human epithelial (HEp-2) cell datasets: ICPR2012 dataset from the ICPR'12 HEp-2 cell classification contest and ICIP2013 training dataset from the ICIP'13 Competition on cells classification by fluorescent image analysis. First, the reading of imaging results is significantly influenced by one’s qualification and reading systems, causing high intra- and inter-laboratory variance. The authors present a low-order LP21 fiber mode for optical single cell manipulation and imaging staining patterns of HEp-2 cells. A focused four-lobed mode distribution is stable and effective in optical...

  19. Multiuser Cellular Network

    CERN Document Server

    Bao, Yi; Chen, Ming

    2011-01-01

    Modern radio communication is faced with a problem about how to distribute restricted frequency to users in a certain space. Since our task is to minimize the number of repeaters, a natural idea is enlarging coverage area. However, coverage has restrictions. First, service area has to be divided economically as repeater's coverage is limited. In this paper, our fundamental method is to adopt seamless cellular network division. Second, underlying physics content in frequency distribution problem is interference between two close frequencies. Consequently, we choose a proper frequency width of 0.1MHz and a relevantly reliable setting to apply one frequency several times. We make a few general assumptions to simplify real situation. For instance, immobile users yield to homogenous distribution; repeaters can receive and transmit information in any given frequency in duplex operation; coverage is mainly decided by antenna height. Two models are built up to solve 1000 users and 10000 users situations respectively....

  20. Engineering Cellular Metabolism.

    Science.gov (United States)

    Nielsen, Jens; Keasling, Jay D

    2016-03-10

    Metabolic engineering is the science of rewiring the metabolism of cells to enhance production of native metabolites or to endow cells with the ability to produce new products. The potential applications of such efforts are wide ranging, including the generation of fuels, chemicals, foods, feeds, and pharmaceuticals. However, making cells into efficient factories is challenging because cells have evolved robust metabolic networks with hard-wired, tightly regulated lines of communication between molecular pathways that resist efforts to divert resources. Here, we will review the current status and challenges of metabolic engineering and will discuss how new technologies can enable metabolic engineering to be scaled up to the industrial level, either by cutting off the lines of control for endogenous metabolism or by infiltrating the system with disruptive, heterologous pathways that overcome cellular regulation.

  1. Studies on the pharmacology of the novel histamine H3 receptor agonist Sch 50971.

    Science.gov (United States)

    Hey, J A; Aslanian, R; Bolser, D C; Chapman, R W; Egan, R W; Rizzo, C A; Shih, N Y; Fernandez, X; McLeod, R L; West, R; Kreutner, W

    1998-09-01

    Experiments were performed to characterize the pharmacology of Sch 50971 ((+)-trans-4-(4(R)-methyl-3(R)-pyrolidinyl)-1H-imidazole dihydrochloride, CAS 167610-28-8), a novel histamine H3 receptor agonist. The activity of Sch 50971 was compared with that of (R)-alpha-methylhistamine (CAS 75614-87-8), a potent and moderately selective agonist of histamine H3 receptors, in a series of in vitro and in vivo assays. Sch 50971 is a high affinity, selective H3 receptor agonist in vitro and in vivo. Sch 50971 inhibits [3H]-N-alpha-methylhistamine (CAS 673-50-7) binding to the histamine H3 receptor in human brain (Ki = 5.0 nmol/l) and guinea pig brain (Ki = 2.5 nmol/l). Sch 50971 also inhibits electric field stimulated guinea pig ileum contractions (pD2 = 7.47) and decreases [3H]-norepinephrine (CAS 51-41-2) release (pD2 = 7.48) from guinea pig pulmonary artery by activation of presynaptic inhibitory H3 receptors. The in vitro effects of Sch 50971 are antagonized by low concentrations of a selective H3 antagonist, thioperamide (CAS 106243-16-7). Sch 50971 has low affinity (IC50's > 10 mumol/l) for histamine H1, dopamine D1 and D2, serotonin 5-HT2 and muscarinic cholinergic receptors. It also does not exhibit histamine H2-antagonist activity. In guinea pigs and cats, Sch 50971 exhibits in vivo H3 agonist activity. Sch 50971 inhibits sympathetic hypertension evoked by stimulation of the medulla oblongata in anesthetized guinea pigs (ED30 = 0.3 mg/kg i.v., ED30 = 1.0 mg/kg i.d.). Sch 50971 also inhibits the effects of sympathetic nerve stimulation on nasal resistance in cats. In these assays, Sch 50971 exhibits an efficacy and potency comparable to H3-agonist (R)-alpha-methylhistamine. However, under in vivo conditions, Sch 50971 does not exhibit histamine H1-mediated responses that are seen with (R)-alpha-methylhistamine at doses close to those that produce H3 effects. Therefore, Sch 50971 is a novel, potent and selective agonist of histamine H3 receptors with an improved in

  2. 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

  3. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    Science.gov (United States)

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  4. Toll-like receptor agonists in cancer therapy

    OpenAIRE

    Adams, Sylvia

    2009-01-01

    Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recen...

  5. The RARgamma selective agonist CD437 inhibits gastric cell growth through the mechanism of apoptosis.

    Science.gov (United States)

    Jiang, S Y; Lin, D Y; Shyu, R Y; Reichert, U; Yeh, M Y

    1999-04-01

    Retinoids are differentiation-inducing agents that exhibit multiple functions. Their activities are mediated through interaction with nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR). We have investigated the activities of synthetic retinoids on the growth of five gastric cancer cell lines. The effects of agonists selective for RARalpha, RARbeta and RARgamma (AM580, CD2019 and CD437, respectively) on cell growth were determined, in comparison to all-trans retinoic acid, by measuring total cellular DNA. AM580 and CD2019 had little or no effect on the growth of all five cell lines. In contrast, the RARgamma agonist CD437 inhibited cell growth up to 90-99% in both retinoic acid sensitive and resistant gastric cancer cells at a concentration of 1 microM. The growth suppression caused by CD437 was accompanied by the induction of apoptosis as judged by morphological criteria and DNA ladder formation. However, the extent of CD437-induced growth suppression was not correlated with RARgamma mRNA levels, which indicates that CD437 induces apoptosis in gastric cancer cells via an RARgamma independent pathway.

  6. Agonist-directed signaling of serotonin 5-HT2C receptors: differences between serotonin and lysergic acid diethylamide (LSD).

    Science.gov (United States)

    Backstrom, J R; Chang, M S; Chu, H; Niswender, C M; Sanders-Bush, E

    1999-08-01

    For more than 40 years the hallucinogen lysergic acid diethylamide (LSD) has been known to modify serotonin neurotransmission. With the advent of molecular and cellular techniques, we are beginning to understand the complexity of LSD's actions at the serotonin 5-HT2 family of receptors. Here, we discuss evidence that signaling of LSD at 5-HT2C receptors differs from the endogenous agonist serotonin. In addition, RNA editing of the 5-HT2C receptor dramatically alters the ability of LSD to stimulate phosphatidylinositol signaling. These findings provide a unique opportunity to understand the mechanism(s) of partial agonism.

  7. Effects of hormone agonists on Sf9 cells, proliferation and cell cycle arrest.

    Science.gov (United States)

    Giraudo, Maeva; Califano, Jérôme; Hilliou, Frédérique; Tran, Trang; Taquet, Nathalie; Feyereisen, René; Le Goff, Gaëlle

    2011-01-01

    Methoxyfenozide and methoprene are two insecticides that mimic the action of the main hormones involved in the control of insect growth and development, 20-hydroxyecdysone and juvenile hormone. We investigated their effect on the Spodoptera frugiperda Sf9 cell line. Methoxyfenozide was more toxic than methoprene in cell viability tests and more potent in the inhibition of cellular proliferation. Cell growth arrest occurred in the G2/M phase after a methoprene treatment and more modestly in G1 after methoxyfenozide treatment. Microarray experiments and real-time quantitative PCR to follow the expression of nuclear receptors ultraspiracle and ecdysone receptor were performed to understand the molecular action of these hormone agonists. Twenty-six genes were differentially expressed after methoxyfenozide treatment and 55 genes after methoprene treatment with no gene in common between the two treatments. Our results suggest two different signalling pathways in Sf9 cells.

  8. Effects of hormone agonists on Sf9 cells, proliferation and cell cycle arrest.

    Directory of Open Access Journals (Sweden)

    Maeva Giraudo

    Full Text Available Methoxyfenozide and methoprene are two insecticides that mimic the action of the main hormones involved in the control of insect growth and development, 20-hydroxyecdysone and juvenile hormone. We investigated their effect on the Spodoptera frugiperda Sf9 cell line. Methoxyfenozide was more toxic than methoprene in cell viability tests and more potent in the inhibition of cellular proliferation. Cell growth arrest occurred in the G2/M phase after a methoprene treatment and more modestly in G1 after methoxyfenozide treatment. Microarray experiments and real-time quantitative PCR to follow the expression of nuclear receptors ultraspiracle and ecdysone receptor were performed to understand the molecular action of these hormone agonists. Twenty-six genes were differentially expressed after methoxyfenozide treatment and 55 genes after methoprene treatment with no gene in common between the two treatments. Our results suggest two different signalling pathways in Sf9 cells.

  9. Activation of Dendritic Cells by the Novel Toll-Like Receptor 3 Agonist RGC100

    Directory of Open Access Journals (Sweden)

    Kai Naumann

    2013-01-01

    Full Text Available Toll-like receptor (TLR 3 agonists emerged as attractive candidates for vaccination strategies against tumors and pathogens. An important mechanism of action of such agonists is based on the activation of TLR3-expressing dendritic cells (DCs, which display a unique capacity to induce and stimulate T-cell responses. In this context, it has been demonstrated that targeting of TLR3 by double-stranded RNA such as poly(I:C results in potent activation of DCs. Major disadvantages of poly(I:C comprise its undefined chemical structure and very poor homogeneity, with subsequent unpredictable pharmacokinetics and high toxicity. In the present study, we evaluated the physicochemical properties and biological activity of the novel TLR3 agonist RGC100. RGC100 has a defined chemical structure, with a defined length (100 bp and molecular weight (64.9 KDa and a good solubility. RGC100 is stable in serum and activates myeloid DCs through TLR3 targeting, as evidenced by gene silencing experiments. Activation of mouse and human myeloid CD1c+ DCs by RGC100 leads to secretion of several proinflammatory cytokines. In addition, RGC100 improves the ability of CD1c+ DCs to stimulate T-cell proliferation. Due to its physicochemical properties and its immunostimulatory properties, RGC100 may represent a promising adjuvant for prophylactic and therapeutic vaccination strategies.

  10. (+)-Dinapsoline: an efficient synthesis and pharmacological profile of a novel dopamine agonist.

    Science.gov (United States)

    Sit, Sing-Yuen; Xie, Kai; Jacutin-Porte, Swanee; Taber, Matthew T; Gulwadi, Amit G; Korpinen, Carolyn D; Burris, Kevin D; Molski, Thaddeus F; Ryan, Elaine; Xu, Cen; Wong, Henry; Zhu, Juliang; Krishnananthan, Subramaniam; Gao, Qi; Verdoorn, Todd; Johnson, Graham

    2002-08-15

    A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7, 11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D(1) Agonist Containing a Rigid beta-Phenyldopamine Pharmacophore. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).

  11. β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.

    Science.gov (United States)

    Vijftigschild, Lodewijk A W; Berkers, Gitte; Dekkers, Johanna F; Zomer-van Ommen, Domenique D; Matthes, Elizabeth; Kruisselbrink, Evelien; Vonk, Annelotte; Hensen, Chantal E; Heida-Michel, Sabine; Geerdink, Margot; Janssens, Hettie M; van de Graaf, Eduard A; Bronsveld, Inez; de Winter-de Groot, Karin M; Majoor, Christof J; Heijerman, Harry G M; de Jonge, Hugo R; Hanrahan, John W; van der Ent, Cornelis K; Beekman, Jeffrey M

    2016-09-01

    We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled β2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, pCFTR activation when administered ex vivo to organoids.This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration.

  12. Cellular Phone Towers

    Science.gov (United States)

    ... IEEE. Baan R, Grosse Y, Lauby-Secretan B, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha ... improve our website. Submit Thank you for your feedback! We appreciate you taking the time to provide ...

  13. An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

    Science.gov (United States)

    Montgomery, Megan D.; Chan, Trevor; Swigart, Philip M.; Myagmar, Bat-erdene; Dash, Rajesh; Simpson, Paul C.

    2017-01-01

    Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35–40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies. PMID:28081170

  14. Inhaling β2 -agonist with heliox-driven in bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    解立新; 刘又宁; 陈良安; 郝凤英; 金桂清; 赵会泽

    2003-01-01

    Objective To evaluate the effectiveness of a helium-oxygen mixture (79%He- 21%O2) as an aerosolizing compressed gas for β2-agonist therapy in patients with an asthma exacerbation. Methods Twenty-four patients in the outpatient department with a mild to moderate exacerbation of asthma were enrolled. The patients were randomly divided into an experimental group (13 cases) and a control group (11 cases). The experimental group inhaled Berotec with heliox-driven, and the control group inhaled Berotec with compressed air-driven. Eight hospitalized patients in the respiratory department with severe exacerbation of asthma were enrolled. The patients inhaled Berotec with heliox-driven or compressed air-driven in a random order.Results The results of spirometric parameters and arterial blood-gas analysis were measured. In the mild to moderate asthma patients, no statistical differences between the two groups for forced vital capacity (FVC), forced expired volume in one second (FEV1), and expiratory flow in 50% forced vital capacity (FEF50) were presented. But the severe patients showed significant differences between heliox-driven and compressed air-driven for FVC, FEV1, FEF50 and partial pressure of oxygen (PaO2). Conclusions Compared with the traditional inhalation of β2-agonist therapy using compressed air-driven, the method of inhaling β2-agonist with heliox-driven has more obvious benefits for those suffering from severe asthma. This is likely due to the cooperative effects between inhaling heliox on its physical gas properties and improving delivery of β2-agonist in the treatment of exacerbation of severe asthma.

  15. A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents.

    Directory of Open Access Journals (Sweden)

    Jian Luo

    Full Text Available Type 2 diabetes is characterized by impaired glucose homeostasis due to defects in insulin secretion, insulin resistance and the incretin response. GPR40 (FFAR1 or FFA1 is a G-protein-coupled receptor (GPCR, primarily expressed in insulin-producing pancreatic β-cells and incretin-producing enteroendocrine cells of the small intestine. Several GPR40 agonists, including AMG 837 and TAK-875, have been disclosed, but no GPR40 synthetic agonists have been reported that engage both the insulinogenic and incretinogenic axes. In this report we provide a molecular explanation and describe the discovery of a unique and potent class of GPR40 full agonists that engages the enteroinsular axis to promote dramatic improvement in glucose control in rodents. GPR40 full agonists AM-1638 and AM-6226 stimulate GLP-1 and GIP secretion from intestinal enteroendocrine cells and increase GSIS from pancreatic islets, leading to enhanced glucose control in the high fat fed, streptozotocin treated and NONcNZO10/LtJ mouse models of type 2 diabetes. The improvement in hyperglycemia by AM-1638 was reduced in the presence of the GLP-1 receptor antagonist Ex(9-39NH(2.

  16. Cellular bioluminescence imaging.

    Science.gov (United States)

    Welsh, David K; Noguchi, Takako

    2012-08-01

    Bioluminescence imaging of live cells has recently been recognized as an important alternative to fluorescence imaging. Fluorescent probes are much brighter than bioluminescent probes (luciferase enzymes) and, therefore, provide much better spatial and temporal resolution and much better contrast for delineating cell structure. However, with bioluminescence imaging there is virtually no background or toxicity. As a result, bioluminescence can be superior to fluorescence for detecting and quantifying molecules and their interactions in living cells, particularly in long-term studies. Structurally diverse luciferases from beetle and marine species have been used for a wide variety of applications, including tracking cells in vivo, detecting protein-protein interactions, measuring levels of calcium and other signaling molecules, detecting protease activity, and reporting circadian clock gene expression. Such applications can be optimized by the use of brighter and variously colored luciferases, brighter microscope optics, and ultrasensitive, low-noise cameras. This article presents a review of how bioluminescence differs from fluorescence, its applications to cellular imaging, and available probes, optics, and detectors. It also gives practical suggestions for optimal bioluminescence imaging of single cells.

  17. Cellular neurothekeoma with melanocytosis.

    Science.gov (United States)

    Wu, Ren-Chin; Hsieh, Yi-Yueh; Chang, Yi-Chin; Kuo, Tseng-Tong

    2008-02-01

    Cellular neurothekeoma (CNT) is a benign dermal tumor mainly affecting the head and neck and the upper extremities. It is characterized histologically by interconnecting fascicles of plump spindle or epithelioid cells with ample cytoplasm infiltrating in the reticular dermis. The histogenesis of CNT has been controversial, although it is generally regarded as an immature counterpart of classic/myxoid neurothekeoma, a tumor with nerve sheath differentiation. Two rare cases of CNT containing melanin-laden cells were described. Immunohistochemical study with NKI/C3, vimentin, epithelial membrane antigen, smooth muscle antigen, CD34, factor XIIIa, collagen type IV, S100 protein and HMB-45 was performed. Both cases showed typical growth pattern of CNT with interconnecting fascicles of epithelioid cells infiltrating in collagenous stroma. One of the nodules contained areas exhibiting atypical cytological features. Melanin-laden epithelioid or dendritic cells were diffusely scattered throughout one nodule, and focally present in the peripheral portion of the other nodule. Both nodules were strongly immunoreactive to NKI/C3 and vimentin, but negative to all the other markers employed. CNT harboring melanin-laden cells may pose diagnostic problems because of their close resemblance to nevomelanocytic lesions and other dermal mesenchymal tumors. These peculiar cases may also provide further clues to the histogenesis of CNT.

  18. Cytisine-based nicotinic partial agonists as novel antidepressant compounds.

    Science.gov (United States)

    Mineur, Yann S; Eibl, Christoph; Young, Grace; Kochevar, Christopher; Papke, Roger L; Gündisch, Daniela; Picciotto, Marina R

    2009-04-01

    Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the beta2 subunit (beta2(*)), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at alpha4/beta2(*) nAChRs, and a full agonist at alpha3/beta4(*) and alpha7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at alpha4/beta2(*) nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.

  19. Romiplostim: a second-generation thrombopoietin agonist.

    Science.gov (United States)

    Cohn, Claudia S; Bussel, James B

    2009-03-01

    in bone marrow reticulin have been reported. Other TPO nonpeptide mimetics have been created by using a similar strategy with libraries of nonpeptide molecules that can stimulate TPO-dependent cell lines. Eltrombopag and AKR-501 are two drugs of this type that have shown positive results in clinical trials. In addition, antibodies that can stimulate the c-Mpl receptor are being engineered to act as potent TPO agonists. These and other drugs in preclinical development represent a new line of therapy for thrombocytopenic patients.

  20. Toward the discovery of novel anti-HIV drugs. Second-generation inhibitors of the cellular ATPase DDX3 with improved anti-HIV activity: synthesis, structure-activity relationship analysis, cytotoxicity studies, and target validation.

    Science.gov (United States)

    Maga, Giovanni; Falchi, Federico; Radi, Marco; Botta, Lorenzo; Casaluce, Gianni; Bernardini, Martina; Irannejad, Hamid; Manetti, Fabrizio; Garbelli, Anna; Samuele, Alberta; Zanoli, Samantha; Esté, José A; Gonzalez, Emmanuel; Zucca, Elisa; Paolucci, Stefania; Baldanti, Fausto; De Rijck, Jan; Debyser, Zeger; Botta, Maurizio

    2011-08-01

    A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.

  1. Effects of the hold and relax-agonist contraction technique on recovery from delayed onset muscle soreness after exercise in healthy adults.

    Science.gov (United States)

    Cha, Hyun-Gyu; Kim, Myoung-Kwon

    2015-10-01

    [Purpose] This study was conducted to verify the effects of the hold relax-agonist contraction and passive straight leg raising techniques on muscle activity, fatigue, and range of motion of the hip joint after the induction of delayed onset muscle soreness in the hamstring muscle. [Subjects] Sixty subjects were randomly assigned to a hold relax-agonist contraction group and a passive straight leg raising group. [Methods] Subjects in the experimental group underwent hold relax-agonist contraction at the hamstring muscle, while subjects in the control group underwent passive straight leg raising at the hamstring muscle. [Results] Subjects in the hold relax-agonist contraction group showed a significant increase in hamstring muscle activity and hip joint angle and a significant decrease in muscle fatigue. In the passive straight leg raising group, the hip joint angle increased significantly after the intervention. In the hold relax-agonist contraction group, hamstring muscle activity increased significantly and muscle fatigue decreased significantly. [Conclusion] We conclude that the hold relax-agonist contraction technique may be beneficial for improving muscle activation and decreasing muscle fatigue.

  2. Free fall and cellular automata

    Directory of Open Access Journals (Sweden)

    Pablo Arrighi

    2016-03-01

    Full Text Available Three reasonable hypotheses lead to the thesis that physical phenomena can be described and simulated with cellular automata. In this work, we attempt to describe the motion of a particle upon which a constant force is applied, with a cellular automaton, in Newtonian physics, in Special Relativity, and in General Relativity. The results are very different for these three theories.

  3. About Strongly Universal Cellular Automata

    Directory of Open Access Journals (Sweden)

    Maurice Margenstern

    2013-09-01

    Full Text Available In this paper, we construct a strongly universal cellular automaton on the line with 11 states and the standard neighbourhood. We embed this construction into several tilings of the hyperbolic plane and of the hyperbolic 3D space giving rise to strongly universal cellular automata with 10 states.

  4. Reactive Programming of Cellular Automata

    OpenAIRE

    Boussinot, Frédéric

    2004-01-01

    Implementation of cellular automata using reactive programming gives a way to code cell behaviors in an abstract and modular way. Multiprocessing also becomes possible. The paper describes the implementation of cellular automata with the reactive programming language LOFT, a thread-based extension of C. Self replicating loops considered in artificial life are coded to show the interest of the approach.

  5. Role of dopamine agonists in Parkinson's disease: an update.

    Science.gov (United States)

    Bonuccelli, Ubaldo; Pavese, Nicola

    2007-10-01

    At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained.

  6. Intracerebroventricular administration of kappa-agonists induces convulsions in mice.

    Science.gov (United States)

    Bansinath, M; Ramabadran, K; Turndorf, H; Shukla, V K

    1991-07-01

    Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

  7. MIMO Communication for Cellular Networks

    CERN Document Server

    Huang, Howard; Venkatesan, Sivarama

    2012-01-01

    As the theoretical foundations of multiple-antenna techniques evolve and as these multiple-input multiple-output (MIMO) techniques become essential for providing high data rates in wireless systems, there is a growing need to understand the performance limits of MIMO in practical networks. To address this need, MIMO Communication for Cellular Networks presents a systematic description of MIMO technology classes and a framework for MIMO system design that takes into account the essential physical-layer features of practical cellular networks. In contrast to works that focus on the theoretical performance of abstract MIMO channels, MIMO Communication for Cellular Networks emphasizes the practical performance of realistic MIMO systems. A unified set of system simulation results highlights relative performance gains of different MIMO techniques and provides insights into how best to use multiple antennas in cellular networks under various conditions. MIMO Communication for Cellular Networks describes single-user,...

  8. β2 agonists in athletes. An ergogenic aid? = β2 agonistas en deportistas. ¿Una ayuda ergogénica?

    Directory of Open Access Journals (Sweden)

    Ospina Uribe, Carlos Fernando

    2013-01-01

    Full Text Available Asthma is a chronic disorder of the airways with bronchial hyperresponsiveness and bronchoconstriction. Exercise can trigger asthma symptoms; this condition is known as exerciseinduced bronchospasm (EIB. Asthma is common in Olympic athletes who therefore use β2 agonists to prevent and treat its episodes. These drugs are preferably supplied by inhalation. In sports, the use of β2 agonists is restricted by anti-doping regulation, arguing that these drugs have the potential to improve physical performance, which can result in a competitive advantage. β2 agonists are prohibited by the WADA (World Anti-Doping Agency, except salbutamol (maximum dose: 1.600 μg over 24 hours and salmeterol. Oral administration of salbutamol can induce ergogenic effects in athletes. It has been documented that when given orally β2 agonists can improve performance in endurance disciplines, increase muscle strength and improve anaerobic power. However, according to scientific evidence, inhaled β2 agonists do not have a relevant performance-enhancing effect in nonasthmatic athletes.

