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Sample records for fxr agonist gw4064

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

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

    2010-09-27

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

  2. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

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

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  3. Impact of bile acids on the growth of human cholangiocarcinoma via FXR

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    Zhang Yinxin

    2011-10-01

    Full Text Available Abstract Background The objective of the study was to investigate the effect of different types of bile acids on proliferation of cholangiocarcinoma and the potential molecular mechanisms. Methods PCR assay and Western blot were performed to detect the expression of farnesoid × receptor (FXR in mRNA and protein level. Immunohistochemical analysis was carried out to monitor the expression of FXR in cholangiocarcinoma tissues from 26 patients and 10 normal controls. The effects on in vivo tumor growth were also studied in nude mouse model. Results Free bile acids induced an increased expression of FXR; on the contrary, the conjugated bile acids decreased the expression of FXR. The FXR effect has been illustrated with the use of the FXR agonist GW4064 and the FXR antagonist GS. More specifically, when the use of free bile acids combined with FXR agonist GW4064, the tumor cell inhibitory effect was even more pronounced. But adding FXR antagonist GS into the treatment attenuated the tumor inhibitory effect caused by free bile acids. Combined treatment of GS and CDCA could reverse the regulating effect of CDCA on the expression of FXR. Administration of CDCA and GW 4064 resulted in a significant inhibition of tumor growth. The inhibitory effect in combination group (CDCA plus GW 4064 was even more pronounced. Again, the conjugated bile acid-GDCA promoted the growth of tumor. We also found that FXR agonist GW4064 effectively blocked the stimulatory effect of GDCA on tumor growth. And the characteristic and difference of FXR expressions were in agreement with previous experimental results in mouse cholangiocarcinoma tissues. There was also significant difference in FXR expression between normal and tumor tissues from patients with cholangiocarcinoma. Conclusions The imbalance of ratio of free and conjugated bile acids may play an important role in tumorigenesis of cholangiocarcinoma. FXR, a member of the nuclear receptor superfamily, may mediate the

  4. Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists

    International Nuclear Information System (INIS)

    Zhang Songwen; Liu Qiangyuan; Wang Juan; Harnish, Douglas C.

    2009-01-01

    C-reactive protein (CRP), a human acute-phase protein, is a risk factor for future cardiovascular events and exerts direct pro-inflammatory and pro-atherogenic properties. The farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily, plays an essential role in the regulation of enterohepatic circulation and lipid homeostasis. In this study, we report that two synthetic FXR agonists, WAY-362450 and GW4064, suppressed interleukin-6-induced CRP expression in human Hep3B hepatoma cells. Knockdown of FXR by short interfering RNA attenuated the inhibitory effect of the FXR agonists and also increased the ability of interleukin-6 to induce CRP production. Furthermore, treatment of wild type C57BL/6 mice with the FXR agonist, WAY-362450, attenuated lipopolysaccharide-induced serum amyloid P component and serum amyloid A3 mRNA levels in the liver, whereas no effect was observed in FXR knockout mice. These data provide new evidence for direct anti-inflammatory properties of FXR.

  5. FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity.

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    Barbier, Olivier; Torra, Ines Pineda; Sirvent, Audrey; Claudel, Thierry; Blanquart, Christophe; Duran-Sandoval, Daniel; Kuipers, Folkert; Kosykh, Vladimir; Fruchart, Jean-Charles; Staels, Bart

    2003-06-01

    Bile acids are essential for bile formation and intestinal absorption of lipids and fat-soluble vitamins. However, the intrinsic toxicity of hydrophobic bile acids demands a tight control of their intracellular concentrations. Bile acids are ligands for the farnesoid X receptor (FXR) that regulates the expression of genes controlling bile acid synthesis and transport. The human uridine 5'-diphosphate-glucuronosyltransferase 2B4 (UGT2B4) converts hydrophobic bile acids into more hydrophilic glucuronide derivatives. In this study, we identify UGT2B4 as an FXR target gene. Human hepatocytes or hepatoblastoma HepG2 cells were treated with chenodeoxycholic acid or the synthetic FXR agonist GW4064, and the levels of UGT2B4 messenger RNA, protein, and activity were determined by using real-time polymerase chain reaction, Western blot, and glucuronidation assays. Treatment of hepatocytes and HepG2 cells with FXR agonists resulted in an increase of UGT2B4 messenger RNA, protein, and activity. A bile acid response element in the UGT2B4 promoter (B4-BARE) to which FXR, but not retinoid X receptor, binds, was identified by site-directed mutagenesis, electromobility shift, and chromatin immunoprecipitation assays. Retinoid X receptor activation abolished the induction of UGT2B4 expression and inhibited binding of FXR to the B4-BARE, suggesting that retinoid X receptor modulates FXR target gene activation. Overexpression of UGT2B4 in HepG2 cells resulted in the attenuation of bile acid induction of the FXR target gene small heterodimeric partner. These data suggest that UGT2B4 gene induction by bile acids contributes to a feed-forward reduction of bile acid toxicity and a decrease of the activity of these biological FXR activators.