  9. In vitro assessment of the agonist properties of the novel 5-HT{sub 1A} receptor ligand, CUMI-101 (MMP), in rat brain tissue

    Energy Technology Data Exchange (ETDEWEB)

    Hendry, Nicola; Christie, Isabel [Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, CM19 5AW Essex (United Kingdom); Rabiner, Eugenii Alfredovich, E-mail: eugenii_a_rabiner@gsk.co [GSK Clinical Imaging Centre, London Hammersmith Hospital-IC, W12 0NN London (United Kingdom); Laruelle, Marc; Watson, Jeannette [Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, CM19 5AW Essex (United Kingdom)

    2011-02-15

    Introduction: Development of agonist positron emission tomography (PET) radioligands for the 5-HT neurotransmitter system is an important target to enable the understanding of human 5-HT function in vivo. [{sup 11}C]CUMI-101, proposed as the first 5-HT{sub 1A} receptor agonist PET ligand, has been reported to behave as a potent 5-HT{sub 1A} agonist in a cellular system stably expressing human recombinant 5-HT{sub 1A} receptors. In this study, we investigate the agonist properties of CUMI-101 in rat brain tissue. Methods: [{sup 35}S]-GTP{gamma}S binding studies were used to determine receptor function in HEK (human embryonic kidney) 293 cells transfected with human recombinant 5-HT{sub 1A} receptors and in rat cortex and rat hippocampal tissue, following administration of CUMI-101 and standard 5-HT1A antagonists (5-HT, 5-CT and 8-OH-DPAT). Results: CUMI-101 behaved as an agonist at human recombinant 5-HT{sub 1A} receptors (pEC{sub 50} 9.2). However, CUMI-101 did not show agonist activity in either rat cortex or hippocampus at concentrations up to 10 {mu}M. In these tissues, CUMI-behaved as an antagonist with pK{sub B}s of 9.2 and 9.3, respectively. Conclusions: Our studies demonstrate that as opposed to its behavior in human recombinant system, in rat brain tissue CUMI-101 behaves as a potent 5-HT{sub 1A} receptor antagonist.

  10. Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Christensen, Mikkel; Knop, Filip K; Holst, Jens Juul;

    2009-01-01

    Lixisenatide, under development by sanofi-aventis, is a novel human glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes). The structure of lixisenatide, based on exendin-4(1-39) modified C-terminally with six Lys...... residues, is able to withstand physiological degradation by dipeptidyl peptidase IV. In vitro, lixisenatide bound to human GLP-1R with a greater affinity than native human GLP-1 (7-36 amide). In various in vitro and in vivo models of T2DM, lixisenatide improved glycemic measures and demonstrated promising...

  11. 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.

  12. Compulsive eating and weight gain related to dopamine agonist use.

    Science.gov (United States)

    Nirenberg, Melissa J; Waters, Cheryl

    2006-04-01

    Dopamine agonists have been implicated in causing compulsive behaviors in patients with Parkinson's disease (PD). These have included gambling, hypersexuality, hobbyism, and other repetitive, purposeless behaviors ("punding"). In this report, we describe 7 patients in whom compulsive eating developed in the context of pramipexole use. All of the affected patients had significant, undesired weight gain; 4 had other comorbid compulsive behaviors. In the 5 patients who lowered the dose of pramipexole or discontinued dopamine agonist treatment, the behavior remitted and no further weight gain occurred. Physicians should be aware that compulsive eating resulting in significant weight gain may occur in PD as a side-effect of dopamine agonist medications such as pramipexole. Given the known risks of the associated weight gain and obesity, further investigation is warranted.

  13. 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.

  14. Comparison between a GnRH Agonist and a GnRH Antagonist Protocol for the Same Patient Undergoing IVF

    Institute of Scientific and Technical Information of China (English)

    Yufeng LI; Yuan LI; Qiaohong LAI; Hanwang ZHANG; Guijin ZHU; Lei JIN; Jing YUE

    2008-01-01

    Summary: In order to compare GnRH agonist with antagonist protocol for the same patient during controlled ovarian stimulation cycles, the in vitro fertilization and embryo transfer (IVF-ET) outcome was retrospectively studied in 81 patients undergoing 105 agonist protocols and 88 antagonist protocols. The results showed that there was no statistically significant difference in duration of ovarian stimulation, number of ampoules, oocytes retrieved, serum estradiol (E2) and progesterone (P) levels,thickness of endometrium, the zygote-and blastocyst-developmcnt rate between GnRH agonist and antagonist protocols (P>0.05). High quality embryo rate was higher in antagonist protocols, but there was no significant difference between two protocols. Implantation rate and clinical pregnant rate were significantly higher in antagonist protocol (15.82% and 30.26%, respectively) than in agonist protocol (5.26% and 10.64% respectively (P<0.05). It was concluded GnRH antagonist protocol probably improved the outcome of pregnancy of older patients with a history of multiple failure of IVF-ET in a GnRH protocol.

  15. 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.

  16. Cysteinyl-Leukotriene Receptors and Cellular Signals

    Directory of Open Access Journals (Sweden)

    G. Enrico Rovati

    2007-01-01

    Full Text Available Cysteinyl-leukotrienes (cysteinyl-LTs exert a range of proinflammatory effects, such as constriction of airways and vascular smooth muscle, increase of endothelial cell permeability leading to plasma exudation and edema, and enhanced mucus secretion. They have proved to be important mediators in asthma, allergic rhinitis, and other inflammatory conditions, including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. The classification into subtypes of the cysteinyl-LT receptors (CysLTRs was based initially on binding and functional data, obtained using the natural agonists and a wide range of antagonists. CysLTRs have proved remarkably resistant to cloning. However, in 1999 and 2000, the CysLT1R and CysLT2R were successfully cloned and both shown to be members of the G-protein coupled receptors (GPCRs superfamily. Molecular cloning has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Recombinant CysLTRs couple to the Gq/11 pathway that modulates inositol phospholipids hydrolysis and calcium mobilization, whereas in native systems, they often activate a pertussis toxin-insensitive Gi/o-protein, or are coupled promiscuously to both G-proteins. Interestingly, recent data provide evidence for the existence of an additional receptor subtype that seems to respond to both cysteinyl-LTs and uracil nucleosides, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Finally, a cross-talk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize recent data derived from studies on the molecular and cellular pharmacology of CysLTRs.

  17. Literature Review on Dynamic Cellular Manufacturing System

    Science.gov (United States)

    Nouri Houshyar, A.; Leman, Z.; Pakzad Moghadam, H.; Ariffin, M. K. A. M.; Ismail, N.; Iranmanesh, H.

    2014-06-01

    In previous decades, manufacturers faced a lot of challenges because of globalization and high competition in markets. These problems arise from shortening product life cycle, rapid variation in demand of products, and also rapid changes in manufcaturing technologies. Nowadays most manufacturing companies expend considerable attention for improving flexibility and responsiveness in order to overcome these kinds of problems and also meet customer's needs. By considering the trend toward the shorter product life cycle, the manufacturing environment is towards manufacturing a wide variety of parts in small batches [1]. One of the major techniques which are applied for improving manufacturing competitiveness is Cellular Manufacturing System (CMS). CMS is type of manufacturing system which tries to combine flexibility of job shop and also productivity of flow shop. In addition, Dynamic cellular manufacturing system which considers different time periods for the manufacturing system becomes an important topic and attracts a lot of attention to itself. Therefore, this paper made attempt to have a brief review on this issue and focused on all published paper on this subject. Although, this topic gains a lot of attention to itself during these years, none of previous researchers focused on reviewing the literature of that which can be helpful and useful for other researchers who intend to do the research on this topic. Therefore, this paper is the first study which has focused and reviewed the literature of dynamic cellular manufacturing system.

  18. Pre-Clinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

    Science.gov (United States)

    Waters, Alicia M.; Stewart, Jerry E.; Atigadda, Venkatram R.; Mroczek-Musulman, Elizabeth; Muccio, Donald D.; Grubbs, Clinton J.; Beierle, Elizabeth A.

    2015-01-01

    Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell cycle analysis, migration, and invasion were studied using alamarBlue® assays, FACS, and Transwell® assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion and migration, cell cycle arrest and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment. PMID:25944918

  19. Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma.

    Science.gov (United States)

    Waters, Alicia M; Stewart, Jerry E; Atigadda, Venkatram R; Mroczek-Musulman, Elizabeth; Muccio, Donald D; Grubbs, Clinton J; Beierle, Elizabeth A

    2015-07-01

    Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell-cycle analysis, migration, and invasion were studied using AlamarBlue assays, FACS, and Transwell assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion, and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment.

  20. 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 inve......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...

  1. Partial agonistic action of endomorphins in the mouse spinal cord.

    Science.gov (United States)

    Mizoguchi, H; Wu, H E; Narita, M

    2001-09-07

    The partial agonistic properties of endogenous mu-opioid peptides endomorphin-1 and endomorphin-2 for G-protein activation were determined in the mouse spinal cord, monitoring the increases in guanosine-5'-o-(3-[35S]thio)triphosphate binding. The G-protein activation induced by endogenous opioid peptide beta-endorphin in the spinal cord was significantly, but partially, attenuated by co-incubation with endomorphin-1 or endomorphin-2. The data indicates that endomorphin-1 and endomorphin-2 are endogenous partial agonists for mu-opioid receptor in the mouse spinal cord.

  2. Alpha-2A Adrenoceptor Agonist Guanfacine Restores Diuretic Efficiency in Experimental Cirrhotic Ascites: Comparison with Clonidine.

    Directory of Open Access Journals (Sweden)

    Giovanni Sansoè

    Full Text Available In human cirrhosis, adrenergic hyperfunction causes proximal tubular fluid retention and contributes to diuretic-resistant ascites, and clonidine, a sympatholytic drug, improves natriuresis in difficult-to-treat ascites.To compare clonidine (aspecific α2-adrenoceptor agonist to SSP-002021R (prodrug of guanfacine, specific α2A-receptor agonist, both associated with diuretics, in experimental cirrhotic ascites.Six groups of 12 rats were studied: controls (G1; controls receiving furosemide and potassium canrenoate (G2; rats with ascitic cirrhosis due to 14-week CCl4 treatment (G3; cirrhotic rats treated (over the 11th-14th CCl4 weeks with furosemide and canrenoate (G4, furosemide, canrenoate and clonidine (G5, or diuretics and SSP002021R (G6. Three rats of each group had their hormonal status and renal function assessed at the end of 11th, 12th, 13th, and 14th weeks of respective treatments.Cirrhotic rats in G3 and G4 gained weight over the 12th-14th CCl4 weeks. In G4, brief increase in sodium excretion over the 11th-12th weeks preceded worsening of inulin clearance and natriuresis (diuretic resistance. In comparison with G4, the addition of clonidine (G5 or guanfacine (G6 to diuretics improved, respectively, sodium excretion over the 11th-12th CCl4 weeks, or GFR and electrolytes excretion over the 13th-14th CCl4 weeks. Natriuretic responses in G5 and G6 were accompanied by reduced catecholamine serum levels.α2A-receptor agonists restore glomerular filtration rate and natriuresis, and delay diuretic-resistant ascites in experimental advanced cirrhosis. Clonidine ameliorates diuretic-dependent natriuresis just for a short time.

  3. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    Science.gov (United States)

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

    2014-08-01

    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 activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.

  4. Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARα Agonists Modulate Mitochondrial Fusion-Fission Dynamics: Relevance to Reactive Oxygen Species (ROS)-Related Neurodegenerative Disorders?

    Science.gov (United States)

    Zolezzi, Juan M.; Silva-Alvarez, Carmen; Ordenes, Daniela; Godoy, Juan A.; Carvajal, Francisco J.; Santos, Manuel J.; Inestrosa, Nibaldo C.

    2013-01-01

    Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of Aβ from the brain of transgenic mice model of Alzheimer’s disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPARγ co-activator 1α (PGC-1α), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPARγ agonist (ciglitazone) and a PPARα agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC-1α and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD. PMID:23675519

  5. A Course in Cellular Bioengineering.

    Science.gov (United States)

    Lauffenburger, Douglas A.

    1989-01-01

    Gives an overview of a course in chemical engineering entitled "Cellular Bioengineering," dealing with how chemical engineering principles can be applied to molecular cell biology. Topics used are listed and some key references are discussed. Listed are 85 references. (YP)

  6. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future

    OpenAIRE

    Sanjay Kalra; Baruah, Manash P.; Rakesh K Sahay; Ambika Gopalakrishnan Unnikrishnan; Shweta Uppal; Omolara Adetunji

    2016-01-01

    Glucagon-like peptide-1 (GLP-1)–based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs) continue to become available, physicians will soon face the challenge of selec...

  7. Energy Landscape of Cellular Networks

    Science.gov (United States)

    Wang, Jin

    2008-03-01

    Cellular Networks are in general quite robust and perform their biological functions against the environmental perturbations. Progresses have been made from experimental global screenings, topological and engineering studies. However, there are so far few studies of why the network should be robust and perform biological functions from global physical perspectives. In this work, we will explore the global properties of the network from physical perspectives. The aim of this work is to develop a conceptual framework and quantitative physical methods to study the global nature of the cellular network. The main conclusion of this presentation is that we uncovered the underlying energy landscape for several small cellular networks such as MAPK signal transduction network and gene regulatory networks, from the experimentally measured or inferred inherent chemical reaction rates. The underlying dynamics of these networks can show bi-stable as well as oscillatory behavior. The global shapes of the energy landscapes of the underlying cellular networks we have studied are robust against perturbations of the kinetic rates and environmental disturbances through noise. We derived a quantitative criterion for robustness of the network function from the underlying landscape. It provides a natural explanation of the robustness and stability of the network for performing biological functions. We believe the robust landscape is a global universal property for cellular networks. We believe the robust landscape is a quantitative realization of Darwinian principle of natural selection at the cellular network level. It may provide a novel algorithm for optimizing the network connections, which is crucial for the cellular network design and synthetic biology. Our approach is general and can be applied to other cellular networks.

  8. Mathematical Modeling of Cellular Metabolism.

    Science.gov (United States)

    Berndt, Nikolaus; Holzhütter, Hermann-Georg

    2016-01-01

    Cellular metabolism basically consists of the conversion of chemical compounds taken up from the extracellular environment into energy (conserved in energy-rich bonds of organic phosphates) and a wide array of organic molecules serving as catalysts (enzymes), information carriers (nucleic acids), and building blocks for cellular structures such as membranes or ribosomes. Metabolic modeling aims at the construction of mathematical representations of the cellular metabolism that can be used to calculate the concentration of cellular molecules and the rates of their mutual chemical interconversion in response to varying external conditions as, for example, hormonal stimuli or supply of essential nutrients. Based on such calculations, it is possible to quantify complex cellular functions as cellular growth, detoxification of drugs and xenobiotic compounds or synthesis of exported molecules. Depending on the specific questions to metabolism addressed, the methodological expertise of the researcher, and available experimental information, different conceptual frameworks have been established, allowing the usage of computational methods to condense experimental information from various layers of organization into (self-) consistent models. Here, we briefly outline the main conceptual frameworks that are currently exploited in metabolism research.

  9. Dipeptidylpeptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) receptor agonists: yes.

    Science.gov (United States)

    Scheen, André J

    2012-03-01

    The pharmacological treatment of type 2 diabetes (T2DM) is becoming increasingly complex, especially since the availability of incretin-based therapies. Compared with other glucose-lowering strategies, these novel drugs offer some advantages such as an absence of weight gain and a negligible risk of hypoglycaemia and, possibly, better cardiovascular and β-cell protection. The physician has now multiple choices to manage his/her patient after secondary failure of metformin, and the question whether it is preferable to add an oral dipeptidylpeptidase-4 (DPP-4) inhibitor (gliptin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist will emerge. Obviously, DPP-4 inhibitors offer several advantages compared with GLP-1 receptor agonists, especially regarding easiness of use, tolerance profile and cost. However, because they can only increase endogenous GLP-1 concentrations to physiological (rather than pharmacological) levels, they are less potent to improve glucose control, promote weight reduction ("weight neutrality") and reduce blood pressure compared to GLP-1 receptor agonists. Of note, none of the two classes have proven long-term safety and positive impact on diabetic complications yet. The role of DPP-4 inhibitors and GLP-1 receptor agonists in the therapeutic armamentarium of T2DM is rapidly evolving, but their respective potential strengths and weaknesses should be better defined in long-term head-to-head comparative controlled trials. Instead of trying to answer the question whether DPP-4 inhibitors are favourable to GLP-1 receptor agonists (or vice versa), it is probably more clinically relevant to look at which T2DM patient will benefit more from one or the other therapy considering all his/her individual clinical characteristics ("personalized medicine").

  10. Passive Matrix Organic Electroluminescent Display for 3G Cellular Phone

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The major features of the display technologies for 3G cellular phone are reviewed. The comparison between their potential candidates for 3G cellular phone is given, and a detailed discussion is made on passive matrix organic electroluminescent display technology. A novel method to improve display contrast ratio is presented. Finally several 3G phone set prototypes with OLED display panels are given as well as the market forecast

  11. A high-efficiency cellular extraction system for biological proteomics

    OpenAIRE

    2015-01-01

    Recent developments in quantitative high-resolution mass spectrometry have led to significant improvements in the sensitivity and specificity of biochemical analyses of cellular reactions, protein-protein interactions, and small molecule drug discovery. These approaches depend on cellular proteome extraction that preserves native protein activities. Here, we systematically analyzed mechanical methods of cell lysis and physical protein extraction to identify those that maximize the extraction ...

  12. [Alpha 2-adrenoceptor agonists for the treatment of chronic pain].

    Science.gov (United States)

    Kulka, P J

    1996-04-25

    The antinociceptive effect of alpha(2)-adrenoceptor agonists is mediated by activation of descending inhibiting noradrenergic systems, which modulates 'wide-dynamic-range' neurones. Furthermore, they inhibit the liberation of substance P and endorphines and activate serotoninergic neurones. Despite this variety of antinociceptive actions, there is still little experience with alpha(2)-adrenoceptor agonists as therapeutic agents for use in chronic pain syndromes. Studies in animals and patients have shown that the transdermal, epidural and intravenous administration of the alpha(2)-adrenoceptor agonist clonidine reduces pain intensity in neuropathic pain syndromes for periods varying from some hours up to 1 month. Patients suffering from lancinating or sharp pain respond best to this therapy. Topically applied clonidine (200-300 microg) relieves hyperalgesia in sympathetically maintained pain. Epidural administration of 300 microg clonidine dissolved in 5 ml NaCl 0.9 % has also been shown to be effective. In patients suffering from cancer pain tolerant to opioids, pain control has proved possible again with combinations of opioids and clonidine. In isolated cases clonidine has been administered epidurally at a dose of 1500 microg/day for almost 5 months without evidence for any histotoxic property of clonidine. Side effects often observed during administration of alpha(2)-adrenoceptor agonists are dry mouth, sedation, hypotension and bradycardia. Therapeutic interventions are usually not required.

  13. 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

    In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk...

  14. Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Bruning, J.B.; Chalmers, M.J.; Prasad, S.; Bushby, S.A.; Kamenecka, T.A.; He, Y.; Nettles, K.W.; Griffin, P.R.

    2009-05-28

    Binding to helix 12 of the ligand-binding domain of PPAR{gamma} is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPAR{gamma} with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPAR{gamma} transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch.

  15. 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...

  16. Dwell time of a Brownian interacting molecule in a cellular microdomain

    CERN Document Server

    Taflia, A; Taflia, Adi; Holcman, David

    2006-01-01

    The time spent by an interacting Brownian molecule inside a bounded microdomain has many applications in cellular biology, because the number of bounds is a quantitative signal, which can initiate a cascade of chemical reactions and thus has physiological consequences. In the present article, we propose to estimate the mean time spent by a Brownian molecule inside a microdomain $\\Omega$ which contains small holes on the boundary and agonist molecules located inside. We found that the mean time depends on several parameters such as the backward binding rate (with the agonist molecules), the mean escape time from the microdomain and the mean time a molecule reaches the binding sites (forward binding rate). In addition, we estimate the mean and the variance of the number of bounds made by a molecule before it exits $\\Omega$. These estimates rely on a boundary layer analysis of a conditional mean first passage time, solution of a singular partial differential equation. In particular, we apply the present results ...

  17. Utility of gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Shen YW

    2015-11-01

    % confidence interval (CI=1.65, 4.01; P<0.0001. A subgroup analysis showed that addition of GnRH agonists significantly improved the resumption of menses rate in patients who were hormone-insensitive. However, the two treatment groups experienced similar spontaneous pregnancy (odds ratio =0.177; 95% CI=0.92, 1.40; P=0.09. Conclusion: GnRH agonists cotreatment with chemotherapy in premenopausal women with breast cancer plays a beneficial role in resumption of ovarian function, with a higher rate of resumption of menses. However, treatment with GnRH agonists does not appear to exhibit its protective effects in fertility. Keywords: GnRH agonists, ovarian damage, breast cancer, chemotherapy, meta-analysis

  18. From Theory to Clinical Practice in the Use of GLP-1 Receptor Agonists and DPP-4 Inhibitors Therapy

    Directory of Open Access Journals (Sweden)

    Ilaria Dicembrini

    2011-01-01

    Full Text Available Promoting long-term adherence to lifestyle modification and choice of antidiabetic agent with low hypoglycemia risk profile and positive weight profile could be the most effective strategy in achieving sustained glycemic control and in reducing comorbidities. From this perspective, vast interest has been generated by glucagon-like peptide-1 (GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i. In this review our ten-year clinical and laboratory experience by in vitro and in vivo studies is reported. Herein, we reviewed available data on the efficacy and safety profile of GLP-1 receptor agonists and DPP-4i. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both GLP-1 receptor agonists and DPP-4i, improve β cell function indexes. All these agents showed trophic effects on beta-cell mass in animal studies. The use of these drugs is associated with positive or neucral effect on body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic steazosis markets, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

  19. From theory to clinical practice in the use of GLP-1 receptor agonists and DPP-4 inhibitors therapy.

    Science.gov (United States)

    Dicembrini, Ilaria; Pala, Laura; Rotella, Carlo Maria

    2011-01-01

    Promoting long-term adherence to lifestyle modification and choice of antidiabetic agent with low hypoglycemia risk profile and positive weight profile could be the most effective strategy in achieving sustained glycemic control and in reducing comorbidities. From this perspective, vast interest has been generated by glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i). In this review our ten-year clinical and laboratory experience by in vitro and in vivo studies is reported. Herein, we reviewed available data on the efficacy and safety profile of GLP-1 receptor agonists and DPP-4i. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both GLP-1 receptor agonists and DPP-4i, improve β cell function indexes. All these agents showed trophic effects on beta-cell mass in animal studies. The use of these drugs is associated with positive or neucral effect on body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic steazosis markets, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

  20. Agonist substitution--a treatment alternative for high-dose benzodiazepine-dependent patients?

    Science.gov (United States)

    Liebrenz, Michael; Boesch, Lukas; Stohler, Rudolf; Caflisch, Carlo

    2010-11-01

    There is vast evidence for the superiority of agonist treatments (methadone, buprenorphine) over a withdrawal approach in opioid-dependent populations. Little research, however, has been conducted on the same approach for the treatment of high-dose benzodiazepine (BZD) dependence. Even large-scale reviews and meta-analyses discussing treatment strategies for benzodiazepine-dependent patients focus solely upon approaches that aim at achieving abstinence, namely on complete BZD withdrawal. While the types of interventions differ (e.g. gradual benzodiazepine taper with a long or a short half-life benzodiazepine, switching to non-benzodiazepine anxiolytics or prescribing adjunctive medications such as antidepressants or anticonvulsants on an in- or out-patient basis), the common aim of treatment still is total abstinence from benzodiazepines. However, the majority of patients suffering from high-dose BZD dependence do not succeed with long-term abstinence, irrespective of the procedure, and clinicians have been using BZD 'substitution' treatment in such cases for decades. Therefore, we suggest the evaluation of a substitution approach in this group, consisting of maintenance treatment with a slow-onset, long-acting BZD. Advantages of such a procedure may be improved health, less craving, fewer withdrawal complications, reduced anxiety, increased treatment retention, improvements in social functioning and less illegal activity. Cognitive impairments, the most problematic side effects of substitution treatment with benzodiazepines, could possibly be minimized by using an optimal agonist.

  1. Pramipexole, a nonergot dopamine agonist, is effective against rest tremor in intermediate to advanced Parkinson's disease.

    Science.gov (United States)

    Künig, G; Pogarell, O; Möller, J C; Delf, M; Oertel, W H

    1999-01-01

    We evaluated the efficacy of the nonergot dopamine receptor agonist pramipexole in 16 patients with advanced Parkinson's disease and marked rest tremor during an "on" period. The patients were drawn from a larger placebo-controlled, double-blind, randomized trial, which was not originally designed to investigate the effect of pramipexole on tremor. Eleven patients received pramipexole. The first effects were seen with a pramipexole dose of 0.75 mg/d with a reduction of the tremor item A of Unified Parkinson's Disease Rating Scale (UPDRS III, "on" state) by 25% and of rigidity and akinesia by 22%. Under the highest dose, 4.5 mg/d, the tremor score was improved by 61% over baseline (p < 0.0056, Wilcoxon signed rank) and the sum of rigidity and akinesia items by 66% (p < 0.0038, Wilcoxon signed rank). Five patients received placebo and did not improve. Based on this sample of patients, the nonergot dopamine receptor agonist pramipexole appears to have a potent anti-rest tremor action while being effective against akinesia and rigidity.

  2. 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.

  3. Effects of the neurotensin NTS₁ receptor agonist PD149163 on visual signal detection in rats.

    Science.gov (United States)

    Hillhouse, Todd M; Prus, Adam J

    2013-12-01

    Antipsychotic drugs provide limited efficacy for cognitive impairment in schizophrenia. Recent studies have found that the neurotensin NTS1 receptor agonist and putative atypical antipsychotic drug PD149163 reverses deficits in sensory-gating and novel object recognition, suggesting that this compound may have the potential to improve cognitive functioning in schizophrenia. The present study sought to extend these investigations by evaluating the effects of PD149163 on sustained attention using a visual signal detection operant task in rats. PD149163, the atypical antipsychotic drug clozapine, and the dopamine D2/3 receptor antagonist raclopride all significantly decreased percent "hit" accuracy, while none of these compounds altered "correct rejections" (compared to vehicle control). Clozapine and raclopride significantly increased response latency, while high doses of PD149163 and raclopride significantly increased trial omissions. Nicotine, which was tested as a positive control, significantly improved overall performance in this task and did not affect response latency or trial omissions. The present findings suggest that neurotensin NTS1 receptor agonists, like antipsychotic drugs, may inhibit sustained attention in this task despite having different pharmacological mechanisms of action.

  4. Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity

    Science.gov (United States)

    Franks, Lirit N.; Ford, Benjamin M.; Prather, Paul L.

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are used to treat estrogen receptor (ER)-positive breast cancer and osteoporosis. Interestingly, tamoxifen and newer classes of SERMs also exhibit cytotoxic effects in cancers devoid of ERs, indicating a non-estrogenic mechanism of action. Indicative of a potential ER-independent target, reports demonstrate that tamoxifen binds to cannabinoid receptors (CBRs) with affinity in the low μM range and acts as an inverse agonist. To identify cannabinoids with improved pharmacological properties relative to tamoxifen, and further investigate the use of different SERM scaffolds for future cannabinoid drug development, this study characterized the affinity and activity of SERMs in newer structural classes at CBRs. Fourteen SERMs from five structurally distinct classes were screened for binding to human CBRs. Compounds from four of five SERM classes examined bound to CBRs. Subsequent studies fully characterized CBR affinity and activity of one compound from each class. Ospemifine (a triphenylethylene) selectively bound to CB1Rs, while bazedoxifine (an indole) bound to CB2Rs with highest affinity. Nafoxidine (a tetrahydronaphthalene) and raloxifene (RAL; a benzothiaphene) bound to CB1 and CB2Rs non-selectively. All four compounds acted as inverse agonists at CB1 and CB2Rs, reducing basal G-protein activity with IC50 values in the nM to low μM range. Ospemifine, bazedoxifene and RAL also acted as inverse agonists to elevate basal intracellular cAMP levels in intact CHO-hCB2 cells. The four SERMs examined also acted as CB1 and CB2R antagonists in the cAMP assay, producing rightward shifts in the concentration-effect curve of the CBR agonist CP-55,940. In conclusion, newer classes of SERMs exhibit improved pharmacological characteristics (e.g., in CBR affinity and selectivity) relative to initial studies with tamoxifen, and thus suggest that different SERM scaffolds may be useful for development of safe and selective drugs acting

  5. OX40 agonists and combination immunotherapy: putting the pedal to the metal

    Directory of Open Access Journals (Sweden)

    Stefanie N Linch

    2015-02-01

    Full Text Available Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient’s own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as checkpoint inhibitors, can inhibit T cell function to suppress anti-tumor immunity. Checkpoint inhibitors, such as CTLA-4 and PD-1, attenuate T cell proliferation and cytokine production. Targeted blockade of CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAb releases the brakes on T cells to boost anti-tumor immunity. Generating optimal killer CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134 and 4-1BB (CD137. OX40 is of particular interest as treatment with an activating (agonist anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors. When used as single agents, these drugs can induce potent clinical and immunologic responses in patients with metastatic disease. However, each of these agents only benefits a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. In this review, we will discuss our current understanding of the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies.

  6. Hierarchical Cellular Structures in High-Capacity Cellular Communication Systems

    CERN Document Server

    Jain, R K; Agrawal, N K

    2011-01-01

    In the prevailing cellular environment, it is important to provide the resources for the fluctuating traffic demand exactly in the place and at the time where and when they are needed. In this paper, we explored the ability of hierarchical cellular structures with inter layer reuse to increase the capacity of mobile communication network by applying total frequency hopping (T-FH) and adaptive frequency allocation (AFA) as a strategy to reuse the macro and micro cell resources without frequency planning in indoor pico cells [11]. The practical aspects for designing macro- micro cellular overlays in the existing big urban areas are also explained [4]. Femto cells are inducted in macro / micro / pico cells hierarchical structure to achieve the required QoS cost effectively.

  7. Cellular Kinetics of Perivascular MSC Precursors

    Directory of Open Access Journals (Sweden)

    William C. W. Chen

    2013-01-01

    Full Text Available Mesenchymal stem/stromal cells (MSCs and MSC-like multipotent stem/progenitor cells have been widely investigated for regenerative medicine and deemed promising in clinical applications. In order to further improve MSC-based stem cell therapeutics, it is important to understand the cellular kinetics and functional roles of MSCs in the dynamic regenerative processes. However, due to the heterogeneous nature of typical MSC cultures, their native identity and anatomical localization in the body have remained unclear, making it difficult to decipher the existence of distinct cell subsets within the MSC entity. Recent studies have shown that several blood-vessel-derived precursor cell populations, purified by flow cytometry from multiple human organs, give rise to bona fide MSCs, suggesting that the vasculature serves as a systemic reservoir of MSC-like stem/progenitor cells. Using individually purified MSC-like precursor cell subsets, we and other researchers have been able to investigate the differential phenotypes and regenerative capacities of these contributing cellular constituents in the MSC pool. In this review, we will discuss the identification and characterization of perivascular MSC precursors, including pericytes and adventitial cells, and focus on their cellular kinetics: cell adhesion, migration, engraftment, homing, and intercellular cross-talk during tissue repair and regeneration.

  8. Dynamic Channel Allocation in Sectored Cellular Systems

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    It is known that dynamic channel assignment(DCA) strategy outperforms the fixed channel assignment(FCA) strategy in omni-directional antenna cellular systems. One of the most important methods used in DCA was channel borrowing. But with the emergence of cell sectorization and spatial division multiple access(SDMA) which are used to increase the capacity of cellular systems, the channel assignment faces a series of new problems. In this paper, a dynamic channel allocation scheme based on sectored cellular systems is proposed. By introducing intra-cell channel borrowing (borrowing channels from neighboring sectors) and inter-cell channel borrowing (borrowing channels from neighboring cells) methods, previous DCA strategies, including compact pattern based channel borrowing(CPCB) and greedy based dynamic channel assignment(GDCA) schemes proposed by the author, are improved significantly. The computer simulation shows that either intra-cell borrowing scheme or inter-cell borrowing scheme is efficient enough to uniform and non-uniform traffic service distributions.

  9. Rhabdomyosarcoma: Advances in Molecular and Cellular Biology

    Directory of Open Access Journals (Sweden)

    Xin Sun

    2015-01-01

    Full Text Available Rhabdomyosarcoma (RMS is the most common soft tissue malignancy in childhood and adolescence. The two major histological subtypes of RMS are alveolar RMS, driven by the fusion protein PAX3-FKHR or PAX7-FKHR, and embryonic RMS, which is usually genetically heterogeneous. The prognosis of RMS has improved in the past several decades due to multidisciplinary care. However, in recent years, the treatment of patients with metastatic or refractory RMS has reached a plateau. Thus, to improve the survival rate of RMS patients and their overall well-being, further understanding of the molecular and cellular biology of RMS and identification of novel therapeutic targets are imperative. In this review, we describe the most recent discoveries in the molecular and cellular biology of RMS, including alterations in oncogenic pathways, miRNA (miR, in vivo models, stem cells, and important signal transduction cascades implicated in the development and progression of RMS. Furthermore, we discuss novel potential targeted therapies that may improve the current treatment of RMS.

  10. Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models.

    Science.gov (United States)

    Guo, Dan-yang; Li, De-wen; Ning, Meng-meng; Dang, Xiang-yu; Zhang, Li-na; Zeng, Li-min; Hu, You-hong; Leng, Ying

    2015-10-30

    G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved β-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and β-cell function, suggesting its promising potential for the treatment of type 2 diabetes.

  11. Nelotanserin, a novel selective human 5-hydroxytryptamine2A inverse agonist for the treatment of insomnia.

    Science.gov (United States)

    Al-Shamma, Hussien A; Anderson, Christen; Chuang, Emil; Luthringer, Remy; Grottick, Andrew J; Hauser, Erin; Morgan, Michael; Shanahan, William; Teegarden, Bradley R; Thomsen, William J; Behan, Dominic

    2010-01-01

    5-Hydroxytryptamine (5-HT)(2A) receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT(2A) inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT(2A) receptor with at least 30- and 5000-fold selectivity compared with 5-HT(2C) and 5-HT(2B) receptors, respectively. Nelotanserin dosed orally prevented (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT(2A) agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.

  12. Structural determinants of agonist-specific kinetics at the ionotropic glutamate receptor 2

    DEFF Research Database (Denmark)

    Holm, Mai Marie; Lunn, Marie-Louise; Traynelis, Stephen F;

    2005-01-01

    Glutamate receptors (GluRs) are the most abundant mediators of the fast excitatory neurotransmission in the human brain. Agonists will, after activation of the receptors, induce different degrees of desensitization. The efficacy of agonists strongly correlates with the agonist-induced closure of ...

  13. Agonist signalling properties of radiotracers used for imaging of dopamine D-2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan

    2014-01-01

    Background: Dopamine D-2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists ar

  14. Classifying cellular automata using grossone

    Science.gov (United States)

    D'Alotto, Louis

    2016-10-01

    This paper proposes an application of the Infinite Unit Axiom and grossone, introduced by Yaroslav Sergeyev (see [7] - [12]), to the development and classification of one and two-dimensional cellular automata. By the application of grossone, new and more precise nonarchimedean metrics on the space of definition for one and two-dimensional cellular automata are established. These new metrics allow us to do computations with infinitesimals. Hence configurations in the domain space of cellular automata can be infinitesimally close (but not equal). That is, they can agree at infinitely many places. Using the new metrics, open disks are defined and the number of points in each disk computed. The forward dynamics of a cellular automaton map are also studied by defined sets. It is also shown that using the Infinite Unit Axiom, the number of configurations that follow a given configuration, under the forward iterations of cellular automaton maps, can now be computed and hence a classification scheme developed based on this computation.

  15. Prognosis of Different Cellular Generations

    Directory of Open Access Journals (Sweden)

    Preetish Ranjan

    2013-04-01

    Full Text Available Technological advancement in mobile telephony from 1G to 3G, 4G and 5G has a very axiomatic fact that made an entire world a global village. The cellular system employs a different design approach and technology that most commercial radio and television system use. In the cellular system, the service area is divided into cells and a transmitter is designed to serve an individual cell. The system seeks to make efficient use of available channels by using low-power transmitters to allow frequency reuse at a smaller distance. Maximizing the number of times each channel can be reused in a given geographical area is the key to an efficient cellular system design. During the past three decades, the world has seen significant changes in telecommunications industry. There have been some remarkable aspects to the rapid growth in wireless communications, as seen by the large expansion in mobile systems. This paper focuses on “Past, Present & Future of Cellular Telephony” and some light has been thrown upon the technologies of the cellular systems, namely 1G, 2G, 2.5G, 3G and future generations like 4G and 5G systems as well.

  16. Preconceptual administration of an alphavirus replicon UL83 (pp65 homolog) vaccine induces humoral and cellular immunity and improves pregnancy outcome in the guinea pig model of congenital cytomegalovirus infection.

    Science.gov (United States)

    Schleiss, Mark R; Lacayo, Juan C; Belkaid, Yasmine; McGregor, Alistair; Stroup, Greg; Rayner, Jon; Alterson, Kimberly; Chulay, Jeffrey D; Smith, Jonathan F

    2007-03-15

    Development of a vaccine against congenital cytomegalovirus (CMV) infection is a major public health priority. We report the use of a propagation-defective, single-cycle, RNA replicon vector system, derived from an attenuated strain of the alphavirus Venezuelan equine encephalitis virus, to produce virus-like replicon particles (VRPs) expressing GP83, the guinea pig CMV (GPCMV) homolog of the human CMV pp65 phosphoprotein. Vaccination with VRP-GP83 induced antibodies and CD4(+) and CD8(+) T cell responses in GPCMV-seronegative female guinea pigs. Guinea pigs immunized with VRP-GP83 vaccine or with a VRP vaccine expressing influenza hemagglutinin (VRP-HA) were bred for pregnancy and subsequent GPCMV challenge during the early third trimester. Dams vaccinated with VRP-GP83 had improved pregnancy outcomes, compared with dams vaccinated with the VRP-HA control. For VRP-GP83-vaccinated dams, there were 28 live pups and 4 dead pups (13% mortality) among 10 evaluable litters, compared with 9 live pups and 12 dead pups (57% mortality) among 8 evaluable litters in the VRP-HA-vaccinated group (P<.001, Fisher's exact test). Improved pregnancy outcome was accompanied by reductions in maternal blood viral load, measured by real-time polymerase chain reaction. These results indicate that cell-mediated immune responses directed against a CMV matrix protein can protect against congenital CMV infection and disease.

  17. Selective imidazoline agonist moxonidine in obese hypertensive patients.

    Science.gov (United States)

    Sanjuliani, A F; de Abreu, V G; Francischetti, E A

    2006-05-01

    Obesity is the major risk factor for the development of hypertension. This association accentuates the risk of cardiovascular disease, as it is frequently accompanied by the components of the metabolic syndrome. This randomised open parallel study evaluated the chronic effects of moxonidine--a selective imidazoline receptor agonist--on blood pressure, plasma catecholamines, leptin, insulin and components of the metabolic syndrome in obese hypertensives. Amlodipine was used as the control drug. Our results showed that moxonidine and amlodipine significantly reduced blood pressure when measured using the oscillometric method and 24-hour blood pressure monitoring. Moxonidine therapy decreased systolic blood pressure from 160.4 +/- 2.4 to 142.1 +/- 3.3 mmHg (p < 0.005) and diastolic blood pressure from 102.4 +/- 1.3 to 89.7 +/- 1.6 mmHg (p < 0.005) after 24 weeks of treatment. Moxonidine administration reduced the supine arterial plasma levels of adrenaline from 63.2 +/- 6.6 to 49.0 +/- 6.7 pg/ml (p < 0.005), the supine arterial plasma levels of noradrenaline from 187.9 +/- 10.7 to 149.7 +/- 13.2 pg/ml (p < 0.01) and the orthostatic venous plasma levels of noradrenaline from 258.6 +/- 25.0 to 190.3 +/- 16.4 pg/ml (p = 0.03). Those variables were not changed by amlodipine. The plasma levels of leptin and insulin 120 min after a glucose load decreased after moxonidine administration from 27.2 +/- 3.5 to 22.6 +/- 2.9 pg/ml (p < 0.05) and from 139.7 +/- 31.2 to 76.0 +/- 15.2 U/ml (p < 0.05), respectively. Amlodipine, however, did not modify those variables. This study showed a comparable reduction in blood pressure with both antihypertensive drugs. Moxonidine decreased sympathetic nervous activity, improved insulin resistance and reduced the plasma levels of leptin.

  18. Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists.

    Science.gov (United States)

    Morin, Matthew D; Wang, Ying; Jones, Brian T; Su, Lijing; Surakattula, Murali M R P; Berger, Michael; Huang, Hua; Beutler, Elliot K; Zhang, Hong; Beutler, Bruce; Boger, Dale L

    2016-05-26

    Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor.

  19. Novel Materials for Cellular Nanosensors

    DEFF Research Database (Denmark)

    Sasso, Luigi

    The monitoring of cellular behavior is useful for the advancement of biomedical diagnostics, drug development and the understanding of a cell as the main unit of the human body. Micro- and nanotechnology allow for the creation of functional devices that enhance the study of cellular dynamics...... modifications for electrochemical nanosensors for the detection of analytes released from cells. Two type of materials were investigated, each pertaining to the two different aspects of such devices: peptide nanostructures were studied for the creation of cellular sensing substrates that mimic in vivo surfaces...... and that offer advantages of functionalization, and conducting polymers were used as electrochemical sensor surface modifications for increasing the sensitivity towards relevant analytes, with focus on the detection of dopamine released from cells via exocytosis. Vertical peptide nanowires were synthesized from...

  20. 5-羟色胺1A受体激动剂改善脊髓损伤大鼠排尿功能障碍的实验研究%Improving the voding dysfunction by a 5-HT1A receptor agonist in rats with chronic spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    曹海兵; 吴刚; 程曙杰; 谷宝军

    2011-01-01

    目的 研究5-羟色胺-1A(5-HTlA)受体激动剂对慢性脊髓损伤(spinal cord injury,SCI)大鼠排尿障碍的改善作用. 方法 雌性SD大鼠14只,体质量175 ~ 200 g.随机分为2组:实验组7只显微镜下大鼠T10棘突水平行脊髓离断建立脊髓损伤模型,正常对照组7只.8周后乌拉坦(1.3 g/kg)麻醉下,2组大鼠颈静脉和膀胱内置管,连接压力感受器,记录膀胱最大容量、残余尿量、排尿量和尿道外括约肌的肌电活动.静脉注入5-HTI A/7受体激动剂8-羟基-丙胺-四氢萘(8-OH-DPAT,0.03 ~1.00 mg/kg),得出剂量—效应曲线后再给予5HTIA受体抑制剂WAY-100635 (0.3g/kg).观察比较2组大鼠用药前后尿动力学指标的变化. 结果 随着8-OH-DPAT剂量增加,SCI大鼠膀胱容量从(33.2 ±8.3)ml降至(22.8±2.4) ml,排尿量从(0.14±0.08)ml增至(0.38 ±0.09) ml,残余尿量从(3.68±1.36)ml降至(1.84±0.21)ml,而膀胱最高压力从(27.1±3.6)mm Hg(1 mm Hg=0.133 kPa)降至(22.8±2.4) mm Hg,用药前后差异均有统计学意义(P<0.05).对照组大鼠用药前后排尿情况变化差异无统计学意义.肌电图显示8-OH-DPAT引起SCI大鼠尿道外括约肌强直收缩中出现阶段性的松弛,正常对照组大鼠作用无明显改变. 结论 8-OH-DPAT可以剂量依赖性地部分恢复SCI大鼠的尿道外括约肌协调性松弛,从而降低膀胱容量,增加排尿量,减少残尿量,增加排尿效率,改善排尿障碍.%Objective To investigate the effect of 5-hydroxytryptamine serotonin receptor-1A (5-HT1 A) agonists on micturition dysfunction in rats with chronic spinal cord injury (SCI).Methods Female SD rats weighing 175 -200 g were used.Seven of the rats were modified for a spinal cord injury model (transsection at T10).Eight weeks later,control rats and SCI rats were tested.Rats were anesthetized with urethane ( 1.3 g/kg ).A polyethylene (PE) -50 catheter was placed in the left jugular vein for intravenous drug administration.A PE-90 catheter was

  1. Cellular models for Parkinson's disease.

    Science.gov (United States)

    Falkenburger, Björn H; Saridaki, Theodora; Dinter, Elisabeth

    2016-10-01

    Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of patients with Parkinson's disease: The degeneration of dopaminergic neurons and the existence of protein aggregates consisting mainly of α-synuclein. Cultured cells offer many advantages over studying Parkinson's disease directly in patients or in animal models. At the same time, the choice of a specific cellular model entails the requirement to focus on one aspect of the disease while ignoring others. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types the aspects of Parkinson's disease they model along with technical advantages and disadvantages. It might also be helpful for researchers from other fields consulting literature on cellular models of Parkinson's disease. Important models for the study of dopaminergic neuron degeneration include Lund human mesencephalic cells and primary neurons, and a case is made for the use of non-dopaminergic cells to model pathogenesis of non-motor symptoms of Parkinson's disease. With regard to α-synuclein aggregates, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. Cellular models reproduce the two most salient changes of Parkinson's disease, the degeneration of dopaminergic neurons and the existence of α-synuclein aggregates. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types and treatments the aspects of Parkinson's disease they model along with technical advantages and disadvantages. Furthermore, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. This article is part of a special issue on Parkinson disease.

  2. The agonist-specific voltage dependence of M2 muscarinic receptors modulates the deactivation of the acetylcholine-gated K(+) current (I KACh).

    Science.gov (United States)

    Moreno-Galindo, Eloy G; Alamilla, Javier; Sanchez-Chapula, José A; Tristani-Firouzi, Martin; Navarro-Polanco, Ricardo A

    2016-07-01

    Recently, it has been shown that G protein-coupled receptors (GPCRs) display intrinsic voltage sensitivity. We reported that the voltage sensitivity of M2 muscarinic receptor (M2R) is also ligand specific. Here, we provide additional evidence to understand the mechanism underlying the ligand-specific voltage sensitivity of the M2R. Using ACh, pilocarpine (Pilo), and bethanechol (Beth), we evaluated the agonist-specific effects of voltage by measuring the ACh-activated K(+) current (I KACh) in feline and rabbit atrial myocytes and in HEK-293 cells expressing M2R-Kir3.1/Kir3.4. The activation of I KACh by the muscarinic agonist Beth was voltage insensitive, suggesting that the voltage-induced conformational changes in M2R do not modify its affinity for this agonist. Moreover, deactivation of the Beth-evoked I KACh was voltage insensitive. By contrast, deactivation of the ACh-induced I KACh was significantly slower at -100 mV than at +50 mV, while an opposite effect was observed when I KACh was activated by Pilo. These findings are consistent with the voltage affinity pattern observed for these three agonists. Our findings suggest that independent of how voltage disturbs the receptor binding site, the voltage dependence of the signaling pathway is ultimately determined by the agonist. These observations emphasize the pharmacological potential to regulate the M2R-parasympathetic associated cardiac function and also other cellular signaling pathways by exploiting the voltage-dependent properties of GPCRs.

  3. Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption.

    Science.gov (United States)

    Agné, Alisa M; Baldin, Jan-Peter; Benjamin, Audra R; Orogo-Wenn, Maria C; Wichmann, Lukas; Olson, Kenneth R; Walters, Dafydd V; Althaus, Mike

    2015-04-01

    In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5-50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance.

  4. A dual TLR agonist adjuvant enhances the immunogenicity and protective efficacy of the tuberculosis vaccine antigen ID93.

    Directory of Open Access Journals (Sweden)

    Mark T Orr

    Full Text Available With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4(+ T cell response characterized by IFN-γ and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co-production of IFN-γ, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG.

  5. Design, synthesis, and biological evaluation of novel investigational nonapeptide KISS1R agonists with testosterone-suppressive activity.