  6. FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model.

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    Ulrich Deuschle

    Full Text Available The farnesoid X receptor (FXR is expressed predominantly in tissues exposed to high levels of bile acids and controls bile acid and lipid homeostasis. FXR(-/- mice develop hepatocellular carcinoma (HCC and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. The N-myc downstream-regulated gene 2 (NDRG2 has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellular carcinoma, colorectal carcinoma and many other malignancies.We show reduced NDRG2 mRNA in livers of FXR(-/- mice compared to wild type mice and both, FXR and NDRG2 mRNAs, are reduced in human HCC compared to normal liver. Gene reporter assays and Chromatin Immunoprecipitation data support that FXR directly controls NDRG2 transcription via IR1-type element(s identified in the first introns of the human, mouse and rat NDRG2 genes. NDRG2 mRNA was induced by non-steroidal FXR agonists in livers of mice and the magnitude of induction of NDRG2 mRNA in three different human hepatoma cell lines was increased when ectopically expressing human FXR. Growth and metastasis of SK-Hep-1 cells was strongly reduced by non-steroidal FXR agonists in an orthotopic liver xenograft tumor model. Ectopic expression of FXR in SK-Hep1 cells reduced tumor growth and metastasis potential of corresponding cells and increased the anti-tumor efficacy of FXR agonists, which may be partly mediated via increased NDRG2 expression. FXR agonists may show a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasing prevalence and limited therapeutic options.

  7. FXR Controls the Tumor Suppressor NDRG2 and FXR Agonists Reduce Liver Tumor Growth and Metastasis in an Orthotopic Mouse Xenograft Model

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    Deuschle, Ulrich; Schüler, Julia; Schulz, Andreas; Schlüter, Thomas; Kinzel, Olaf; Abel, Ulrich; Kremoser, Claus

    2012-01-01

    The farnesoid X receptor (FXR) is expressed predominantly in tissues exposed to high levels of bile acids and controls bile acid and lipid homeostasis. FXR−/− mice develop hepatocellular carcinoma (HCC) and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. The N-myc downstream-regulated gene 2 (NDRG2) has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellular carcinoma, colorectal carcinoma and many other malignancies. We show reduced NDRG2 mRNA in livers of FXR−/− mice compared to wild type mice and both, FXR and NDRG2 mRNAs, are reduced in human HCC compared to normal liver. Gene reporter assays and Chromatin Immunoprecipitation data support that FXR directly controls NDRG2 transcription via IR1-type element(s) identified in the first introns of the human, mouse and rat NDRG2 genes. NDRG2 mRNA was induced by non-steroidal FXR agonists in livers of mice and the magnitude of induction of NDRG2 mRNA in three different human hepatoma cell lines was increased when ectopically expressing human FXR. Growth and metastasis of SK-Hep-1 cells was strongly reduced by non-steroidal FXR agonists in an orthotopic liver xenograft tumor model. Ectopic expression of FXR in SK-Hep1 cells reduced tumor growth and metastasis potential of corresponding cells and increased the anti-tumor efficacy of FXR agonists, which may be partly mediated via increased NDRG2 expression. FXR agonists may show a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasing prevalence and limited therapeutic options. PMID:23056173

  8. Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

    Energy Technology Data Exchange (ETDEWEB)

    Bass, Jonathan Y.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Mills, Wendy Y.; Navas, III, Frank; Parks, Derek J.; Smalley, Jr., Terrence L.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce (GSKNC)

    2014-08-13

    To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

  9. Structural Investigation for Optimization of Anthranilic Acid Derivatives as Partial FXR Agonists by in Silico Approaches

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    Chen, Meimei; Yang, Xuemei; Lai, Xinmei; Kang, Jie; Gan, Huijuan; Gao, Yuxing