    Science.gov (United States)

    Asami, Taiji; Nishizawa, Naoki; Matsui, Hisanori; Nishibori, Kimiko; Ishibashi, Yoshihiro; Horikoshi, Yasuko; Nakayama, Masaharu; Matsumoto, Shin-ichi; Tarui, Naoki; Yamaguchi, Masashi; Matsumoto, Hirokazu; Ohtaki, Tetsuya; Kitada, Chieko

    2013-11-14

    Metastin/kisspeptin is a 54 amino acid peptide ligand of the KISS1R receptor and is a critical regulator of GnRH secretion. The N-terminally truncated peptide, metastin(45-54), possesses a 10-fold higher receptor-binding affinity than full-length metastin and agonistic KISS1R activity but is rapidly inactivated in rodent plasma. We have developed a decapeptide analog [D-Tyr(45),D-Trp(47),azaGly(51),Arg(Me)(53)]metastin(45-54) with improved serum stability compared with metastin(45-54) but with decreased KISS1R agonistic activity. Amino acid replacements at positions 45-47 led to an enhancement of KISS1R agonistic activity and metabolic stability. N-terminal truncation resulted in a stable nonapeptide, [D-Tyr(46),D-Pya(4)(47),azaGly(51),Arg(Me)(53)]metastin(46-54), compound 26, which displayed KISS1R binding affinities comparable to metastin(45-54) and had improved serum stability. Compound 26 reduced plasma testosterone in male rats and is the first short-length metastin analog to possess testosterone suppressive activities. Compound 26 has led to the elucidation of investigational analogs TAK-683 and TAK-448, both of which have undergone clinical evaluation for hormone-dependent diseases such as prostate cancer.

  6. Lorcaserin: a selective serotonin receptor (5-HT2C agonist for the treatment of obesity

    Directory of Open Access Journals (Sweden)

    Bhaven C. Kataria

    2012-02-01

    Full Text Available Lorcaserin is a selective serotonin receptor (5-HT2C agonist that recently received the U.S. Food and Drug Administration (FDA approval for chronic weight management. The efficacy of this drug in reducing body weight and improving metabolic parameters of obese patients has been demonstrated in three phase-3 clinical trials. The available evidence indicates that this drug does not show heart valve abnormalities, and the treatment improves the risk factors for type 2 diabetes and cardiovascular diseases. However, the drug's manufacturer will be required to conduct postmarketing studies, including a long-term cardiovascular outcomes trial to assess the effect of Lorcaserin on the risk for major adverse cardiac events such as heart attack and stroke. [Int J Basic Clin Pharmacol 2012; 1(1.000: 45-47

  7. Sulfonylureas and Glinides as New PPARγ Agonists:. Virtual Screening and Biological Assays

    Science.gov (United States)

    Scarsi, Marco; Podvinec, Michael; Roth, Adrian; Hug, Hubert; Kersten, Sander; Albrecht, Hugo; Schwede, Torsten; Meyer, Urs A.; Rücker, Christoph

    2007-12-01

    This work combines the predictive power of computational drug discovery with experimental validation by means of biological assays. In this way, a new mode of action for type 2 diabetes drugs has been unvealed. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target PPARγ improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides bind to PPARγ and exhibit PPARγ agonistic activity. This result was predicted in silico by virtual screening and confirmed in vitro by three biological assays. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, since it provides evidence that drugs can be designed which target both the sulfonylurea receptor and PPARγ. Targeting both receptors could in principle allow to increase pancreatic insulin secretion, as well as to improve insulin resistance.

  8. [Cardiogenic pulmonary edema following β2 agonist infusion for acute, severe asthma].

    Science.gov (United States)

    Bahloul, M; Chaari, A; Dammak, H; Medhioub, F; Abid, L; Chtourou, K; Rekik, N; Chelly, H; Kallel, H; Bouaziz, M

    2015-09-01

    We report the case of a severe acute pulmonary edema secondary to the administration of salbutamol to a patient admitted for severe asthma. The diagnosis of acute pulmonary edema was suspected on the clinical examination, chest radiography, biological (plasmatic Pro-BNP rate) and echocardiographic findings. Rapid improvement under dobutamine and mechanical ventilation argue in favour of cardiogenic pulmonary edema. The young age of our patient, the absence of history of cardiovascular disease and the chronology of this complication onset regarded to salbutamol infusion could suggest β2 agonist involvement in this event. The improvement of cardiac function on echocardiography and the normal results obtained with myocardial perfusion scintigraphy performed 35 days later show the left ventricular reversible dysfunction.

  9. Cellular basis of Alzheimer's disease.

    Science.gov (United States)

    Bali, Jitin; Halima, Saoussen Ben; Felmy, Boas; Goodger, Zoe; Zurbriggen, Sebastian; Rajendran, Lawrence

    2010-12-01

    Alzheimer's disease (AD) is the most common form of neurodegenerative disease. A characteristic feature of the disease is the presence of amyloid-β (Aβ) which either in its soluble oligomeric form or in the plaque-associated form is causally linked to neurodegeneration. Aβ peptide is liberated from the membrane-spanning -amyloid precursor protein by sequential proteolytic processing employing β- and γ-secretases. All these proteins involved in the production of Aβ peptide are membrane associated and hence, membrane trafficking and cellular compartmentalization play important roles. In this review, we summarize the key cellular events that lead to the progression of AD.

  10. Sulforaphane restores cellular glutathione levels and reduces chronic periodontitis neutrophil hyperactivity in vitro.

    Directory of Open Access Journals (Sweden)

    Irundika H K Dias

    Full Text Available The production of high levels of reactive oxygen species by neutrophils is associated with the local and systemic destructive phenotype found in the chronic inflammatory disease periodontitis. In the present study, we investigated the ability of sulforaphane (SFN to restore cellular glutathione levels and reduce the hyperactivity of circulating neutrophils associated with chronic periodontitis. Using differentiated HL60 cells as a neutrophil model, here we show that generation of extracellular O2 (. - by the nicotinamide adenine dinucleotide (NADPH oxidase complex is increased by intracellular glutathione depletion. This may be attributed to the upregulation of thiol regulated acid sphingomyelinase driven lipid raft formation. Intracellular glutathione was also lower in primary neutrophils from periodontitis patients and, consistent with our previous findings, patients neutrophils were hyper-reactive to stimuli. The activity of nuclear factor erythroid-2-related factor 2 (Nrf2, a master regulator of the antioxidant response, is impaired in circulating neutrophils from chronic periodontitis patients. Although patients' neutrophils exhibit a low reduced glutathione (GSH/oxidised glutathione (GSSG ratio and a higher total Nrf2 level, the DNA-binding activity of nuclear Nrf2 remained unchanged relative to healthy controls and had reduced expression of glutamate cysteine ligase catalytic (GCLC, and modifier (GCLM subunit mRNAs, compared to periodontally healthy subjects neutrophils. Pre-treatment with SFN increased expression of GCLC and GCM, improved intracellular GSH/GSSG ratios and reduced agonist-activated extracellular O2 (. - production in both dHL60 and primary neutrophils from patients with periodontitis and controls. These findings suggest that a deficiency in Nrf2-dependent pathways may underpin susceptibility to hyper-reactivity in circulating primary neutrophils during chronic periodontitis.

  11. Sulforaphane restores cellular glutathione levels and reduces chronic periodontitis neutrophil hyperactivity in vitro.

    Science.gov (United States)

    Dias, Irundika H K; Chapple, Ian L C; Milward, Mike; Grant, Melissa M; Hill, Eric; Brown, James; Griffiths, Helen R

    2013-01-01

    The production of high levels of reactive oxygen species by neutrophils is associated with the local and systemic destructive phenotype found in the chronic inflammatory disease periodontitis. In the present study, we investigated the ability of sulforaphane (SFN) to restore cellular glutathione levels and reduce the hyperactivity of circulating neutrophils associated with chronic periodontitis. Using differentiated HL60 cells as a neutrophil model, here we show that generation of extracellular O2 (. -) by the nicotinamide adenine dinucleotide (NADPH) oxidase complex is increased by intracellular glutathione depletion. This may be attributed to the upregulation of thiol regulated acid sphingomyelinase driven lipid raft formation. Intracellular glutathione was also lower in primary neutrophils from periodontitis patients and, consistent with our previous findings, patients neutrophils were hyper-reactive to stimuli. The activity of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of the antioxidant response, is impaired in circulating neutrophils from chronic periodontitis patients. Although patients' neutrophils exhibit a low reduced glutathione (GSH)/oxidised glutathione (GSSG) ratio and a higher total Nrf2 level, the DNA-binding activity of nuclear Nrf2 remained unchanged relative to healthy controls and had reduced expression of glutamate cysteine ligase catalytic (GCLC), and modifier (GCLM) subunit mRNAs, compared to periodontally healthy subjects neutrophils. Pre-treatment with SFN increased expression of GCLC and GCM, improved intracellular GSH/GSSG ratios and reduced agonist-activated extracellular O2 (. -) production in both dHL60 and primary neutrophils from patients with periodontitis and controls. These findings suggest that a deficiency in Nrf2-dependent pathways may underpin susceptibility to hyper-reactivity in circulating primary neutrophils during chronic periodontitis.

  12. Effects of β₂-agonists on force during and following anoxia in rat extensor digitorum longus muscle

    DEFF Research Database (Denmark)

    Fredsted, A; Gissel, H; Ortenblad, N

    2012-01-01

    of salbutamol on force recovery were prevented by blocking the Na(+),K(+)- pumps with ouabain or by blocking glycolysis with 2-deoxyglucose. Dibutyryl cAMP (1 mM) or theophylline (1 mM) also improved force recovery remarkably. In anoxic muscles, salbutamol decreased intracellular Na(+), increased (86)Rb uptake...... and K(+) content indicating stimulation of the Na(+),K(+) - pumps. In fatigued muscles salbutamol induced recovery of excitability. Thus, β(2)-agonists reduce the anoxia-induced loss of force leading to partial force recovery. These data strongly suggest that this effect is mediated by cAMP stimulation......Electrical stimulation of isolated muscles may lead to membrane depolarization, gain of Na(+), loss of K(+) and fatigue. These effects can be counteracted with β(2)-agonists possibly via activation of the Na(+),K(+)- pumps. Anoxia induces loss of force; however, it is not known whether β(2...

  13. Improved humoral and cellular immune responses against the gp120 V3 loop of HIV-1 following genetic immunization with a chimeric DNA vaccine encoding the V3 inserted into the hepatitis B surface antigen

    DEFF Research Database (Denmark)

    Fomsgaard, A; Nielsen, H V; Bryder, K

    1998-01-01

    with the HIV MN gp160 envelope plasmid induced a slow and low titred anti-MN V3 antibody response at 12 weeks post-inoculation (p.i.) and a late appearing (7 weeks), weak and variable CTL response. In contrast, DNA vaccination with the HBsAg-encoding plasmid induced a rapid and high titred anti-HBsAg antibody...... response and a uniform strong anti-HBs CTL response already 1 week p.i. in all mice. DNA vaccination with the chimeric MN V3/HBsAg plasmid elicited humoral responses against both viruses within 3-6 weeks which peaked at 6-12 weeks and remained stable for at least 25 weeks. In addition, specific CTL......-2d-restricted cytotoxic T lymphocyte (CTL) epitope. In an attempt to improve the immunogenicity of V3 in DNA vaccines, a plasmid expressing MN V3 as a fusion protein with the highly immunogenic middle (pre-S2 + S) surface antigen of hepatitis B virus (HBsAg) was constructed. Epidermal inoculation...

  14. Improved humoral and cellular immune response against the gp120 V3 loop of HIV-1 following genetic immunization with a chimeric DNA vaccine encoding the V3 inserted into the hepatites B surface antigen

    DEFF Research Database (Denmark)

    Fomsgaard, A.; Nielsen, H.V.; Bryder, K.

    1998-01-01

    MN gp160 envelope plasmid induced a slow and low titred anti-MN V3 antibody response at 12 weeks post-inoculation (p.i.) and a late appearing (7 weeks), weak and variable CTL response. In contrast, DNA vaccination with the HBsAg-encoding plasmid induced a rapid and high titred anti-HBsAg antibody...... response and a uniform strong anti-HBs CTL response already 1 week p.i. in all mice. DNA vaccination with the chimeric MN V2/HBsAg plasmid elicited humoral responses against both viruses within 3-6 weeks which peaked at 6-12 weeks and remained stable for at least 25 weeks. In addition, specific CTL......-2d-restricted cytotoxic T lymphocyte (CTL) epitope. In an attempt to improve the immunogenicity of V3 in DNA vaccines, a plasmid expressing MN V3 as a fusion protein with the highly immunogenic middle (pre-S2+S) surface antigen of hepatitis B virus (HBsAg) was constructed. Epidermal inoculation...

  15. Influence of corona charging in cellular polyethylene film

    Energy Technology Data Exchange (ETDEWEB)

    Ortega Brana, Gustavo; Magraner, Francisco; Quijano, Alfredo [Instituto Tecnologico de la Energia (ITE), Av. Juan de la Cierva 24, Parque Tecnologico de Valencia, 46980 Paterna-Valencia (Spain); Llovera Segovia, Pedro, E-mail: gustavo.ortega@ite.es [Instituto de TecnologIa Electrica - Universitat Politecnica de Valencia, Camino de Vera s/n 46022-Valencia (Spain)

    2011-06-23

    Cellular polymers have recently attracted attention for their property of exhibiting a piezoelectric constant when they are electrically charged. The electrostatic charge generated in the voids by the internal discharges creates and internal macrodipole which is responsible for the piezoelectric effect. Charging by corona discharge is the most used method for cellular polymers. Many works has been published on polypropylene and polyethylene films mainly focused on the required expansion process or on the results obtained for raw cellular materials electrically activated. Our work is based on commercial polyethylene cellular films which have been physically characterized and electrically activated. The effect of thermal treatment, physical uniaxial or biaxial stretching and corona charging was investigated. The new method of corona charging improved the piezoelectric constant under other activation conditions.

  16. Probing the GnRH receptor agonist binding site identifies methylated triptorelin as a new anti-proliferative agent

    Directory of Open Access Journals (Sweden)

    Robert P Millar

    2012-06-01

    Full Text Available D-amino acid substitutions at Glycine postion-6 in GnRH-I decapeptide can possess super-agonist activity and enhanced in vivo pharmacokinetics. Agonists elicit growth-inhibition in tumorigenic cells expressing the GnRH receptor above threshold levels. However, new agonists with modified properties are required to improve the anti-proliferative range. Effects of residue substitutions and methylations on tumourigenic HEK293[SCL60] and WPE-1-NB26-3 prostate cells expressing the rat GnRH receptor were compared. Peptides were ranked according to receptor binding affinity, induction of inositol phosphate production and cell growth-inhibition. Analogues possessing D-Trp6 (including Triptorelin, D-Leu6 (including Leuprolide, D-Ala6, D-Lys6, or D-Arg6 exhibited agonist and anti-proliferative activity. Residues His5 or His5,Trp7,Tyr8, corresponding to residues found in GnRH-II , were tolerated, with retention of sub-nanomolar/low nanomolar binding affinities and EC50s for receptor activation and IC50s for cell growth-inhibition. His5D-Arg6-GnRH-I exhibited reduced binding affinity and potency, effective in the mid-nanomolar range. However, all GnRH-II-like analogues were less potent than Triptorelin. By comparison, three methylated-Trp6 Triptorelin variants showed differential binding, receptor activation and anti-proliferation potency. Significantly, 5-Methyl-DL-Trp6-Triptorelin was equipotent to triptorelin. Subsequent studies should determine whether pharmacologically enhanced derivatives of Triptorelin can be developed by further alkylations, without substitutions or cleavable cytotoxic adducts, to improve the extent of growth-inhibition of tumour cells expressing the GnRH receptor.

  17. Renoprotective Effects of AVE0991, a Nonpeptide Mas Receptor Agonist, in Experimental Acute Renal Injury

    Directory of Open Access Journals (Sweden)

    Lívia Corrêa Barroso

    2012-01-01

    Full Text Available Renal ischemia and reperfusion (I/R is the major cause of acute kidney injury in hospitalized patients. Mechanisms underlying reperfusion-associated injury include recruitment and activation of leukocytes and release of inflammatory mediators. In this study, we investigated the renal effects of acute administration of AVE0991, an agonist of Mas, the angiotensin-(1–7 receptor, the angiotensin-(1–7 receptor, in a murine model of renal I/R. Male C57BL/6 wild-type or Mas−/− mice were subjected to 30 min of bilateral ischemia and 24 h of reperfusion. Administration of AVE0991 promoted renoprotective effects, as seen by improvement of function, decreased tissue injury, prevention of local and remote leucocyte infiltration, and release of the chemokine, CXCL1. I/R injury was similar in WT and Mas−/− mice, suggesting that endogenous activation of this receptor does not control renal damage under baseline conditions. In conclusion, pharmacological interventions using Mas receptor agonists may represent a therapeutic opportunity for the treatment of renal I/R injury.

  18. [Albiglutide (Eperzan): a new once-weekly agonist of glucagon-like peptide-1 receptors].

    Science.gov (United States)

    Scheen, A J

    2015-04-01

    Albiglutide (Eperzan) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors that is indicated in the treatment of type 2 diabetes. Two doses are available, 30 mg and 50 mg, to be injected subcutaneously once a week. It has been extensively evaluated in the HARMONY programme of eight large randomised controlled trials that were performed at different stages of type 2 diabetes, in comparison with placebo or an active comparator. The endocrine and metabolic effects of albiglutide are similar to those of other GLP-1 receptor agonists: stimulation of insulin secretion (incretin effect) and inhibition of glucagon secretion, both in a glucose-dependent manner, retardation of gastric emptying and increase of satiety. These effects lead to a reduction in glycated haemoglobin (HbA(1c)) levels, combined with a weight reduction. The overall tolerance profile is good. Albiglutide is currently reimbursed in Belgium after failure (HbA(1c) > 7.5%) of and in combination with a dual therapy with metformin and a sulfonylurea as well as in combination with a basal insulin (with or without oral antidiabetic drugs). To avoid hypoglycaemia, a reduction in the dose of sulfonylurea or insulin may be recommended. A once-weekly administration should increase patient's acceptance of injectable therapy and improve compliance.

  19. KR-62980: a novel peroxisome proliferator-activated receptor gamma agonist with weak adipogenic effects.

    Science.gov (United States)

    Kim, Kwang Rok; Lee, Jeong Hyung; Kim, Seung Jun; Rhee, Sang Dal; Jung, Won Hoon; Yang, Sung-Don; Kim, Sung Soo; Ahn, Jin Hee; Cheon, Hyae Gyeong

    2006-08-14

    The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is the target for the anti-diabetic drugs including thiazolidinediones. We report here the identification and characterization of a novel PPARgamma agonist KR-62980. KR-62980 acted as a selective PPARgamma agonist in transactivation assay with an EC50 of 15 nM. In fully differentiated 3T3-L1 adipocytes, KR-62980 induced [3H]-deoxyglucose uptake in a concentration-dependent manner in the presence of insulin. KR-62980 was weakly adipogenic with little induction of aP2 mRNA, and was able to antagonize the adipogenic effects of rosiglitazone in C3H10T1/2 cells. In vivo pharmacokinetic profile of KR-62980 revealed that the compound exhibited good oral bioavailability of 65% with a terminal elimination half-life of 2.5 h in the rat. Treatment of high fat diet-induced C57BL/6J mice with KR-62980 for 14 days reduced plasma glucose levels with little side effects with regard to weight gain, cardiac hypertrophy and hepatotoxicity. These results suggest that KR-62980 acts as a selective PPARgamma modulator with anti-hyperglycemic activity, and that the mechanism of actions of KR-62980 appears to be different from that of rosiglitazone with improved side effect profiles.

  20. GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease.

    Science.gov (United States)

    Liu, Jia; Wang, Guang; Jia, Yumei; Xu, Yuan

    2015-05-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and its incidence has been increasing recently. In addition to hepatic complications, NAFLD is also recognized as an independent risk factor for cardiovascular disease. Unfortunately, the current therapies for NAFLD display variable efficacy; a novel and effective drug is urgently needed. Glucagon-like peptide-1 (GLP-1), a receptor agonist is a new drug approved for treating type 2 diabetes. Recently, these types of agents have shown a novel therapeutic effect on NAFLD. However, the mechanisms of GLP-1 receptor agonists on the treatment of NAFLD have not yet been explained precisely. Recent studies have demonstrated that GLP-1 reverses the progression of NAFLD not only indirectly through an incretin effect that improves key parameters involved in NAFLD, but also a direct effect on lipid metabolism of hepatocytes and inflammation in liver. In this review, we provided an overview of the role and mechanisms of GLP-1 in the therapy of NAFLD.

  1. Engineering of a Novel Simplified Human Insulin-Like Peptide 5 Agonist.

    Science.gov (United States)

    Patil, Nitin A; Hughes, Richard A; Rosengren, K Johan; Kocan, Martina; Ang, Sheng Yu; Tailhades, Julien; Separovic, Frances; Summers, Roger J; Grosse, Johannes; Wade, John D; Bathgate, Ross A D; Hossain, Mohammed Akhter

    2016-03-10

    Insulin-like peptide 5 (INSL5) has recently been discovered as only the second orexigenic gut hormone after ghrelin. As we have previously reported, INSL5 is extremely difficult to assemble and oxidize into its two-chain three-disulfide structure. The focus of this study was to generate structure-activity relationships (SARs) of INSL5 and use it to develop a potent and simpler INSL5 mimetic with RXFP4 agonist activity. A series of human and mouse INSL5 (hINSL5/mINSL5) analogues were designed and chemically synthesized, resulting in a chimeric INSL5 analogue exhibiting more than 10-fold higher potency (0.35 nM) at human RXFP4 compared with native hINSL5 (4.57 nM). The SAR study also identified a key residue (K(A15)) in the A-chain of mINSL5 that contributes to improved RXFP4 affinity and potency of mINSL5 compared with hINSL5. This knowledge ultimately led us to engineer a minimized hINSL5 mimetic agonist that retains native hINSL5-like RXFP4 affinity and potency at human RXFP4. This minimized analogue was synthesized in 17.5-fold higher yield and in less time compared with hINSL5.

  2. Grooming, rank, and agonistic support in tufted capuchin monkeys.

    Science.gov (United States)

    Schino, Gabriele; Di Giuseppe, Francesca; Visalberghi, Elisabetta

    2009-02-01

    Studies investigating the relation between allogrooming and social rank in capuchin monkeys (genus Cebus) have yielded inconsistent results. In this study, we investigated the relation between grooming, agonistic support, aggression and social rank in a captive group of tufted capuchin monkeys (C. apella). Differently from most previous studies, we based our analyses on a relatively large database and studied a group with known genealogical relationships. Tufted capuchin females did not exchange grooming for rank-related benefits such as agonistic support or reduced aggression. Coherently with this picture, they did not groom up the hierarchy and did not compete for accessing high-ranking grooming partners. It is suggested that a small group size, coupled with a strong kin bias, may make the exchange of grooming for rank-related benefits impossible or unprofitable, thus eliminating the advantages of grooming up the hierarchy. We provide several possible explanations for the heterogeneity of results across capuchin studies that have addressed similar questions.

  3. On Cellular MIMO Channel Capacity

    Science.gov (United States)

    Adachi, Koichi; Adachi, Fumiyuki; Nakagawa, Masao

    To increase the transmission rate without bandwidth expansion, the multiple-input multiple-output (MIMO) technique has recently been attracting much attention. The MIMO channel capacity in a cellular system is affected by the interference from neighboring co-channel cells. In this paper, we introduce the cellular channel capacity and evaluate its outage capacity, taking into account the frequency-reuse factor, path loss exponent, standard deviation of shadowing loss, and transmission power of a base station (BS). Furthermore, we compare the cellular MIMO downlink channel capacity with those of other multi-antenna transmission techniques such as single-input multiple-output (SIMO) and space-time block coded multiple-input single-output (STBC-MISO). We show that the optimum frequency-reuse factor F that maximizes 10%-outage capacity is 3 and both 50%- and 90%-outage capacities is 1 irrespective of the type of multi-antenna transmission technique, where q%-outage capacity is defined as the channel capacity that gives an outage probability of q%. We also show that the cellular MIMO channel capacity is always higher than those of SIMO and STBC-MISO.

  4. Cellular uptake of metallated cobalamins

    DEFF Research Database (Denmark)

    Tran, MQT; Stürup, Stefan; Lambert, Ian H.;

    2016-01-01

    Cellular uptake of vitamin B12-cisplatin conjugates was estimated via detection of their metal constituents (Co, Pt, and Re) by inductively coupled plasma mass spectrometry (ICP-MS). Vitamin B12 (cyano-cob(iii)alamin) and aquo-cob(iii)alamin [Cbl-OH2](+), which differ in the β-axial ligands (CN(-...

  5. Agonistic Vocalisations in Domestic Cats : A Case Study

    OpenAIRE

    Schötz, Susanne

    2015-01-01

    Introducing a new cat to a home with resident cats may lead to stress, aggression and even fights. In this case study 468 agonistic cat vocalisations were recorded as one cat was introduced to three resident cats in her new home. Six vocalisation types were identified: growl, howl, howl-growl, hiss, spit and snarl. Numerous other intermediate and complex vocalisations were also observed. An acoustic analysis showed differences within and between all types. Future studies include further acous...

  6. Cellular senescence mediates fibrotic pulmonary disease

    Science.gov (United States)

    Schafer, Marissa J.; White, Thomas A.; Iijima, Koji; Haak, Andrew J.; Ligresti, Giovanni; Atkinson, Elizabeth J.; Oberg, Ann L.; Birch, Jodie; Salmonowicz, Hanna; Zhu, Yi; Mazula, Daniel L.; Brooks, Robert W.; Fuhrmann-Stroissnigg, Heike; Pirtskhalava, Tamar; Prakash, Y. S.; Tchkonia, Tamara; Robbins, Paul D.; Aubry, Marie Christine; Passos, João F.; Kirkland, James L.; Tschumperlin, Daniel J.; Kita, Hirohito; LeBrasseur, Nathan K.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function. PMID:28230051

  7. Cellular membrane trafficking of mesoporous silica nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Fang, I-Ju [Iowa State Univ., Ames, IA (United States)

    2012-01-01

    This dissertation mainly focuses on the investigation of the cellular membrane trafficking of mesoporous silica nanoparticles. We are interested in the study of endocytosis and exocytosis behaviors of mesoporous silica nanoparticles with desired surface functionality. The relationship between mesoporous silica nanoparticles and membrane trafficking of cells, either cancerous cells or normal cells was examined. Since mesoporous silica nanoparticles were applied in many drug delivery cases, the endocytotic efficiency of mesoporous silica nanoparticles needs to be investigated in more details in order to design the cellular drug delivery system in the controlled way. It is well known that cells can engulf some molecules outside of the cells through a receptor-ligand associated endocytosis. We are interested to determine if those biomolecules binding to cell surface receptors can be utilized on mesoporous silica nanoparticle materials to improve the uptake efficiency or govern the mechanism of endocytosis of mesoporous silica nanoparticles. Arginine-glycine-aspartate (RGD) is a small peptide recognized by cell integrin receptors and it was reported that avidin internalization was highly promoted by tumor lectin. Both RGD and avidin were linked to the surface of mesoporous silica nanoparticle materials to investigate the effect of receptor-associated biomolecule on cellular endocytosis efficiency. The effect of ligand types, ligand conformation and ligand density were discussed in Chapter 2 and 3. Furthermore, the exocytosis of mesoporous silica nanoparticles is very attractive for biological applications. The cellular protein sequestration study of mesoporous silica nanoparticles was examined for further information of the intracellular pathway of endocytosed mesoporous silica nanoparticle materials. The surface functionality of mesoporous silica nanoparticle materials demonstrated selectivity among the materials and cancer and normal cell lines. We aimed to determine

  8. 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.

  9. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    Directory of Open Access Journals (Sweden)

    Fergus Keane

    2016-06-01

    Full Text Available Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour.

  10. 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.

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

    Science.gov (United States)

    Petersen, Rasmus K.; Christensen, Kathrine B.; Assimopoulou, Andreana N.; Fretté, Xavier; Papageorgiou, Vassilios P.; Kristiansen, Karsten; Kouskoumvekaki, Irene

    2011-02-01

    In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk 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 mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery.

  12. RGS proteins destroy spare receptors: Effects of GPCR-interacting proteins and signal deamplification on measurements of GPCR agonist potency.

    Science.gov (United States)

    Chidiac, Peter

    2016-01-01

    Many GPCRs are able to activate multiple distinct signaling pathways, and these may include biochemical cascades activated via either heterotrimeric G proteins or by β-arrestins. The relative potencies and/or efficacies among a series of agonists that act on a common receptor can vary depending upon which signaling pathway is being activated. This phenomenon is known as biased signaling or functional selectivity, and is presumed to reflect underlying differences in ligand binding affinities for alternate conformational states of the receptor. The first part of this review discusses how various cellular GPCR interacting proteins (GIPs) can influence receptor conformation and thereby affect ligand-receptor interactions and contribute to signaling bias. Upon activation, receptors trigger biochemical cascades that lead to altered cellular function, and measuring points along the cascade (e.g., second messenger production) conveys information about receptor activity. As a signal continues along its way, the observed concentration dependence of a GPCR ligand may change due to amplification and saturation of biochemical steps. The second part of this review considers additional cellular factors that affect signal processing, focusing mainly on structural elements and deamplification mechanisms, and discusses the relevance of these to measurements of potency and functional selectivity.

  13. Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects

    Directory of Open Access Journals (Sweden)

    Esposito Emanuela

    2011-04-01

    Full Text Available Abstract Background Permanent functional deficits following spinal cord injury (SCI arise both from mechanical injury and from secondary tissue reactions involving inflammation. Enhanced release of adenosine and glutamate soon after SCI represents a component in the sequelae that may be responsible for resulting functional deficits. The role of adenosine A2A receptor in central ischemia/trauma is still to be elucidated. In our previous studies we have demonstrated that the adenosine A2A receptor-selective agonist CGS21680, systemically administered after SCI, protects from tissue damage, locomotor dysfunction and different inflammatory readouts. In this work we studied the effect of the adenosine A2A receptor antagonist SCH58261, systemically administered after SCI, on the same parameters. We investigated the hypothesis that the main action mechanism of agonists and antagonists is at peripheral or central sites. Methods Spinal trauma was induced by extradural compression of SC exposed via a four-level T5-T8 laminectomy in mouse. Three drug-dosing protocols were utilized: a short-term systemic administration by intraperitoneal injection, a chronic administration via osmotic minipump, and direct injection into the spinal cord. Results SCH58261, systemically administered (0.01 mg/kg intraperitoneal. 1, 6 and 10 hours after SCI, reduced demyelination and levels of TNF-α, Fas-L, PAR, Bax expression and activation of JNK mitogen-activated protein kinase (MAPK 24 hours after SCI. Chronic SCH58261 administration, by mini-osmotic pump delivery for 10 days, improved the neurological deficit up to 10 days after SCI. Adenosine A2A receptors are physiologically expressed in the spinal cord by astrocytes, microglia and oligodendrocytes. Soon after SCI (24 hours, these receptors showed enhanced expression in neurons. Both the A2A agonist and antagonist, administered intraperitoneally, reduced expression of the A2A receptor, ruling out the possibility that the

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

    Directory of Open Access Journals (Sweden)

    Morten S Thomsen

    Full Text Available 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 repeated administration of α7 nAChR agonists. We further compare the effect of agonists to that of α7 nAChR positive allosteric modulators (PAMs, which do not induce upregulation of the α7 nAChR. Using the social discrimination test as a measure of short-term memory, we show that the α7 nAChR agonist A-582941 improves short-term memory immediately after repeated (7× daily, but not a single administration. The α7 nAChR PAMs PNU-120596 and AVL-3288 do not affect short-term memory immediately after a single or repeated administration. This demonstrates a fundamental difference in the behavioral effects 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. Subsequent [(125I]-bungarotoxin autoradiography revealed no direct correlation between α7 nAChR levels in frontal cortical or hippocampal brain regions and short-term memory with either compound. Additionally, repeated treatment with A-582941 did not affect mRNA expression of RIC-3 or the lynx-like gene products lynx1, lynx2, PSCA, or Ly6H, which are known to affect nAChR function. In conclusion, both α7 nAChR agonists and PAMs exhibit sustained pro-cognitive effects after repeated administration, and altered levels of the α7 nAChR per se, or that of endogenous regulators of nAChR function, are likely not the major cause of this effect.

  15. Preventive and treatment value of dopamine receptor agonists in ovarian hyperstimulation syndrome%多巴胺受体激动剂在卵巢过度刺激综合征的防治价值

    Institute of Scientific and Technical Information of China (English)

    杨蕊; 马彩虹

    2012-01-01

    The vascular endothelial growth factor (VEGF) is a crucial element for increased vascular permeability which determines ovarian hyperstimulation syndrome (OHSS). Dopamine receptor agonists can selectively inhibit VEGF-induced vascular permeability without interfering with angiogenesis. Vascular endothelial growth factor receptor-2 (VEGFR-2) phosphorylation reduction seems to he associated with this effect. The preventive use of dopamine receptor agonists reduces the risk of OHSS in women after ovarian stimulation for in vitro fertilization (IVF). Statistically, evidence of their preventive effect on the severe OHSS is not as clear as on the moderate OHSS. The use of dopamine receptor agonists does not influence the outcome of IVF cycles. The occurrence of obstetric or neonatal complications is similar with that in control groups. The oral administration of cahergoline is the best studied dopamine receptor agonists regimen in the prevention of OHSS. High-dose quinagolide is rarely applied due to its intolerable side effects. Oral bromocriptine can also be occasionally associated with severe gastric discomfort, although less frequently than with quinagoline. Rectal bromocriptine is used with more and more frequency because of its safety, but it still requires further study. Although published data suggest that dopamine agonists also improve the clinical evolution of established OHSS, no randomized controlled trials have been reported to confirm their effectiveness. The use of dopamine receptor agonists may be combined with with other strategies to prevent or control OHSS, such as GnRH antagonists, in order to improve its efficacy.

  16. Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Bräuner-Osborne, Hans

    1999-01-01

    A number of CXC chemokines competed with similar, nanomolar affinity against 125I-interleukin-8 (IL-8) binding to ORF-74, a constitutively active seven-transmembrane receptor encoded by human herpesvirus 8. However, in competition against 125I-labeled growth-related oncogene (GRO)-alpha, the ORF-74...... receptor was highly selective for GRO peptides, with IL-8 being 10,000-fold less potent. The constitutive stimulating activity of ORF-74 on phosphatidylinositol turnover was not influenced by, for example, IL-8 binding. In contrast, GRO peptides acted as potent agonists in stimulating ORF-74 signaling......, whereas IP-10 and stromal cell-derived factor-1alpha surprisingly acted as inverse agonists. These peptides had similar pharmacological properties with regard to enhancing or inhibiting, respectively, the stimulatory effect of ORF-74 on NIH-3T3 cell proliferation. Construction of a high affinity zinc...

  17. NOD2 Agonist Promotes the Production of Inflammatory Cytokines in VSMC in Synergy with TLR2 and TLR4 Agonists

    Directory of Open Access Journals (Sweden)

    Jinghua Sun

    2012-01-01

    Full Text Available Objective. To investigate the expression of NOD2 in human VSMCs, its role in the production of inflammatory cytokines in VSMC and the possible interaction of NOD2-mediated signaling pathway with those mediated by TLR2 and TLR4. Methods. Human coronary artery smooth muscle cells were stimulated with NOD2 agonist MDP alone or in combination with either TLR2 agonist PAM3 or TLR4 agonist LPSs. The mRNA expression of NOD2 and FGF-2 were measured by RT-PCR. The concentration of IL-8 and TNF-α in the culture supernatants was determined by ELISA. VSMC proliferation ability was analyzed by MTT assay. Results. MDP up regulated the expression of NOD2 mRNA in VSMC in a time-dependent manner, up regulated the expression of FGF-2 mRNA in VSMC, induced the production of IL-8 and TNF-α, and promoted the proliferation of VSMC. Additionally, MDP synergied with LPS and PAM3 to promote the proliferation of VSMC and induce the production of IL-8 and TNF-α. Conclusion. The activation of NOD2-mediated innate immune signaling pathway can increase the proliferation ability of VSMC and induce the production of inflammatory cytokines in VSMC. It is also shown a synergistic effect with TLR2- and TLR4-mediated signaling pathways in this process.

  18. Multivalent porous silicon nanoparticles enhance the immune activation potency of agonistic CD40 antibody.

    Science.gov (United States)

    Gu, Luo; Ruff, Laura E; Qin, Zhengtao; Corr, Maripat; Hedrick, Stephen M; Sailor, Michael J

    2012-08-01

    One of the fundamental paradigms in the use of nanoparticles to treat disease is to evade or suppress the immune system in order to minimize systemic side effects and deliver sufficient nanoparticle quantities to the intended tissues. However, the immune system is the body's most important and effective defense against diseases. It protects the host by identifying and eliminating foreign pathogens as well as self-malignancies. Here we report a nanoparticle engineered to work with the immune system, enhancing the intended activation of antigen presenting cells (APCs). We show that luminescent porous silicon nanoparticles (LPSiNPs), each containing multiple copies of an agonistic antibody (FGK45) to the APC receptor CD40, greatly enhance activation of B cells. The cellular response to the nanoparticle-based stimulators is equivalent to a 30-40 fold larger concentration of free FGK45. The intrinsic near-infrared photoluminescence of LPSiNPs is used to monitor degradation and track the nanoparticles inside APCs.

  19. Novel leukocyte agonists are released by endothelial cells exposed to peroxide.

    Science.gov (United States)

    Patel, K D; Zimmerman, G A; Prescott, S M; McIntyre, T M

    1992-07-25

    Reactive oxygen species do not activate isolated neutrophils, yet in vivo, such oxidants promote their adhesion to, and subsequent migration through, the vascular wall. We show human endothelial cells exposed to t-butylhydroperoxide shed large, sealed membrane vesicles that contained potent neutrophil agonists. This activity migrated on TLC like platelet-activating factor (PAF). Since neutrophils have a receptor for this phospholipid, which recognizes its unique characteristics including the short sn-2 acetyl residue, we examined the effect of PAF receptor antagonists and PAF acetylhydrolase on this activity. Structurally unrelated PAF receptor antagonists blocked neutrophil stimulation by vesicular phospholipids, and digestion with PAF acetylhydrolase, which is specific for short sn-2 residues, destroyed this activity. However, metabolic labeling, inhibition of synthesis, phospholipase A1 digestion, and high performance liquid chromatographic studies demonstrated that the vesicles did not contain PAF. Instead, the bioactivity migrated on high performance liquid chromatography like the phospholipids generated by oxidative fragmentation of synthetic arachidonoyl phosphatidylcholine that we have shown previously (Smiley, P. L., Stremler, K. E., Prescott, S. M., Zimmerman, G. A., and McIntyre, T. M. (1991) J. Biol. Chem. 266, 11104-11110) to stimulate neutrophils through their receptor for PAF. Thus, peroxide treatment of endothelial cells fragments cellular phosphatidylcholines, forming novel PAF-like phospholipids, and induces the shedding of membrane vesicles that contain these bioactive phospholipids.

  20. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR γ activators and pan-PPAR partial agonists.

    Directory of Open Access Journals (Sweden)

    Marcelo Vizoná Liberato

    Full Text Available Thiazolidinediones (TZDs act through peroxisome proliferator activated receptor (PPAR γ to increase insulin sensitivity in type 2 diabetes (T2DM, but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD and found that the ligand binding pocket (LBP is occupied by bacterial medium chain fatty acids (MCFAs. We verified that MCFAs (C8-C10 bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5, linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products.

  1. Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes.

    Science.gov (United States)

    Milioto, Carmelo; Malena, Adriana; Maino, Eleonora; Polanco, Maria J; Marchioretti, Caterina; Borgia, Doriana; Pereira, Marcelo Gomes; Blaauw, Bert; Lieberman, Andrew P; Venturini, Roberta; Plebani, Mario; Sambataro, Fabio; Vergani, Lodovica; Pegoraro, Elena; Sorarù, Gianni; Pennuto, Maria

    2017-01-24

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA.

  2. Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

    Science.gov (United States)

    Milioto, Carmelo; Malena, Adriana; Maino, Eleonora; Polanco, Maria J.; Marchioretti, Caterina; Borgia, Doriana; Pereira, Marcelo Gomes; Blaauw, Bert; Lieberman, Andrew P.; Venturini, Roberta; Plebani, Mario; Sambataro, Fabio; Vergani, Lodovica; Pegoraro, Elena; Sorarù, Gianni; Pennuto, Maria

    2017-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA. PMID:28117338

  3. Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice.

    Science.gov (United States)

    Qin, Cheng Xue; May, Lauren T; Li, Renming; Cao, Nga; Rosli, Sarah; Deo, Minh; Alexander, Amy E; Horlock, Duncan; Bourke, Jane E; Yang, Yuan H; Stewart, Alastair G; Kaye, David M; Du, Xiao-Jun; Sexton, Patrick M; Christopoulos, Arthur; Gao, Xiao-Ming; Ritchie, Rebecca H

    2017-02-07

    Effective treatment for managing myocardial infarction (MI) remains an urgent, unmet clinical need. Formyl peptide receptors (FPR) regulate inflammation, a major contributing mechanism to cardiac injury following MI. Here we demonstrate that FPR1/FPR2-biased agonism may represent a novel therapeutic strategy for the treatment of MI. The small-molecule FPR1/FPR2 agonist, Compound 17b (Cmpd17b), exhibits a distinct signalling fingerprint to the conventional FPR1/FPR2 agonist, Compound-43 (Cmpd43). In Chinese hamster ovary (CHO) cells stably transfected with human FPR1 or FPR2, Compd17b is biased away from potentially detrimental FPR1/2-mediated calcium mobilization, but retains the pro-survival signalling, ERK1/2 and Akt phosphorylation, relative to Compd43. The pathological importance of the biased agonism of Cmpd17b is demonstrable as superior cardioprotection in both in vitro (cardiomyocytes and cardiofibroblasts) and MI injury in mice in vivo. These findings reveal new insights for development of small molecule FPR agonists with an improved cardioprotective profile for treating MI.

  4. Effects of TLR agonists on maturation and function of 3-day dendritic cells from AML patients in complete remission

    Directory of Open Access Journals (Sweden)

    Merk Martina

    2011-09-01

    Full Text Available Abstract Background Active dendritic cell (DC immunization protocols are rapidly gaining interest as therapeutic options in patients with acute myeloid leukemia (AML. Here we present for the first time a GMP-compliant 3-day protocol for generation of monocyte-derived DCs using different synthetic Toll-like receptor (TLR agonists in intensively pretreated patients with AML. Methods Four different maturation cocktails were compared for their impact on cell recovery, phenotype, cytokine secretion, migration, and lymphocyte activation in 20 AML patients and 25 healthy controls. Results Maturation cocktails containing the TLR7/8 agonists R848 or CL075, with and without the addition of the TLR3 agonist poly(I:C, induced DCs that had a positive costimulatory profile, secreted high levels of IL-12(p70, showed chemotaxis to CCR7 ligands, had the ability to activate NK cells, and efficiently stimulated antigen-specific CD8+ T cells. Conclusions Our results demonstrate that this approach translates into biologically improved DCs, not only in healthy controls but also in AML patients. This data supports the clinical application of TLR-matured DCs in patients with AML for activation of innate and adaptive immune responses.

  5. Reversibly assembled cellular composite materials.

    Science.gov (United States)

    Cheung, Kenneth C; Gershenfeld, Neil

    2013-09-13

    We introduce composite materials made by reversibly assembling a three-dimensional lattice of mass-produced carbon fiber-reinforced polymer composite parts with integrated mechanical interlocking connections. The resulting cellular composite materials can respond as an elastic solid with an extremely large measured modulus for an ultralight material (12.3 megapascals at a density of 7.2 milligrams per cubic centimeter). These materials offer a hierarchical decomposition in modeling, with bulk properties that can be predicted from component measurements and deformation modes that can be determined by the placement of part types. Because site locations are locally constrained, structures can be produced in a relative assembly process that merges desirable features of fiber composites, cellular materials, and additive manufacturing.

  6. Differential mechanisms of action of the mucolipin synthetic agonist, ML-SA1, on insect TRPML and mammalian TRPML1.

    Science.gov (United States)

    Feng, Xinghua; Xiong, Jian; Lu, Yungang; Xia, Xuefeng; Zhu, Michael X

    2014-12-01

    Mucolipin synthetic agonist 1 (ML-SA1) was recently identified to activate mammalian TRPML channels and shown to alleviate lipid accumulation in lysosomes of cellular models of lysosome storage diseases, mucolipidosis type IV (MLIV) and Niemann-Pick's disease type C (NPC). Owning to its potential use in complimenting genetic studies in Drosophila melanogaster to elucidate the cellular and physiological functions of TRPML channels, we examined the effect of ML-SA1 on Drosophila TRPML expressed in HEK293 cells using whole-cell, inside-out, and whole-lysosome electrophysiological recordings. We previously showed that when expressed in HEK293 cells, Drosophila TRPML was localized and functional on both plasma membrane and endolysosome. We show here that in both inside-out patches excised from the plasma membrane and whole-lysosome recordings from enlarged endolysosome vacuoles, ML-SA1 failed to activate TRPML unless exogenous phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] was applied. At 1 μM ML-SA1, the sensitivity of TRPML to PI(3,5)P2 increased approximately by 10-fold and at 10 μM ML-SA1, the deactivation of PI(3,5)P2-evoked TRPML currents was markedly slowed. On the other hand, constitutive activation of TRPML by a mutation that mimics the varitint-waddler (Va) mutation of mouse TRPML3 rendered the insect channel sensitive to activation by ML-SA1 alone. Moreover, different from the insect TRPML, mouse TRPML1 was readily activated by ML-SA1 independent of PI(3,5)P2. Thus, our data reveal that while ML-SA1 acts as a true agonist at mouse TRPML1, it behaves as an allosteric activator of the Drosophila TRPML, showing dependence on and the ability to stabilize open conformation of the insect channels.

  7. Glycosylation regulates prestin cellular activity.

    Science.gov (United States)

    Rajagopalan, Lavanya; Organ-Darling, Louise E; Liu, Haiying; Davidson, Amy L; Raphael, Robert M; Brownell, William E; Pereira, Fred A

    2010-03-01

    Glycosylation is a common post-translational modification of proteins and is implicated in a variety of cellular functions including protein folding, degradation, sorting and trafficking, and membrane protein recycling. The membrane protein prestin is an essential component of the membrane-based motor driving electromotility changes (electromotility) in the outer hair cell (OHC), a central process in auditory transduction. Prestin was earlier identified to possess two N-glycosylation sites (N163, N166) that, when mutated, marginally affect prestin nonlinear capacitance (NLC) function in cultured cells. Here, we show that the double mutant prestin(NN163/166AA) is not glycosylated and shows the expected NLC properties in the untreated and cholesterol-depleted HEK 293 cell model. In addition, unlike WT prestin that readily forms oligomers, prestin(NN163/166AA) is enriched as monomers and more mobile in the plasma membrane, suggesting that oligomerization of prestin is dependent on glycosylation but is not essential for the generation of NLC in HEK 293 cells. However, in the presence of increased membrane cholesterol, unlike the hyperpolarizing shift in NLC seen with WT prestin, cells expressing prestin(NN163/166AA) exhibit a linear capacitance function. In an attempt to explain this finding, we discovered that both WT prestin and prestin(NN163/166AA) participate in cholesterol-dependent cellular trafficking. In contrast to WT prestin, prestin(NN163/166AA) shows a significant cholesterol-dependent decrease in cell-surface expression, which may explain the loss of NLC function. Based on our observations, we conclude that glycosylation regulates self-association and cellular trafficking of prestin(NN163/166AA). These observations are the first to implicate a regulatory role for cellular trafficking and sorting in prestin function. We speculate that the cholesterol regulation of prestin occurs through localization to and internalization from membrane microdomains by

  8. Stochastic Nature in Cellular Processes

    Institute of Scientific and Technical Information of China (English)

    刘波; 刘圣君; 王祺; 晏世伟; 耿轶钊; SAKATA Fumihiko; GAO Xing-Fa

    2011-01-01

    The importance of stochasticity in cellular processes is increasingly recognized in both theoretical and experimental studies. General features of stochasticity in gene regulation and expression are briefly reviewed in this article, which include the main experimental phenomena, classification, quantization and regulation of noises. The correlation and transmission of noise in cascade networks are analyzed further and the stochastic simulation methods that can capture effects of intrinsic and extrinsic noise are described.

  9. Cellular fiber–reinforced concrete

    OpenAIRE

    Isachenko S.; Kodzoev M.