    2016-01-01

    In this paper, a three level in silico approach was applied to investigate some important structural and physicochemical aspects of a series of anthranilic acid derivatives (AAD) newly identified as potent partial farnesoid X receptor (FXR) agonists. Initially, both two and three-dimensional quantitative structure activity relationship (2D- and 3D-QSAR) studies were performed based on such AAD by a stepwise technology combined with multiple linear regression and comparative molecular field analysis. The obtained 2D-QSAR model gave a high predictive ability (R2train = 0.935, R2test = 0.902, Q2LOO = 0.899). It also uncovered that number of rotatable single bonds (b_rotN), relative negative partial charges (RPC−), oprea's lead-like (opr_leadlike), subdivided van der Waal’s surface area (SlogP_VSA2) and accessible surface area (ASA) were important features in defining activity. Additionally, the derived3D-QSAR model presented a higher predictive ability (R2train = 0.944, R2test = 0.892, Q2LOO = 0.802). Meanwhile, the derived contour maps from the 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving FXR agonist activity. Finally, nine newly designed AAD with higher predicted EC50 values than the known template compound were docked into the FXR active site. The excellent molecular binding patterns of these molecules also suggested that they can be robust and potent partial FXR agonists in agreement with the QSAR results. Overall, these derived models may help to identify and design novel AAD with better FXR agonist activity. PMID:27070594

  10. An extract from date palm fruit (Phoenix dactylifera acts as a co-agonist ligand for the nuclear receptor FXR and differentially modulates FXR target-gene expression in vitro.

    Directory of Open Access Journals (Sweden)

    Emilia Alfaro-Viquez

    Full Text Available Date palm fruit (Phoenix dactylifera consumption reduces serum triglyceride levels in human subjects. The objective of this study was to prepare an extract from dates and determine whether it acts as a ligand for the farnesoid x receptor (FXR, a nuclear receptor important for maintaining triglyceride and cholesterol homeostasis. Freeze-dried extracts were isolated from California-grown dates (Deglet Noor and Medjool from the 2014 and 2015 harvests, by means of liquid extraction and solid phase separation. Each date palm extract (DPE was characterized via HPLC and MALDI-TOF mass spectrometry, and the procyanidin content was qualitatively determined. Extracts were tested to determine their ability to modulate nuclear receptor-mediated transactivation using transient transfection. The effect of DPE on FXR-target genes regulating bile acid absorption and transport was then assessed in vitro, in Caco-2 cells. Characterization reveals that DPE is a rich source of polyphenols including hydroxycinnamic acids, proanthocyanidins, and lipohilic polyphenols, and comprises 13% proanthocyanidins. Transactivation results show that DPE acts as a co-agonist ligand for both mouse and human FXR, wherein it activates bile acid-bound FXR greater than that seen with bile acid alone. Additionally, DPE alone activated a peroxisome proliferator activated receptor alpha (PPARα chimera in a dose-dependent manner. Consistent with DPE as a co-agonist ligand for FXR, studies in Caco-2 cells reveal that co-incubation with bile acid, dose-dependently enhances the expression of fibroblast growth factor 19 (FGF19, compared to treatment with bile acid alone. In contrast, DPE inhibited bile acid-induced expression of ileal bile acid binding protein (IBABP. Our results demonstrate that DPE acts as a potent co-agonist ligand for FXR, and that it differentially regulates FXR-target gene expression in vitro in human intestinal cells. This study provides novel insight into a potential

  11. An extract from date palm fruit (Phoenix dactylifera) acts as a co-agonist ligand for the nuclear receptor FXR and differentially modulates FXR target-gene expression in vitro.

    Science.gov (United States)

    Alfaro-Viquez, Emilia; Roling, Brent F; Krueger, Christian G; Rainey, Charlene J; Reed, Jess D; Ricketts, Marie-Louise