    2016-01-01

    Methods disperse reinforcement of concrete matrix using polypropylene, glass, basalt and metal fibers allows to make the construction of complex configuration, solve the problem of frost products. Dispersed reinforcement reduces the overall weight of the structures. The fiber replaces the secondary reinforcement, reducing the volume of use of structural steel reinforcement. Cellular Fiber concretes are characterized by high-performance properties, especially increased bending strength and...

  10. Identification of Nonstationary Cellular Automata

    Institute of Scientific and Technical Information of China (English)

    AndrewI.Adamatzky

    1992-01-01

    The principal feature of nonstationary cellular automata(NCA) is that a local transitiol rule of each cell is changed at each time step depending on neighborhood configuration at previous time step.The identification problem for NCA is extraction of local transition rules and the establishment of mechanism for changing these rules using sequence of NCA configurations.We present serial and parallel algorithms for identification of NCA.

  11. CELLULAR INTERACTIONS MEDIATED BY GLYCONECTIDS

    OpenAIRE

    Popescu, O.; Sumanovski, L. T.; I. Checiu; Elisabeta Popescu; G. N. Misevic

    1999-01-01

    Cellular interactions involve many types of cell surface molecules and operate via homophilic and/or heterophilic protein-protein and protein-carbohydrate binding. Our investigations in different model-systems (marine invertebrates and mammals) have provided direct evidence that a novel class of primordial proteoglycans, named by us gliconectins, can mediate cell adhesion via a new alternative molecular mechanism of polyvalent carbohydrate-carbohydrate binding. Biochemical characterization of...

  12. Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties.

    Science.gov (United States)

    Meyer, E M; Tay, E T; Zoltewicz, J A; Meyers, C; King, M A; Papke, R L; De Fiebre, C M

    1998-03-01

    The goals of this study were to develop compounds that were selective and highly efficacious agonists at alpha-7 receptors, while varying in antagonist activity; and to test the hypothesis that these compounds had memory-related and neuroprotective actions associated with both agonist and antagonist alpha-7 receptor activities. Three compounds were identified; E,E-3-(cinnamylidene)anabaseine (3-CA), E,E-3-(2-methoxycinnamylidene) anabaseine (2-MeOCA) and E,E-3-(4-methoxycinnamylidene) anabaseine (4-MeOCA) each displaced [125I]alpha-bungarotoxin binding from rat brain membranes and activated rat alpha-7 receptors in a Xenopus oocyte expression system fully efficaciously. The potency series for binding and receptor activation was 2-MeOCA > 4-MeOCA = 3-CA and 2-MeOCA = 3-CA > 4-MeOCA, respectively. No compound significantly activated oocyte-expressed alpha-4beta-2 receptors. Although each cinnamylidene-anabaseine caused a long-term inhibition of alpha-7 receptors, as measured by ACh-application 5 min later, this inhibition ranged considerably, from less than 20% (3-CA) to 90% (2-MeOCA) at an identical concentration (10 microM). These compounds improved passive avoidance behavior in nucleus basalis lesioned rats, with 2-MeOCA most potent in this respect. In contrast, only 3-CA was neuroprotective against neurite loss during nerve growth factor deprivation in differentiated rat pheochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist without antagonist activity, was also protective in this model. These results suggest that the neurite-protective action of alpha-7 receptor agonists may be more sensitive to potential long-term antagonist properties than acute behavioral actions are.

  13. Pioglitazone, a PPARγ agonist, provides comparable protection to angiotensin converting enzyme inhibitor ramipril against adriamycin nephropathy in rat.

    Science.gov (United States)

    Ochodnicky, Peter; Mesarosova, Lucia; Cernecka, Hana; Klimas, Jan; Krenek, Peter; Goris, Maaike; van Dokkum, Richard P E; Henning, Robert H; Kyselovic, Jan

    2014-05-05

    Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to ameliorate diabetic nephropathy, but much less are known about their effects in non-diabetic nephropathies. In the present study, metabolic parameters, blood pressure, aortic endothelial function along with molecular and structural markers of glomerular and tubulointerstitial renal damage, were studied in a rat model of normotensive nephropathy induced by adriamycin and treated with PPARγ agonist pioglitazone (12mg/kg, po), angiotensin converting enzyme (ACE) inhibitor ramipril (1mg/kg, po) or their combination. Pioglitazone had no effect on systolic blood pressure, marginally reduced glycemia and improved aortic endothelium-dependent relaxation. In the kidney, pioglitazone prevented the development of proteinuria and focal glomerulosclerosis to the similar extent as blood-pressure lowering ramipril. Renoprotection provided by either treatment was associated with a reduction in the cortical expression of profibrotic plasminogen activator inhibitor-1 and microvascular damage-inducing endothelin-1, and a limitation of interstitial macrophage influx. Treatment with PPARγ agonist, as well as ACE inhibitor comparably affected renal expression of the renin-angiotensin system (RAS) components, normalizing increased renal expression of ACE and enhancing the expression of Mas receptor. Interestingly, combined pioglitazone and ramipril treatment did not provide any additional renoprotection. These results demonstrate that in a nondiabetic renal disease, such as adriamycin-induced nephropathy, PPARγ agonist pioglitazone provides renoprotection to a similar extent as an ACE inhibitor by interfering with the expression of local RAS components and attenuating related profibrotic and inflammatory mechanisms. The combination of the both agents, however, does not lead to any additional renal benefit.

  14. A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China); Hsu, Ya-Wen [SunWay Biotechnology Company, Taipei, Taiwan (China); Pan, Tzu-Ming, E-mail: tmpan@ntu.edu.tw [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China)

    2013-11-01

    Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.

  15. The insect cellular immune response

    Institute of Scientific and Technical Information of China (English)

    Michael R. Strand

    2008-01-01

    The innate immune system of insects is divided into humoral defenses that include the production of soluble effector molecules and cellular defenses like phagocytosis and encapsulation that are mediated by hemocytes. This review summarizes current understanding of the cellular immune response. Insects produce several terminally differentiated types of hemocytes that are distinguished by morphology, molecular and antigenic markers, and function. The differentiated hemocytes that circulate in larval or nymphal stage insects arise from two sources: progenitor cells produced during embryogenesis and mesodermally derived hematopoietic organs. Regulation of hematopoiesis and hemocyte differentiation also involves several different signaling pathways. Phagocytosis and encapsulation require that hemocytes first recognize a given target as foreign followed by activation of downstream signaling and effector responses. A number of humoral and cellular receptors have been identified that recognize different microbes and multicellular parasites. In turn, activation of these receptors stimulates a number of signaling pathways that regulate different hemocyte functions. Recent studies also identify hemocytes as important sources of a number of humoral effector molecules required for killing different foreign invaders.

  16. Progress of cellular dedifferentiation research

    Institute of Scientific and Technical Information of China (English)

    LIU Hu-xian; HU Da-hai; JIA Chi-yu; FU Xiao-bing

    2006-01-01

    Differentiation, the stepwise specialization of cells, and transdifferentiation, the apparent switching of one cell type into another, capture much of the stem cell spotlight. But dedifferentiation, the developmental reversal of a cell before it reinvents itself, is an important process too. In multicellular organisms, cellular dedifferentiation is the major process underlying totipotency, regeneration and formation of new stem cell lineages. In humans,dedifferentiation is often associated with carcinogenesis.The study of cellular dedifferentiation in animals,particularly early events related to cell fate-switch and determination, is limited by the lack of a suitable,convenient experimental system. The classic example of dedifferentiation is limb and tail regeneration in urodele amphibians, such as salamanders. Recently, several investigators have shown that certain mammalian cell types can be induced to dedifferentiate to progenitor cells when stimulated with the appropriate signals or materials. These discoveries open the possibility that researchers might enhance the endogenous regenerative capacity of mammals by inducing cellular dedifferentiation in vivo.

  17. Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance

    Directory of Open Access Journals (Sweden)

    Zhao Jing

    2012-05-01

    Full Text Available Abstract The age-dependency of opioid analgesia and tolerance has been noticed in both clinical observation and laboratory studies. Evidence shows that many molecular and cellular events that play essential roles in opioid analgesia and tolerance are actually age-dependent. For example, the expression and functions of endogenous opioid peptides, multiple types of opioid receptors, G protein subunits that couple to opioid receptors, and regulators of G protein signaling (RGS proteins change with development and age. Other signaling systems that are critical to opioid tolerance development, such as N-methyl-D-aspartic acid (NMDA receptors, also undergo age-related changes. It is plausible that the age-dependent expression and functions of molecules within and related to the opioid signaling pathways, as well as age-dependent cellular activity such as agonist-induced opioid receptor internalization and desensitization, eventually lead to significant age-dependent changes in opioid analgesia and tolerance development.

  18. Treatment of type 2 diabetes by free Fatty Acid receptor agonists

    DEFF Research Database (Denmark)

    Watterson, Kenneth R; Hudson, Brian D; Ulven, Trond

    2014-01-01

    Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for free fatty acid receptors (FFA1-4) have consequently...... been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long-chain FFA receptor, FFA1, improved glycemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand...... was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss, and reduces inflammation and the metabolic and anti...

  19. [Treatment strategy for elderly diabetic patient with insulin or GLP-1 receptor agonist].

    Science.gov (United States)

    Ando, Yasuyo

    2013-11-01

    It has been established that diabetes is an independent risk factor for microvascular and macrovascular complications, and many studies indicate that diabetic subjects are at greater risk of dementia, depression and fracture. Risk reductions for microvascular, macrovascular and death were observed by intensive therapy using insulin or oral diabetic agents. But a history of hypoglycemia was increased myocardial infarction, mortality, dementia and fracture. So it is important that optimum glycemic control has to be achieved without hypoglycemia. Treatment with a long-acting basal insulin analogue or glucagon-like peptide-1(GLP-1) receptor agonist, provide effective glycemic control without serious hypoglycemia in elderly patients. Self-monitoring of blood glucose might be effective in improving glycemic control in elderly patients, and it is useful for the diagnosis of hypoglycemia.

  20. Some applications and prospects of cellular automata in traffic problems

    NARCIS (Netherlands)

    Goldengorin, Boris; Makarenko, Alexander; Smelyanec, Natalia; Yacoubi, SE; Chopard, B; Bandini, S

    2006-01-01

    In this paper we deal with mathematical modeling of participants' movement based on cellular automata (CA). We describe some improvements of CA models of pedestrian motion taking into account the real geometrical constraints induced by a specific restricted space. Also some presumable optimization p

  1. Cellular communications a comprehensive and practical guide

    CERN Document Server

    Tripathi, Nishith

    2014-01-01

    Even as newer cellular technologies and standards emerge, many of the fundamental principles and the components of the cellular network remain the same. Presenting a simple yet comprehensive view of cellular communications technologies, Cellular Communications provides an end-to-end perspective of cellular operations, ranging from physical layer details to call set-up and from the radio network to the core network. This self-contained source forpractitioners and students represents a comprehensive survey of the fundamentals of cellular communications and the landscape of commercially deployed

  2. CUSTOMER SATISFACTION MEASUREMENT TOWARDS IDEA CELLULAR

    Directory of Open Access Journals (Sweden)

    Yousef Mehdipour

    2013-05-01

    Full Text Available Measuring customer satisfaction provides an indication of how successful the organization is at providing products and/or services to the marketplace. Customer satisfaction is a collective outcome of perception, evaluation, and psychological reactions to the consumption experience with a product or service. This researcharticle investigated the attitude of Idea cellular customers to Idea services. All the customers of Idea cellular in Hyderabad city (Andhra Pradesh constituted the population. The sample of the study is 2000 customers that randomly selected. A questionnaire was developed and validated through pilot testing and administered to thesample for the collection of data. The researcher personally visited respondents, thus 100% data were collected.The collected data were tabulated and analyzed by SPSS. Results showed that majority of the respondents of Idea prefer post-paid service than to pre paid and largest segment of respondents are of idea then comes Cell one, Airtel and Vodafone. this study showed that most of the respondents need improvement in service. Majority of respondents gave an excellent rate for “Idea Cellular” services.

  3. Effect of a Selective Mas Receptor Agonist in Cerebral Ischemia In Vitro and In Vivo.

    Directory of Open Access Journals (Sweden)

    Seyoung Lee

    Full Text Available Functional modulation of the non-AT1R arm of the renin-angiotensin system, such as via AT2R activation, is known to improve stroke outcome. However, the relevance of the Mas receptor, which along with the AT2R forms the protective arm of the renin-angiotensin system, as a target in stroke is unclear. Here we tested the efficacy of a selective MasR agonist, AVE0991, in in vitro and in vivo models of ischemic stroke. Primary cortical neurons were cultured from E15-17 mouse embryos for 7-9 d, subjected to glucose deprivation for 24 h alone or with test drugs, and percentage cell death was determined using trypan blue exclusion assay. Additionally, adult male mice were subjected to 1 h middle cerebral artery occlusion and were administered either vehicle or AVE0991 (20 mg/kg i.p. at the commencement of 23 h reperfusion. Some animals were also treated with the MasR antagonist, A779 (80 mg/kg i.p. 1 h prior to surgery. Twenty-four h after MCAo, neurological deficits, locomotor activity and motor coordination were assessed in vivo, and infarct and edema volumes estimated from brain sections. Following glucose deprivation, application of AVE0991 (10-8 M to 10-6 M reduced neuronal cell death by ~60% (P<0.05, an effect prevented by the MasR antagonist. By contrast, AVE0991 administration in vivo had no effect on functional or histological outcomes at 24 h following stroke. These findings indicate that the classical MasR agonist, AVE0991, can directly protect neurons from injury following glucose-deprivation. However, this effect does not translate into an improved outcome in vivo when administered systemically following stroke.

  4. Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding.

    Directory of Open Access Journals (Sweden)

    Alessandro Marchiori

    Full Text Available Bitter molecules in humans are detected by ∼25 G protein-coupled receptors (GPCRs. The lack of atomic resolution structure for any of them is complicating an in depth understanding of the molecular mechanisms underlying bitter taste perception. Here, we investigate the molecular determinants of the interaction of the TAS2R38 bitter taste receptor with its agonists phenylthiocarbamide (PTC and propylthiouracil (PROP. We use the recently developed hybrid Molecular Mechanics/Coarse Grained (MM/CG method tailored specifically for GPCRs. The method, through an extensive exploration of the conformational space in the binding pocket, allows the identification of several residues important for agonist binding that would have been very difficult to capture from the standard bioinformatics/docking approach. Our calculations suggest that both agonists bind to Asn103, Phe197, Phe264 and Trp201, whilst they do not interact with the so-called extra cellular loop 2, involved in cis-retinal binding in the GPCR rhodopsin. These predictions are consistent with data sets based on more than 20 site-directed mutagenesis and functional calcium imaging experiments of TAS2R38. The method could be readily used for other GPCRs for which experimental information is currently lacking.

  5. Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding.

    Science.gov (United States)

    Marchiori, Alessandro; Capece, Luciana; Giorgetti, Alejandro; Gasparini, Paolo; Behrens, Maik; Carloni, Paolo; Meyerhof, Wolfgang

    2013-01-01

    Bitter molecules in humans are detected by ∼25 G protein-coupled receptors (GPCRs). The lack of atomic resolution structure for any of them is complicating an in depth understanding of the molecular mechanisms underlying bitter taste perception. Here, we investigate the molecular determinants of the interaction of the TAS2R38 bitter taste receptor with its agonists phenylthiocarbamide (PTC) and propylthiouracil (PROP). We use the recently developed hybrid Molecular Mechanics/Coarse Grained (MM/CG) method tailored specifically for GPCRs. The method, through an extensive exploration of the conformational space in the binding pocket, allows the identification of several residues important for agonist binding that would have been very difficult to capture from the standard bioinformatics/docking approach. Our calculations suggest that both agonists bind to Asn103, Phe197, Phe264 and Trp201, whilst they do not interact with the so-called extra cellular loop 2, involved in cis-retinal binding in the GPCR rhodopsin. These predictions are consistent with data sets based on more than 20 site-directed mutagenesis and functional calcium imaging experiments of TAS2R38. The method could be readily used for other GPCRs for which experimental information is currently lacking.

  6. Metabotropic glutamate and GABA receptors modulate cellular excitability and glutamatergic transmission in chicken cochlear nucleus angularis neurons.

    Science.gov (United States)

    Shi, Wei; Lu, Yong

    2017-03-01

    Neurons in the avian cochlear nucleus angularis (NA) receive glutamatergic input from the auditory nerve, and GABAergic input from the superior olivary nucleus. Physiologically heterogeneous, NA neurons perform multiple functions including encoding sound intensity information. Using in vitro whole-cell patch recordings from acute brain slices and immunohistochemistry staining, we investigated neuromodulation mediated by metabotropic glutamate and GABA receptors (mGluRs and GABABRs) in NA neurons. Based on their intrinsic firing patterns in response to somatic current injections, NA neurons were classified into onset, damped, and tonic cells. Pharmacological activation of group II mGluRs, group III mGluRs, and GABABRs, by their respective agonists, suppressed the cellular excitability of non-onset firing NA neurons. Each of these agonists inhibited the glutamatergic transmission in NA neurons, in a cell type-independent manner. The frequency but not the amplitude of spontaneous release of glutamate was reduced by each of these agonists, suggesting that the modulation of the glutamatergic transmission was via presynaptic actions. Interestingly, activation of group I mGluRs increased cellular excitability and suppressed glutamatergic transmission in non-onset neurons. These results elaborate that auditory processing in NA neurons is subject to neuromodulation mediated by metabotropic receptors activated by native neurotransmitters released at NA.

  7. Identification of human dopamine receptors agonists from Chinese herbs

    Institute of Scientific and Technical Information of China (English)

    Yi-lin ZHANG; Hai-qing ZHANG; Xiao-yu LIU; Shi-neng HUA; Lu-bing ZHOU; Jun YU; Xue-hai TAN

    2007-01-01

    Aim: To find human dopamine receptors, especially D1-like receptor specific ago-nists from Chinese herbs as potential antihypertension drug leads. Methods: Two D1-like receptor cell lines carrying a β-lactamase reporter gene, and a D2 receptor cell line coexpressing a promiscuous G protein G15 were constructed using HEK293 cells. A natural compound library made from fractionated samples of herbal ex-tracts was used for high-throughput screening (HTS) against one of the cell lines,HEK/D5R/CRE-blax. The interested hits were evaluated for their activities against various dopamine receptors. Results: Fourteen hits were identified from primary screening, of which 2 of the better hit samples, HD0522 and HD0059, were selected for further material and activity analysis, and to obtain 2 compounds that ap-peared as 2 single peaks in HPLC, HD0522H01 and HD0059H01. HD0059H01 could activate D1, D2, and D5 receptors, with EC50 values of 2.28 μg/mL, 0.85 μg/mL, and 1.41 μg/mL, respectively. HD0522H01 could only activate D1R and D5R with EC50 values of 2.95 μg/mL and 8.38 μg/mL. Conclusion: We established cell-based assays for 3 different human dopamine receptors and identified specific agonists HD0522H01 and HD0059H01 through HTS. The specific agonist to D1-like receptors, HD0522H01, may become a new natural product-based drug lead for antihypertension treatment.

  8. Comparative endpoint sensitivity of in vitro estrogen agonist assays.

    Science.gov (United States)

    Dreier, David A; Connors, Kristin A; Brooks, Bryan W

    2015-07-01

    Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less

  9. 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.

  10. Discovery of a potent and selective GPR120 agonist.

    Science.gov (United States)

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel; Milligan, Graeme; Ulven, Trond

    2012-05-10

    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.

  11. Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine.

    Science.gov (United States)

    Simeon, D; Hollander, E; Stein, D J; DeCaria, C; Cohen, L J; Saoud, J B; Islam, N; Hwang, M

    1995-09-29

    Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization.

  12. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    Science.gov (United States)

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter.

  13. Particles and Patterns in Cellular Automata

    Energy Technology Data Exchange (ETDEWEB)

    Jen, E.; Das, R.; Beasley, C.E.

    1999-06-03

    This is the final report of a three-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). Our objective has been to develop tools for studying particle interactions in a class of dynamical systems characterized by discreteness, determinism, local interaction, and an inherently parallel form of evolution. These systems can be described by cellular automata (CA) and the behavior we studied has improved our understanding of the nature of patterns generated by CAs, their ability to perform global computations, and their relationship to continuous dynamical systems. We have also developed a rule-table mathematics that enables one to custom-design CA rule tables to generate patterns of specified types, or to perform specified computational tasks.

  14. Wireless traffic steering for green cellular networks

    CERN Document Server

    Zhang, Shan; Zhou, Sheng; Niu, Zhisheng; Shen, Xuemin (Sherman)

    2016-01-01

    This book introduces wireless traffic steering as a paradigm to realize green communication in multi-tier heterogeneous cellular networks. By matching network resources and dynamic mobile traffic demand, traffic steering helps to reduce on-grid power consumption with on-demand services provided. This book reviews existing solutions from the perspectives of energy consumption reduction and renewable energy harvesting. Specifically, it explains how traffic steering can improve energy efficiency through intelligent traffic-resource matching. Several promising traffic steering approaches for dynamic network planning and renewable energy demand-supply balancing are discussed. This book presents an energy-aware traffic steering method for networks with energy harvesting, which optimizes the traffic allocated to each cell based on the renewable energy status. Renewable energy demand-supply balancing is a key factor in energy dynamics, aimed at enhancing renewable energy sustainability to reduce on-grid energy consum...

  15. Cellular immune responses to HIV

    Science.gov (United States)

    McMichael, Andrew J.; Rowland-Jones, Sarah L.

    2001-04-01

    The cellular immune response to the human immunodeficiency virus, mediated by T lymphocytes, seems strong but fails to control the infection completely. In most virus infections, T cells either eliminate the virus or suppress it indefinitely as a harmless, persisting infection. But the human immunodeficiency virus undermines this control by infecting key immune cells, thereby impairing the response of both the infected CD4+ T cells and the uninfected CD8+ T cells. The failure of the latter to function efficiently facilitates the escape of virus from immune control and the collapse of the whole immune system.

  16. Repaglinide at a cellular level

    DEFF Research Database (Denmark)

    Krogsgaard Thomsen, M; Bokvist, K; Høy, M

    2002-01-01

    To investigate the hormonal and cellular selectivity of the prandial glucose regulators, we have undertaken a series of experiments, in which we characterised the effects of repaglinide and nateglinide on ATP-sensitive potassium ion (KATP) channel activity, membrane potential and exocytosis in rat...... pancreatic alpha-cells and somatotrophs. We found a pharmacological dissociation between the actions on KATP channels and exocytosis and suggest that compounds that, unlike repaglinide, have direct stimulatory effects on exocytosis in somatotrophs and alpha- and beta-cells, such as sulphonylureas...

  17. Game of Life Cellular Automata

    CERN Document Server

    Adamatzky, Andrew

    2010-01-01

    In the late 1960s, British mathematician John Conway invented a virtual mathematical machine that operates on a two-dimensional array of square cell. Each cell takes two states, live and dead. The cells' states are updated simultaneously and in discrete time. A dead cell comes to life if it has exactly three live neighbours. A live cell remains alive if two or three of its neighbours are alive, otherwise the cell dies. Conway's Game of Life became the most programmed solitary game and the most known cellular automaton. The book brings together results of forty years of study into computational

  18. Cellular automata a parallel model

    CERN Document Server

    Mazoyer, J

    1999-01-01

    Cellular automata can be viewed both as computational models and modelling systems of real processes. This volume emphasises the first aspect. In articles written by leading researchers, sophisticated massive parallel algorithms (firing squad, life, Fischer's primes recognition) are treated. Their computational power and the specific complexity classes they determine are surveyed, while some recent results in relation to chaos from a new dynamic systems point of view are also presented. Audience: This book will be of interest to specialists of theoretical computer science and the parallelism challenge.

  19. ING proteins in cellular senescence.

    Science.gov (United States)

    Menéndez, Camino; Abad, María; Gómez-Cabello, Daniel; Moreno, Alberto; Palmero, Ignacio

    2009-05-01

    Cellular senescence is an effective anti-tumor barrier that acts by restraining the uncontrolled proliferation of cells carrying potentially oncogenic alterations. ING proteins are putative tumor suppressor proteins functionally linked to the p53 pathway and to chromatin regulation. ING proteins exert their tumor-protective action through different types of responses. Here, we review the evidence on the participation of ING proteins, mainly ING1 and ING2, in the implementation of the senescent response. The currently available data support an important role of ING proteins as regulators of senescence, in connection with the p53 pathway and chromatin organization.

  20. Cellular Analogs of Operant Behavior.

    Science.gov (United States)

    1992-07-31

    ing of single units can be demonstrated, does such a cellular subset of neighboring pyramidal cells and interneurons as well as process contribute...excite dopamine neurons by -hyperpolarization of local interneurons . J. Neurosci. 12:483-488; 1992. Kosterlitz, H. W. Biosynthesis of morphine in the...II 197 1 1 ocation preltereite iindiis- HOIdlod VA. artdo \\M I . \\.ill I ’’’’i i R i l’)89) ( pioid mediationl lserilI1 reintoree-Cd bK amlphetcamine

  1. 5G Ultra-Dense Cellular Networks

    OpenAIRE

    Ge, Xiaohu; Tu, Song; Mao, Guoqiang; Wang, Cheng-xiang; Han, Tao

    2015-01-01

    Traditional ultra-dense wireless networks are recommended as a complement for cellular networks and are deployed in partial areas, such as hotspot and indoor scenarios. Based on the massive multiple-input multi-output (MIMO) antennas and the millimeter wavecommunication technologies, the 5G ultra-dense cellular network is proposed to deploy in overall cellular scenarios. Moreover, a distribution network architecture is presented for 5G ultra-dense cellular networks. Furthermore, the backhaul ...

  2. TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity

    Science.gov (United States)

    Zambad, Shitalkumar P; Tuli, Davinder; Mathur, Anoop; Ghalsasi, Sameer A; Chaudhary, Anita R; Deshpande, Shailesh; Gupta, Ramesh C; Chauthaiwale, Vijay; Dutt, Chaitanya

    2014-01-01

    Background Patients with diabesity have a significantly increased risk of developing cardiovascular disease. Therefore, therapy addressing the multiple metabolic abnormalities linked with diabesity and leading to further reduction of cardiovascular risk is highly desirable. Activation of the TGR5 receptor holds therapeutic potential for diabesity. In the present study, we evaluated the efficacy of TRC210258, a novel TGR5 agonist, in clinically relevant animal models of diabesity. Methods A novel small molecule, TRC210258 (N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo (1, 2-a) pyrimidine-3-carboxamide), was synthesized. The in vitro TGR5 receptor activation potential of TRC210258 was assessed by cyclic adenosine monophosphate (cAMP) assay and cAMP-responsive element reporter assay using cells overexpressing the human TGR5 receptor. The effect of TRC210258 on glucagon-like peptide-1 release was evaluated in vitro using a human enteroendocrine cell line. The effect of TRC210258 on energy expenditure and glycemic control was evaluated in high-fat diet-induced obese mice. Additionally, the effect of TRC210258 on dyslipidemic parameters was determined in high fat-fed hamsters. Results TRC210258 demonstrated potent TGR5 agonist activity, with enhanced glucagon-like peptide-1 release and energy expenditure. Treatment with TRC210258 resulted in better glycemic control and improved parameters of dyslipidemia such as plasma triglyceride, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol levels. Treatment with TRC210258 also improved emerging dyslipidemic cardiovascular risk parameters, including remnant cholesterol and triglyceride clearance. Conclusion This study highlights the potential of TRC210258, a novel TGR5 agonist, to improve dyslipidemic cardiovascular risk beyond glycemic control in patients with type 2 diabetes. PMID:24379686

  3. EP4 agonist alleviates indomethacin-induced gastric lesions and promotes chronic gastric ulcer healing

    Institute of Scientific and Technical Information of China (English)

    Guang-Liang Jiang; Wha Bin Im; Yariv Donde; Larry A Wheeler

    2009-01-01

    AIM: To investigate EP4-selective agonist effect on indomethacin-induced gastric lesions and on the spontaneous healing of chronic gastric ulcers. METHODS: In a mouse model of gastric bleeding with high dose of indomethacin (20 mg/kg), an EP4-selective agonist was administered orally. Stomach lesions and gastric mucous regeneration were monitored. In a mouse model of chronic gastric ulcer induced by acetic acid, EP4 agonist effect on the healing of chronic gastric ulcer was evaluated in the presence or absence of low dose indomethacin (3 mg/kg). In cultured human gastric mucous cells, EP4 agonist effect on indomethacininduced apoptosis was assessed by flow cytometry. RESULTS: The EP4-selective agonist reduced high dose indomethacin-induced acute hemorrhagic damage and promoted mucous epithelial regeneration. Low-dose indomethacin aggravated ulcer bleeding and inflammation, and delayed the healing of the established chronic gastric ulcer. The EP4 agonist, when applied locally, not only offset indomethacin-induced gastric bleeding and inflammation, but also accelerated ulcer healing. In the absence of indomethacin, the EP4 agonist even accelerated chronic gastric ulcer healing and suppressed inflammatory cell infiltration in the granulation tissue. In vitro , the EP4 agonist protected human gastric mucous cells from indomethacin-induced apoptosis. CONCLUSION: EP4-selective agonist may prevent indomethacin-induced gastric lesions and promote healing of existing and indomethacin-aggravated gastric ulcers, via promoting proliferation and survival of mucous epithelial cells.

  4. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple system atrophy.

    Science.gov (United States)

    Klos, Kevin J; Bower, James H; Josephs, Keith A; Matsumoto, Joseph Y; Ahlskog, J Eric

    2005-09-01

    Pathological hypersexuality developed in 13 patients with PD and two patients ultimately diagnosed clinically with MSA. Hypersexuality began within 8 months after starting dopamine agonist therapy in 14 of 15 cases, including four on agonist monotherapy. It resolved in the four cases where the agonist was stopped, despite continued levodopa therapy. This was not an isolated behavioral problem in most, with additional compulsive or addictive behaviors coinciding in nine patients (60%). A systematic literature review of pathological hypersexuality in PD revealed similar medication histories; combining these cases with our series, 26 of 29 patients (90%) were on adjuvant dopamine agonists.

  5. 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......, long-acting beta(2)-agonists provide effective bronchodilatation and bronchoprotection when used as intermittent, single-dose treatment of asthma in children, but not when used as regular treatment. Future studies should examine the positioning of long-acting beta(2)-agonists as an "as needed" rescue...... medication instead of short-acting beta(2)-agonists for pediatric asthma management....

  6. How does agonistic behaviour differ in albino and pigmented fish?

    Directory of Open Access Journals (Sweden)

    Ondřej Slavík

    2016-04-01

    Full Text Available 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.

  7. The evolution of histamine H₃ antagonists/inverse agonists.

    Science.gov (United States)

    Lebois, Evan P; Jones, Carrie K; Lindsley, Craig W

    2011-01-01

    This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H₃ antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H₃R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H₃ ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H₃ ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H₃R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists.

  8. 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.

  9. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    Science.gov (United States)

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

  10. Identification of agonists for a group of human odorant receptors

    Directory of Open Access Journals (Sweden)

    Daniela eGonzalez-Kristeller

    2015-03-01

    Full Text Available Olfaction plays a critical role in several aspects of the human life. Odorants are detected by hundreds of odorant receptors (ORs which belong to the superfamily of G protein-coupled receptors. These receptors are expressed in the olfactory sensory neurons of the nose. The information provided by the activation of different combinations of ORs in the nose is transmitted to the brain, leading to odorant perception and emotional and behavioral responses. There are ~400 intact human ORs, and to date only a small percentage of these receptors (~10% have known agonists. The determination of the specificity of the human ORs will contribute to a better understanding of how odorants are discriminated by the olfactory system. In this work, we aimed to identify human specific ORs, that is, ORs that are present in humans but absent from other species, and their corresponding agonists. To do this, we first selected 22 OR gene sequences from the human genome with no counterparts in the mouse, rat or dog genomes. Then we used a heterologous expression system to screen a subset of these human ORs against a panel of odorants of biological relevance, including foodborne aroma volatiles. We found that different types of odorants are able to activate some of these previously uncharacterized human ORs.

  11. 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.

  12. AMP is an adenosine A1 receptor agonist.

    Science.gov (United States)

    Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J

    2012-02-17

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

  13. GLP-1 receptor agonist-induced polyarthritis: a case report.

    Science.gov (United States)

    Ambrosio, Maria Luisa; Monami, Matteo; Sati, Lavinia; Marchionni, Niccolò; Di Bari, Mauro; Mannucci, Edoardo

    2014-08-01

    Occasional cases of bilateral, symmetrical, seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase-4 inhibitors (Crickx et al. in Rheumatol Int, 2013). We report here a similar case observed during treatment with a GLP-1 receptor agonist. A 42-year-old man with type 2 diabetes treated with metformin 1,500 mg/day and liraglutide 1.8 mg/day. After 6 months from the beginning of treatment, the patient complained of bilateral arthralgia (hands, feet, ankles, knees, and hips). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and leukocytes were increased. Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear antibodies, anti-Borrelia, and burgdorferi antibodies were all negative, and myoglobin and calcitonin were normal. Liraglutide was withdrawn, and the symptoms completely disappeared within 1 week, with normalization of ESR, CRP, fibrinogen, and leukocytes. Previously described cases of polyarthritis associated with DPP4 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme. The present case, occurred during treatment with a GLP-1 receptor agonists, suggests a possibly different mechanism, mediated by GLP-1 receptor stimulation, which deserved further investigation.

  14. Melatonin and melatonin agonist for delirium in the elderly patients.

    Science.gov (United States)

    Chakraborti, Dwaipayan; Tampi, Deena J; Tampi, Rajesh R

    2015-03-01

    The objective of this review is to summarize the available data on the use of melatonin and melatonin agonist for the prevention and management of delirium in the elderly patients from randomized controlled trials (RCTs). A systematic search of 5 major databases PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library was conducted. This search yielded a total of 2 RCTs for melatonin. One study compared melatonin to midazolam, clonidine, and control groups for the prevention and management of delirium in individuals who were pre- and posthip post-hip arthroplasty. The other study compared melatonin to placebo for the prevention of delirium in older adults admitted to an inpatient internal medicine service. Data from these 2 studies indicate that melatonin may have some benefit in the prevention and management of delirium in older adults. However, there is no evidence that melatonin reduces the severity of delirium or has any effect on behaviors or functions in these individuals. Melatonin was well tolerated in these 2 studies. The search for a melatonin agonist for delirium in the elderly patients yielded 1 study of ramelteon. In this study, ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo. Ramelteon was well tolerated in this study.

  15. Cold suppresses agonist-induced activation of TRPV1.

    Science.gov (United States)

    Chung, M-K; Wang, S

    2011-09-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

  16. Effects of single dose GnRH agonist as luteal support on pregnancy outcome in frozen-thawed embryo transfer cycles: an RCT

    Directory of Open Access Journals (Sweden)

    Robab Davar

    2015-08-01

    Full Text Available Background: There is no doubt that luteal phase support is essential to enhance the reproductive outcome in IVF cycles. In addition to progesterone and human chorionic gonadotropin, several studies have described GnRH agonists as luteal phase support to improve implantation rate, pregnancy rate and live birth rate, whereas other studies showed dissimilar conclusions. All of these studies have been done in fresh IVF cycles. Objective: To determine whether an additional GnRH agonist administered at the time of implantation for luteal phase support in frozen-thawed embryo transfer (FET improves the embryo developmental potential. Materials and Methods: This is a prospective controlled trial study in 200 FET cycles, patients were randomized on the day of embryo transfer into group 1 (n=100 to whom a single dose of GnRH agonist (0.1 mg triptorelin was administered three days after transfer and group 2 (n=100, who did not receive agonist. Both groups received daily vaginal progesterone suppositories plus estradiol valerate 6 mg daily. Primary outcome measure was clinical pregnancy rate. Secondary outcome measures were implantation rate, chemical, ongoing pregnancy rate and abortion rate. Results: A total of 200 FET cycles were analyzed. Demographic data and embryo quality were comparable between two groups. No statistically significant difference in clinical and ongoing pregnancy rates was observed between the two groups (26% versus 21%, p=0.40 and 21% versus 17%, p=0.37, respectively. Conclusion: Administration of a subcutaneous GnRH agonist at the time of implantation does not increase clinical or ongoing pregnancy.

  17. Characterization of a novel, brain-penetrating CB1 receptor inverse agonist: metabolic profile in diet-induced obese models and aspects of central activity.

    Science.gov (United States)

    Jacobson, Laura H; Commerford, S Renee; Gerber, Sarah P; Chen, Yu Alice; Dardik, Beatriz; Chaperon, Frederique; Schwartzkopf, Chad; Nguyen-Tran, Van; Hollenbeck, Thomas; McNamara, Peter; He, Xiaohui; Liu, Hong; Seidel, H Martin; Jaton, Anne-Liese; Gromada, Jesper; Teixeira, Sandra

    2011-12-01

    Pharmacologic antagonism of cannabinoid 1 receptors (CB1 receptors) in the central nervous system (CNS) suppresses food intake, promotes weight loss, and improves the metabolic profile. Since the CB1 receptor is expressed both in the CNS and in peripheral tissues, therapeutic value may be gained with CB1 receptor inverse agonists acting on receptors in both domains. The present report examines the metabolic and CNS actions of a novel CB1 receptor inverse agonist, compound 64, a 1,5,6-trisubstituted pyrazolopyrimidinone. Compound 64 showed similar or superior binding affinity, in vitro potency, and pharmacokinetic profile compared to rimonabant. Both compounds improved the metabolic profile in diet-induced obese (DIO) rats and obese cynomolgus monkeys. Weight loss tended to be greater in compound 64-treated DIO rats compared to pair-fed counterparts, suggesting that compound 64 may have metabolic effects beyond those elicited by weight loss alone. In the CNS, reversal of agonist-induced hypothermia and hypolocomotion indicated that compound 64 possessed an antagonist activity in vivo. Dosed alone, compound 64 suppressed extinction of conditioned freezing (10 mg/kg) and rapid eye movement (REM) sleep (30 mg/kg), consistent with previous reports for rimonabant, although for REM sleep, compound 64 was greater than threefold less potent than for metabolic effects. Together, these data suggested that (1) impairment of extinction learning and REM sleep suppression are classic, centrally mediated responses to CB1 receptor inverse agonists, and (2) some separation may be achievable between central and peripheral effects with brain-penetrating CB1 receptor inverse agonists while maintaining metabolic efficacy. Furthermore, chronic treatment with compound 64 contributes to evidence that peripheral CB1 receptor blockade may yield beneficial outcomes that exceed those elicited by weight loss alone.

  18. Melanoma screening with cellular phones.

    Directory of Open Access Journals (Sweden)

    Cesare Massone

    Full Text Available BACKGROUND: Mobile teledermatology has recently been shown to be suitable for teledermatology despite limitations in image definition in preliminary studies. The unique aspect of mobile teledermatology is that this system represents a filtering or triage system, allowing a sensitive approach for the management of patients with emergent skin diseases. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigated the feasibility of teleconsultation using a new generation of cellular phones in pigmented skin lesions. 18 patients were selected consecutively in the Pigmented Skin Lesions Clinic of the Department of Dermatology, Medical University of Graz, Graz (Austria. Clinical and dermoscopic images were acquired using a Sony Ericsson with a built-in two-megapixel camera. Two teleconsultants reviewed the images on a specific web application (http://www.dermahandy.net/default.asp where images had been uploaded in JPEG format. Compared to the face-to-face diagnoses, the two teleconsultants obtained a score of correct telediagnoses of 89% and of 91.5% reporting the clinical and dermoscopic images, respectively. CONCLUSIONS/SIGNIFICANCE: The present work is the first study performing mobile teledermoscopy using cellular phones. Mobile teledermatology has the potential to become an easy applicable tool for everyone and a new approach for enhanced self-monitoring for skin cancer screening in the spirit of the eHealth program of the European Commission Information for Society and Media.

  19. Cellular functions of the microprocessor.

    Science.gov (United States)

    Macias, Sara; Cordiner, Ross A; Cáceres, Javier F

    2013-08-01

    The microprocessor is a complex comprising the RNase III enzyme Drosha and the double-stranded RNA-binding protein DGCR8 (DiGeorge syndrome critical region 8 gene) that catalyses the nuclear step of miRNA (microRNA) biogenesis. DGCR8 recognizes the RNA substrate, whereas Drosha functions as an endonuclease. Recent global analyses of microprocessor and Dicer proteins have suggested novel functions for these components independent of their role in miRNA biogenesis. A HITS-CLIP (high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation) experiment designed to identify novel substrates of the microprocessor revealed that this complex binds and regulates a large variety of cellular RNAs. The microprocessor-mediated cleavage of several classes of RNAs not only regulates transcript levels, but also modulates alternative splicing events, independently of miRNA function. Importantly, DGCR8 can also associate with other nucleases, suggesting the existence of alternative DGCR8 complexes that may regulate the fate of a subset of cellular RNAs. The aim of the present review is to provide an overview of the diverse functional roles of the microprocessor.

  20. Cellular automata modelling of SEIRS

    Institute of Scientific and Technical Information of China (English)

    Liu Quan-Xing; Jin Zhen

    2005-01-01

    In this paper the SEIRS epidemic spread is analysed, and a two-dimensional probability cellular automata model for SEIRS is presented. Each cellular automation cell represents a part of the population that may be found in one of five states of individuals: susceptible, exposed (or latency), infected, immunized (or recovered) and death. Here studied are the effects of two cases on the epidemic spread. i.e. the effects of non-segregation and segregation on the latency and the infected of population. The conclusion is reached that the epidemic will persist in the case of non-segregation but it will decrease in the case of segregation. The proposed model can serve as a basis for the development of algorithms to simulate real epidemics based on real data. Last we find the density series of the exposed and the infected will fluctuate near a positive equilibrium point, when the constant for the immunized is less than its corresponding constant τ0. Our theoretical results are verified by numerical simulations.

  1. Proteoglycans act as cellular hepatitis delta virus attachment receptors.

    Science.gov (United States)

    Lamas Longarela, Oscar; Schmidt, Tobias T; Schöneweis, Katrin; Romeo, Raffaella; Wedemeyer, Heiner; Urban, Stephan; Schulze, Andreas

    2013-01-01

    The hepatitis delta virus (HDV) is a small, defective RNA virus that requires the presence of the hepatitis B virus (HBV) for its life cycle. Worldwide more than 15 million people are co-infected with HBV and HDV. Although much effort has been made, the early steps of the HBV/HDV entry process, including hepatocyte attachment and receptor interaction are still not fully understood. Numerous possible cellular HBV/HDV binding partners have been described over the last years; however, so far only heparan sulfate proteoglycans have been functionally confirmed as cell-associated HBV attachment factors. Recently, it has been suggested that ionotrophic purinergic receptors (P2XR) participate as receptors in HBV/HDV entry. Using the HBV/HDV susceptible HepaRG cell line and primary human hepatocytes (PHH), we here demonstrate that HDV entry into hepatocytes depends on the interaction with the glycosaminoglycan (GAG) side chains of cellular heparan sulfate proteoglycans. We furthermore provide evidence that P2XR are not involved in HBV/HDV entry and that effects observed with inhibitors for these receptors are a consequence of their negative charge. HDV infection was abrogated by soluble GAGs and other highly sulfated compounds. Enzymatic removal of defined carbohydrate structures from the cell surface using heparinase III or the obstruction of GAG synthesis by sodium chlorate inhibited HDV infection of HepaRG cells. Highly sulfated P2XR antagonists blocked HBV/HDV infection of HepaRG cells and PHH. In contrast, no effect on HBV/HDV infection was found when uncharged P2XR antagonists or agonists were applied. In summary, HDV infection, comparable to HBV infection, requires binding to the carbohydrate side chains of hepatocyte-associated heparan sulfate proteoglycans as attachment receptors, while P2XR are not actively involved.

  2. Widrow-cellular neural network and optoelectronic implementation

    Science.gov (United States)

    Bal, Abdullah

    A new type of optoelectronic cellular neural network has been developed by providing the capability of coefficients adjusment of cellular neural network (CNN) using Widrow based perceptron learning algorithm. The new supervised cellular neural network is called Widrow-CNN. Despite the unsupervised CNN, the proposed learning algorithm allows to use the Widrow-CNN for various image processing applications easily. Also, the capability of CNN for image processing and feature extraction has been improved using basic joint transform correlation architecture. This hardware application presents high speed processing capability compared to digital applications. The optoelectronic Widrow-CNN has been tested for classic CNN feature extraction problems. It yields the best results even in case of hard feature extraction problems such as diagonal line detection and vertical line determination.

  3. Nipah virus matrix protein: expert hacker of cellular machines.

    Science.gov (United States)

    Watkinson, Ruth E; Lee, Benhur

    2016-08-01

    Nipah virus (NiV, Henipavirus) is a highly lethal emergent zoonotic paramyxovirus responsible for repeated human outbreaks of encephalitis in South East Asia. There are no approved vaccines or treatments, thus improved understanding of NiV biology is imperative. NiV matrix protein recruits a plethora of cellular machinery to scaffold and coordinate virion budding. Intriguingly, matrix also hijacks cellular trafficking and ubiquitination pathways to facilitate transient nuclear localization. While the biological significance of matrix nuclear localization for an otherwise cytoplasmic virus remains enigmatic, the molecular details have begun to be characterized, and are conserved among matrix proteins from divergent paramyxoviruses. Matrix protein appropriation of cellular machinery will be discussed in terms of its early nuclear targeting and later role in virion assembly.

  4. The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists

    Science.gov (United States)

    Kalani, M. Yashar S.; Vaidehi, Nagarajan; Hall, Spencer E.; Trabanino, Rene J.; Freddolino, Peter L.; Kalani, Maziyar A.; Floriano, Wely B.; Tak Kam, Victor Wai; Goddard, William A., III

    2004-03-01

    Dopamine neurotransmitter and its receptors play a critical role in the cell signaling process responsible for information transfer in neurons functioning in the nervous system. Development of improved therapeutics for such disorders as Parkinson's disease and schizophrenia would be significantly enhanced with the availability of the 3D structure for the dopamine receptors and of the binding site for dopamine and other agonists and antagonists. We report here the 3D structure of the long isoform of the human D2 dopamine receptor, predicted from primary sequence using first-principles theoretical and computational techniques (i.e., we did not use bioinformatic or experimental 3D structural information in predicting structures). The predicted 3D structure is validated by comparison of the predicted binding site and the relative binding affinities of dopamine, three known dopamine agonists (antiparkinsonian), and seven known antagonists (antipsychotic) in the D2 receptor to experimentally determined values. These structures correctly predict the critical residues for binding dopamine and several antagonists, identified by mutation studies, and give relative binding affinities that correlate well with experiments. The predicted binding site for dopamine and agonists is located between transmembrane (TM) helices 3, 4, 5, and 6, whereas the best antagonists bind to a site involving TM helices 2, 3, 4, 6, and 7 with minimal contacts to TM helix 5. We identify characteristic differences between the binding sites of agonists and antagonists.

  5. Non-equivalence of Key Positively Charged Residues of the Free Fatty Acid 2 Receptor in the Recognition and Function of Agonist Versus Antagonist Ligands*

    Science.gov (United States)

    Sergeev, Eugenia; Hansen, Anders Højgaard; Pandey, Sunil K.; MacKenzie, Amanda E.; Hudson, Brian D.; Ulven, Trond; Milligan, Graeme

    2016-01-01

    Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled free fatty acid 2 (FFA2) receptor, and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabeled FFA2 antagonist to probe ligand binding to FFA2, and in combination with mutagenesis and molecular modeling studies, we define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, although agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor. PMID:26518871

  6. The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis.

    Science.gov (United States)

    Cheng, Huawei; Shang, Yuping; Jiang, Ling; Shi, Tian-lu; Wang, Lin

    2016-01-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-analysis was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by December 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calculated to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta-analysis. We found the effect of PPAR-γ agonists on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-analysis. There is insufficient evidence of statistically incognition of AD and mild-to-moderate AD patients have been improved who were treated with PPAR-γ agonists in our research. However, PPAR-γ agonists may be a promising therapeutic approach in future, especially pioglitazone, with large-scale randomized controlled trials to confirm.