    2018-01-01

    Date palm fruit (Phoenix dactylifera) consumption reduces serum triglyceride levels in human subjects. The objective of this study was to prepare an extract from dates and determine whether it acts as a ligand for the farnesoid x receptor (FXR), a nuclear receptor important for maintaining triglyceride and cholesterol homeostasis. Freeze-dried extracts were isolated from California-grown dates (Deglet Noor and Medjool) from the 2014 and 2015 harvests, by means of liquid extraction and solid phase separation. Each date palm extract (DPE) was characterized via HPLC and MALDI-TOF mass spectrometry, and the procyanidin content was qualitatively determined. Extracts were tested to determine their ability to modulate nuclear receptor-mediated transactivation using transient transfection. The effect of DPE on FXR-target genes regulating bile acid absorption and transport was then assessed in vitro, in Caco-2 cells. Characterization reveals that DPE is a rich source of polyphenols including hydroxycinnamic acids, proanthocyanidins, and lipohilic polyphenols, and comprises 13% proanthocyanidins. Transactivation results show that DPE acts as a co-agonist ligand for both mouse and human FXR, wherein it activates bile acid-bound FXR greater than that seen with bile acid alone. Additionally, DPE alone activated a peroxisome proliferator activated receptor alpha (PPARα) chimera in a dose-dependent manner. Consistent with DPE as a co-agonist ligand for FXR, studies in Caco-2 cells reveal that co-incubation with bile acid, dose-dependently enhances the expression of fibroblast growth factor 19 (FGF19), compared to treatment with bile acid alone. In contrast, DPE inhibited bile acid-induced expression of ileal bile acid binding protein (IBABP). Our results demonstrate that DPE acts as a potent co-agonist ligand for FXR, and that it differentially regulates FXR-target gene expression in vitro in human intestinal cells. This study provides novel insight into a potential mechanism by

  12. A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice.

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    Wang, Xiaoxin X; Luo, Yuhuan; Wang, Dong; Adorini, Luciano; Pruzanski, Mark; Dobrinskikh, Evgenia; Levi, Moshe

    2017-07-21

    Even in healthy individuals, renal function gradually declines during aging. However, an observed variation in the rate of this decline has raised the possibility of slowing or delaying age-related kidney disease. One of the most successful interventional measures that slows down and delays age-related kidney disease is caloric restriction. We undertook the present studies to search for potential factors that are regulated by caloric restriction and act as caloric restriction mimetics. Based on our prior studies with the bile acid-activated nuclear hormone receptor farnesoid X receptor (FXR) and G protein-coupled membrane receptor TGR5 that demonstrated beneficial effects of FXR and TGR5 activation in the kidney, we reasoned that FXR and TGR5 could be excellent candidates. We therefore determined the effects of aging and caloric restriction on the expression of FXR and TGR5 in the kidney. We found that FXR and TGR5 expression levels are decreased in the aging kidney and that caloric restriction prevents these age-related decreases. Interestingly, in long-lived Ames dwarf mice, renal FXR and TGR5 expression levels were also increased. A 2-month treatment of 22-month-old C57BL/6J mice with the FXR-TGR5 dual agonist INT-767 induced caloric restriction-like effects and reversed age-related increases in proteinuria, podocyte injury, fibronectin accumulation, TGF-β expression, and, most notably, age-related impairments in mitochondrial biogenesis and mitochondrial function. Furthermore, in podocytes cultured in serum obtained from old mice, INT-767 prevented the increases in the proinflammatory markers TNF-α, toll-like receptor 2 (TLR2), and TLR4. In summary, our results indicate that FXR and TGR5 may play an important role in modulation of age-related kidney disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. The FXR agonist 6ECDCA reduces hepatic steatosis and oxidative stress induced by ethanol and low-protein diet in mice.

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    Lívero, F A R; Stolf, Aline Maria; Dreifuss, Arturo Alejandro; Bastos-Pereira, Amanda Leite; Chicorski, Raphaella; de Oliveira, Liana Gomes; de Souza, Carlos Eduardo Alves; Fabossi, Isabella Aviles; Rabitto, I S; Gremski, Luiza Helena; Henneberg, Raílson; Telles, José Ederaldo Queiroz; Oude Elferink, Ronald P J; Acco, Alexandra

    2014-06-25

    Excessive ethanol consumption can lead to development of hepatic steatosis. Since the FXR receptor regulates adipose cell function and liver lipid metabolism, the aim of this work was to examine the effects of the FXR agonist 6ECDCA on alcoholic liver steatosis development and on oxidative stress induced by ethanol consumption. Swiss mice (n=24) received a low-protein diet (6%) and a liquid diet containing 10% ethanol or water for 6weeks. In the last 15days mice received oral treatment with 6ECDCA (3mgkg(-1)) or 1% tween (vehicle). The experimental groups (n=6) were: water+tween, water+6ECDCA, ethanol+tween and ethanol+6ECDCA. Moreover, as a diet control, we used a basal group (n=6), fed by a normal-proteic diet (23%) and water. After the treatment period, the animals were anesthetized for sample