  7. Screening for PPAR γ agonist from Myristica fragrans Houtt seeds for the treatment of Type 2 diabetes by in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Keri Lestari

    2012-10-01

    Full Text Available In general, a type two diabetes mellitus (T2DM patient suffers for hyperglycaemia and insulin resistance. Nowadays, there is an anti diabetes drug working as a PPAR/ agonist and has a significant effect to improve the hyperglycemia and insulin resistance condition. However, this drug gives a negative effect on lipid circulation parameters. In this investigation, nutmeg (Myristica fragrans extracts (NuSE was tested against PPARγ using cell-based GAL4/PPAR chimera transactivation and trancient transvection assay with three PPAR response element (PPREs containing reporters. The results demonstrate that the NuSE has significant PPARγ agonist activity, although their potency was less than the standard PPARγ full agonist. An investigation of antidiabetic activity of the NuSE has been carried out on rats. Rats were treated orally every day for six days with the ethanol of NuSE in several doses. The result of the experiment showed that each dose of NuSE gave hypoglycemic activity (p= 0.01 and p=0.05. The experiment also showed that an increase in dosage caused an increased in the hypoglycemic activity. Therefore, nutmeg (Myristica fragrans seeds might be potential against antidiabetic agent for the treatment of type two diabetes with a PPAR /. agonistic mechanism.

  8. Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

    Directory of Open Access Journals (Sweden)

    Anowara Khatun

    2016-12-01

    Full Text Available Vitamin D (VD reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca2+-activated K+ channel KCa1.1 regulates intracellular Ca2+ signaling pathways and is associated with high grade tumors and poor prognoses. In the present study, we examined the effects of treatments with VD receptor (VDR agonists on the expression and activity of KCa1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, flow cytometry, and voltage-sensitive dye imaging. Treatments with VDR agonists for 72 h markedly decreased the expression levels of KCa1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific KCa1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in KCa1.1 protein expression. These results suggest that KCa1.1 is a new downstream target of VDR signaling and the down-regulation of KCa1.1 through the transcriptional repression of KCa1.1 and enhancement of KCa1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells.

  9. Predictive model to describe water migration in cellular solid foods during storage

    NARCIS (Netherlands)

    Voogt, J.A.; Hirte, A.; Meinders, M.B.J.

    2011-01-01

    BACKGROUND: Water migration in cellular solid foods during storage causes loss of crispness. To improve crispness retention, physical understanding of this process is needed. Mathematical models are suitable tools to gain this physical knowledge. RESULTS: Water migration in cellular solid foods invo

  10. Predictive model to describe water migration in cellular solid foods during storage

    NARCIS (Netherlands)

    Voogt, J.A.; Hirte, A.; Meinders, M.B.J.

    2011-01-01

    Background: Water migration in cellular solid foods during storage causes loss of crispness. To improve crispness retention, physical understanding of this process is needed. Mathematical models are suitable tools to gain this physical knowledge. Results: Water migration in cellular solid foods invo

  11. A weakly universal cellular automaton in the hyperbolic 3D space with three states

    CERN Document Server

    Maurice, Margenstern

    2010-01-01

    In this paper, we significantly improve a previous result by the same author showing the existence of a weakly universal cellular automaton with five states living in the hyperbolic 3D-space. Here, we get such a cellular automaton with three states only.

  12. In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist.

    Science.gov (United States)

    Panayi, Fany; Sors, Aurore; Bert, Lionel; Martin, Brigitte; Rollin-Jego, Gaelle; Billiras, Rodolphe; Carrié, Isabelle; Albinet, Karine; Danober, Laurence; Rogez, Nathalie; Thomas, Jean-Yves; Pira, Luigi; Bertaina-Anglade, Valérie; Lestage, Pierre

    2017-03-14

    S 38093, a novel histamine H3 receptor inverse agonist, was tested in a series of neurochemical and behavioral paradigms designed to evaluate its procognitive and arousal properties. In intracerebral microdialysis studies performed in rats, S 38093 dose-dependently increased histamine extracellular levels in the prefrontal cortex and facilitated cholinergic transmission in the prefrontal cortex and hippocampus of rats after acute and chronic administration (10mg/kg i.p.). Acute oral administration of S 38093 at 0.1mg/kg significantly improved spatial working memory in rats in the Morris water maze test. The compound also displayed cognition enhancing properties in the two-trial object recognition task in rats, in a natural forgetting paradigm at 0.3 and 1mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3mg/kg p.o. The property of S 38093 to promote episodic memory was confirmed in a social recognition test in rats at 0.3 and 1mg/kg i.p. Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10mg/kg i.p., S 38093 significantly reduced slow wave sleep delta power and induced at the highest dose a delay in sleep latency. S 38093 at 10mg/kg p.o. also decreased the barbital-induced sleeping time in rats. Taken together these data indicate that S 38093, a novel H3 inverse agonist, displays cognition enhancing at low doses and arousal properties at higher doses in rodents.

  13. AT2 receptor non-peptide agonist C21 promotes natriuresis in obese Zucker rats.

    Science.gov (United States)

    Ali, Quaisar; Hussain, Tahir

    2012-06-01

    Previously, we demonstrated that angiotensin II type 2 (AT(2)) receptors have a role in natriuresis in obese Zucker rats (OZR). In the present study, we investigated the role of a novel, non-peptide agonist, C21, in natriuresis via AT(2) receptor activation in OZR. Infusion of C21 (1 and 5 μg kg(-1) min(-1)) into rats under anesthesia caused a dose-dependent increase in urine flow (UF) and urinary Na volume (U(Na)V). These effects of C21 were blocked by pre-infusion of the AT(2) receptor antagonist, PD123319, (50 μg kg(-1) min(-1)), suggesting involvement of the AT(2) receptor. Infusion of C21 (5 μg kg(-1) min(-1)) significantly increased the fractional excretion of sodium without changing the glomerular filtration rate or blood pressure, suggesting a tubular effect. Similarly, C21 infusion increased the fractional excretion of lithium, suggesting a proximal tubular effect. Furthermore, we tested the effect of C21 on natriuresis after blocking two main, distal-nephron Na transporters, the epithelial Na channels (ENaC), with amiloride (AM, 3 mg kg(-1) body wt), and the NaCl cotransporters (NCC), with bendroflumethiazide (BFTZ, 7 mg kg(-1) body wt). Infusion of AM + BFTZ caused significant increases in both diuresis and natriuresis, which were further increased by infusion of C21 (5 μg kg(-1) min(-1)). Natriuresis in response to C21 was associated with increases in urinary NO and cGMP levels. The data indicate that the AT(2) receptor agonist, C21, promotes natriuresis via AT(2) receptor activation and that this effect is potentially based in the proximal tubules and linked to the nitric oxide/cyclic guanosine monophosphate pathway. The natriuretic response to C21 may have therapeutic significance by improving kidney function in obesity.

  14. The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.

    Directory of Open Access Journals (Sweden)

    Alexander Fuchs

    Full Text Available Magnolol (4-allyl-2-(5-allyl-2-hydroxyphenylphenol, the main bioactive constituent of the medicinal plant Magnolia officinalis, and its main metabolite tetrahydromagnolol were recently found to activate cannabinoid (CB receptors. We now investigated the structure-activity relationships of (tetrahydromagnolol analogs with variations of the alkyl chains and the phenolic groups and could considerably improve potency. Among the most potent compounds were the dual CB1/CB2 full agonist 2-(2-methoxy-5-propyl-phenyl-4-hexylphenol (61a, K(i CB1:0.00957 µM; K(i CB2:0.0238 µM, and the CB2-selective partial agonist 2-(2-hydroxy-5-propylphenyl-4-pentylphenol (60, K(i CB1:0.362 µM; K(i CB2:0.0371 µM, which showed high selectivity versus GPR18 and GPR55. Compound 61b, an isomer of 61a, was the most potent GPR55 antagonist with an IC50 value of 3.25 µM but was non-selective. The relatively simple structures, which possess no stereocenters, are easily accessible in a four- to five-step synthetic procedure from common starting materials. The central reaction step is the well-elaborated Suzuki-Miyaura cross-coupling reaction, which is suitable for a combinatorial chemistry approach. The scaffold is versatile and may be fine-tuned to obtain a broad range of receptor affinities, selectivities and efficacies.

  15. Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study.

    Science.gov (United States)

    Marcus, Monica M; Björkholm, Carl; Malmerfelt, Anna; Möller, Annie; Påhlsson, Ninni; Konradsson-Geuken, Åsa; Feltmann, Kristin; Jardemark, Kent; Schilström, Björn; Svensson, Torgny H

    2016-09-01

    Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.

  16. Five hTRPA1 Agonists Found in Indigenous Korean Mint, Agastache rugosa.

    Directory of Open Access Journals (Sweden)

    Hana Moon

    Full Text Available Transient receptor potential ankyrin1 (TRPA1 and transient receptor potential vanilloid 1 (TRPV1 are members of the TRP superfamily of structurally related, nonselective cation channels and mediators of several signaling pathways. Previously, we identified methyl syringate as an hTRPA1 agonist with efficacy against gastric emptying. The aim of this study was to find hTRPA1 and/or hTRPV1 activators in Agastache rugosa (Fisch. et Meyer O. Kuntze (A.rugosa, commonly known as Korean mint to improve hTRPA1-related phenomena. An extract of the stem and leaves of A.rugosa (Labiatae selectively activated hTRPA1 and hTRPV1. We next investigated the effects of commercially available compounds found in A.rugosa (acacetin, 4-allylanisole, p-anisaldehyde, apigenin 7-glucoside, L-carveol, β-caryophyllene, trans-p-methoxycinnamaldehyde, methyl eugenol, pachypodol, and rosmarinic acid on cultured hTRPA1- and hTRPV1-expressing cells. Of the ten compounds, L-carveol, trans-p-methoxycinnamaldehyde, methyl eugenol, 4-allylanisole, and p-anisaldehyde selectively activated hTRPA1, with EC50 values of 189.1±26.8, 29.8±14.9, 160.2±21.9, 1535±315.7, and 546.5±73.0 μM, respectively. The activities of these compounds were effectively inhibited by the hTRPA1 antagonists, ruthenium red and HC-030031. Although the five active compounds showed weaker calcium responses than allyl isothiocyanate (EC50=7.2±1.4 μM, our results suggest that these compounds from the stem and leaves of A.rugosa are specific and selective agonists of hTRPA1.

  17. Handover management in dense cellular networks: A stochastic geometry approach

    KAUST Repository

    Arshad, Rabe

    2016-07-26

    Cellular operators are continuously densifying their networks to cope with the ever-increasing capacity demand. Furthermore, an extreme densification phase for cellular networks is foreseen to fulfill the ambitious fifth generation (5G) performance requirements. Network densification improves spectrum utilization and network capacity by shrinking base stations\\' (BSs) footprints and reusing the same spectrum more frequently over the spatial domain. However, network densification also increases the handover (HO) rate, which may diminish the capacity gains for mobile users due to HO delays. In highly dense 5G cellular networks, HO delays may neutralize or even negate the gains offered by network densification. In this paper, we present an analytical paradigm, based on stochastic geometry, to quantify the effect of HO delay on the average user rate in cellular networks. To this end, we propose a flexible handover scheme to reduce HO delay in case of highly dense cellular networks. This scheme allows skipping the HO procedure with some BSs along users\\' trajectories. The performance evaluation and testing of this scheme for only single HO skipping shows considerable gains in many practical scenarios. © 2016 IEEE.

  18. Impact Performance of 3D Integrated Cellular Woven Composite Panel

    Institute of Scientific and Technical Information of China (English)

    TIAN Wei; ZHU Cheng-yan

    2006-01-01

    This paper studied the impact resistance of 3D integrated cellular woven composite panel under persudo-static impact,comprised the test result with property of typical 3D woven composites, analyzed some parameters that maybe affect composites' impact resistance and at last used SEM to observe the damage process and mechanism of samples. The result shows that the impact resistance of 3D integrated cellular woven composites is much better than the performance of typical 3D woven composites; it is an active method to improve the impact resistance of composites that developing preform with cellular on the basis of typical 3D woven structure; for different 3D integrated cellular woven structure, the value of absorbed-energy is incrensing with the hollow percentage; tiny deformation will not emerge on samples until the acting force gets to 85% of the maximum;similar with typical 3D woven composites, the delaminated phenomenon of 3D integrated cellular woven composites is also unapparent during impact process.

  19. Movies of cellular and sub-cellular motion by digital holographic microscopy

    Directory of Open Access Journals (Sweden)

    Yu Lingfeng

    2006-03-01

    Full Text Available Abstract Background Many biological specimens, such as living cells and their intracellular components, often exhibit very little amplitude contrast, making it difficult for conventional bright field microscopes to distinguish them from their surroundings. To overcome this problem phase contrast techniques such as Zernike, Normarsky and dark-field microscopies have been developed to improve specimen visibility without chemically or physically altering them by the process of staining. These techniques have proven to be invaluable tools for studying living cells and furthering scientific understanding of fundamental cellular processes such as mitosis. However a drawback of these techniques is that direct quantitative phase imaging is not possible. Quantitative phase imaging is important because it enables determination of either the refractive index or optical thickness variations from the measured optical path length with sub-wavelength accuracy. Digital holography is an emergent phase contrast technique that offers an excellent approach in obtaining both qualitative and quantitative phase information from the hologram. A CCD camera is used to record a hologram onto a computer and numerical methods are subsequently applied to reconstruct the hologram to enable direct access to both phase and amplitude information. Another attractive feature of digital holography is the ability to focus on multiple focal planes from a single hologram, emulating the focusing control of a conventional microscope. Methods A modified Mach-Zender off-axis setup in transmission is used to record and reconstruct a number of holographic amplitude and phase images of cellular and sub-cellular features. Results Both cellular and sub-cellular features are imaged with sub-micron, diffraction-limited resolution. Movies of holographic amplitude and phase images of living microbes and cells are created from a series of holograms and reconstructed with numerically adjustable

  20. Dynamic Topology Re-Configuration in Multihop Cellular Networks Using Sequential Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    B.Shantha Kumari

    2014-10-01

    thesis provide significant improvement with respect to the existing results, and are expected to have significant impact in the analysis and design of future cellular networks.

  1. Cellular uptake of metallated cobalamins

    DEFF Research Database (Denmark)

    Tran, Mai Thanh Quynh; Stürup, Stefan; Lambert, Ian Henry

    2016-01-01

    Cellular uptake of vitamin B12-cisplatin conjugates was estimated via detection of their metal constituents (Co, Pt, and Re) by inductively coupled plasma mass spectrometry (ICP-MS). Vitamin B12 (cyano-cob(iii)alamin) and aquo-cob(iii)alamin [Cbl-OH2](+), which differ in the β-axial ligands (CN...... including [Cbl-OH2](+), [{Co}-CN-{cis-PtCl(NH3)2}](+), [{Re}-{Co}-CN-{cis-PtCl(NH3)2}](+), and [{Co}-CN-{trans-Pt(Cyt)(NH3)2}](2+) (Cyt = cytarabin) was high compared to neutral B12, which implied the existence of an additional internalization pathway for charged B12 vitamin analogs. The affinities...

  2. Discrete geodesics and cellular automata

    CERN Document Server

    Arrighi, Pablo

    2015-01-01

    This paper proposes a dynamical notion of discrete geodesics, understood as straightest trajectories in discretized curved spacetime. The notion is generic, as it is formulated in terms of a general deviation function, but readily specializes to metric spaces such as discretized pseudo-riemannian manifolds. It is effective: an algorithm for computing these geodesics naturally follows, which allows numerical validation---as shown by computing the perihelion shift of a Mercury-like planet. It is consistent, in the continuum limit, with the standard notion of timelike geodesics in a pseudo-riemannian manifold. Whether the algorithm fits within the framework of cellular automata is discussed at length. KEYWORDS: Discrete connection, parallel transport, general relativity, Regge calculus.

  3. Thermomechanical characterisation of cellular rubber

    Science.gov (United States)

    Seibert, H.; Scheffer, T.; Diebels, S.

    2016-09-01

    This contribution discusses an experimental possibility to characterise a cellular rubber in terms of the influence of multiaxiality, rate dependency under environmental temperature and its behaviour under hydrostatic pressure. In this context, a mixed open and closed cell rubber based on an ethylene propylene diene monomer is investigated exemplarily. The present article intends to give a general idea of the characterisation method and the considerable effects of this special type of material. The main focus lies on the experimental procedure and the used testing devices in combination with the analysis methods such as true three-dimensional digital image correlation. The structural compressibility is taken into account by an approach for a material model using the Theory of Porous Media with additional temperature dependence.

  4. Cellular compartmentalization of secondary metabolism

    Directory of Open Access Journals (Sweden)

    H. Corby eKistler

    2015-02-01

    Full Text Available Fungal secondary metabolism is often considered apart from the essential housekeeping functions of the cell. However, there are clear links between fundamental cellular metabolism and the biochemical pathways leading to secondary metabolite synthesis. Besides utilizing key biochemical precursors shared with the most essential processes of the cell (e.g. amino acids, acetyl CoA, NADPH, enzymes for secondary metabolite synthesis are compartmentalized at conserved subcellular sites that position pathway enzymes to use these common biochemical precursors. Co-compartmentalization of secondary metabolism pathway enzymes also may function to channel precursors, promote pathway efficiency and sequester pathway intermediates and products from the rest of the cell. In this review we discuss the compartmentalization of three well-studied fungal secondary metabolite biosynthetic pathways for penicillin G, aflatoxin and deoxynivalenol, and summarize evidence used to infer subcellular localization. We also discuss how these metabolites potentially are trafficked within the cell and may be exported.

  5. PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

    Directory of Open Access Journals (Sweden)

    Monica Puligheddu

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα, nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p. or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2% for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.. Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key

  6. Fundamental Limits to Cellular Sensing

    Science.gov (United States)

    ten Wolde, Pieter Rein; Becker, Nils B.; Ouldridge, Thomas E.; Mugler, Andrew

    2016-03-01

    In recent years experiments have demonstrated that living cells can measure low chemical concentrations with high precision, and much progress has been made in understanding what sets the fundamental limit to the precision of chemical sensing. Chemical concentration measurements start with the binding of ligand molecules to receptor proteins, which is an inherently noisy process, especially at low concentrations. The signaling networks that transmit the information on the ligand concentration from the receptors into the cell have to filter this receptor input noise as much as possible. These networks, however, are also intrinsically stochastic in nature, which means that they will also add noise to the transmitted signal. In this review, we will first discuss how the diffusive transport and binding of ligand to the receptor sets the receptor correlation time, which is the timescale over which fluctuations in the state of the receptor, arising from the stochastic receptor-ligand binding, decay. We then describe how downstream signaling pathways integrate these receptor-state fluctuations, and how the number of receptors, the receptor correlation time, and the effective integration time set by the downstream network, together impose a fundamental limit on the precision of sensing. We then discuss how cells can remove the receptor input noise while simultaneously suppressing the intrinsic noise in the signaling network. We describe why this mechanism of time integration requires three classes (groups) of resources—receptors and their integration time, readout molecules, energy—and how each resource class sets a fundamental sensing limit. We also briefly discuss the scheme of maximum-likelihood estimation, the role of receptor cooperativity, and how cellular copy protocols differ from canonical copy protocols typically considered in the computational literature, explaining why cellular sensing systems can never reach the Landauer limit on the optimal trade

  7. Cooperative Handover Management in Dense Cellular Networks

    KAUST Repository

    Arshad, Rabe

    2017-02-07

    Network densification has always been an important factor to cope with the ever increasing capacity demand. Deploying more base stations (BSs) improves the spatial frequency utilization, which increases the network capacity. However, such improvement comes at the expense of shrinking the BSs\\' footprints, which increases the handover (HO) rate and may diminish the foreseen capacity gains. In this paper, we propose a cooperative HO management scheme to mitigate the HO effect on throughput gains achieved via cellular network densification. The proposed HO scheme relies on skipping HO to the nearest BS at some instances along the user\\'s trajectory while enabling cooperative BS service during HO execution at other instances. To this end, we develop a mathematical model, via stochastic geometry, to quantify the performance of the proposed HO scheme in terms of coverage probability and user throughput. The results show that the proposed cooperative HO scheme outperforms the always best connected based association at high mobility. Also, the value of BS cooperation along with handover skipping is quantified with respect to the HO skipping only that has recently appeared in the literature. Particularly, the proposed cooperative HO scheme shows throughput gains of 12% to 27% and 17% on average, when compared to the always best connected and HO skipping only schemes at user velocity ranging from 80 km/h to 160 Km/h, respectively.

  8. Antinociceptive interactions between Mu-opioid receptor agonists and the serotonin uptake inhibitor clomipramine in rhesus monkeys: role of Mu agonist efficacy.

    Science.gov (United States)

    Banks, Matthew L; Rice, Kenner C; Negus, S Stevens

    2010-11-01

    Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.

  9. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice

    Science.gov (United States)

    Sharma, Pawan; Yi, Roslyn; Nayak, Ajay P.; Wang, Nadan; Tang, Francesca; Knight, Morgan J.; Pan, Shi; Oliver, Brian; Deshpande, Deepak A.

    2017-01-01

    Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.

  10. Trialkyltin rexinoid-X receptor agonists selectively potentiate thyroid hormone induced programs of xenopus laevis metamorphosis

    NARCIS (Netherlands)

    Mengeling, Brenda J.; Murk, Albertinka J.; Furlow, J.D.

    2016-01-01

    The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the

  11. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview.

    Science.gov (United States)

    Soltani, Hoda; Pardakhty, Abbas

    2016-04-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of "new drug delivery systems" is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  12. Synthesis of urea acetates as potential PPARα/γ,dual agonists

    Institute of Scientific and Technical Information of China (English)

    Chang Yan Zhao; Chang Qing Shi; Yuan Wei Chen

    2008-01-01

    In the quest for novel PPARα/γ dual agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia,we designed and synthesized a series of urea acetates as potential PPARα/γ dual agonists.The structure of the target compounds,intermediates were characterized by 1H NMR,HRMS.

  13. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview

    OpenAIRE

    Soltani, Hoda; Pardakhty, Abbas

    2016-01-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of “new drug delivery systems” is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  14. Sumatriptan (5-HT1D receptor agonist) does not exacerbate symptoms in obsessive compulsive disorder

    NARCIS (Netherlands)

    Pian, KLH; Westerberg, HGM; van Megen, HJGM; den Boer, JA

    1998-01-01

    The non-selective serotonin (5-HT) receptor agonist meta-chlorophenylpiperazine (mCPP) has been reported to elicit symptoms in patients with obsessive compulsive disorder (OCD). MK-212, another nonselective 5-HT receptor agonist, does not seem to induce obsessive compulsive symptoms in OCD patients.

  15. Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta-analysis.

    NARCIS (Netherlands)

    Dekkers, O.M.; Lagro, J.; Burman, P.; Jorgensen, J.O.; Romijn, J.A.; Pereira, A.M.

    2010-01-01

    CONTEXT: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details. OBJECTIVE: The aim of the study was to assess the effect of dopamine agonist withdrawal

  16. The 5-HT(1F) receptor agonist lasmiditan as a potential treatment of migraine attacks

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer C; Olesen, Jes

    2012-01-01

    Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo...

  17. Efficacy and safety of the PPARγ partial agonist balaglitazone compared with pioglitazone and placebo

    DEFF Research Database (Denmark)

    Henriksen, Kim; Byrjalsen, Inger; Qvist, Per;

    2011-01-01

    Treatment of patients with perioxisome proliferator-activated receptor-¿ full agonists are associated with weight gain, heart failure, peripheral oedema, and bone loss. However, the safety of partial perioxisome proliferator-activated receptor-¿ agonists has not been established in a clinical tri...

  18. Drug-induced Hypothermia by 5HT1A Agonists Provide Neuroprotection in Experimental Stroke

    DEFF Research Database (Denmark)

    Johansen, Flemming Fryd; Hasseldam, Henrik; Nybro Smith, Matthias;

    2014-01-01

    with .55°C ranging between .1-1.4°C. CONCLUSIONS: 5-hydroxytryptamine receptor 1A (5HT1A) agonists significantly reduce infarct volumes in MCAO rats primarily because of the hypothermic drug effect. 5HT1A agonists may be introduced to reduce body temperatures rapidly and prepare patients for further...

  19. Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120).

    Science.gov (United States)

    Sparks, Steven M; Chen, Grace; Collins, Jon L; Danger, Dana; Dock, Steven T; Jayawickreme, Channa; Jenkinson, Stephen; Laudeman, Christopher; Leesnitzer, M Anthony; Liang, Xi; Maloney, Patrick; McCoy, David C; Moncol, David; Rash, Vincent; Rimele, Thomas; Vulimiri, Padmaja; Way, James M; Ross, Sean

    2014-07-15

    The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.

  20. A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites

    DEFF Research Database (Denmark)

    Kongsbak, Kristine Grønning; Bergmann, Rikke; Sørensen, Pernille Louise

    2013-01-01

    We present a full-length a1b2c2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate...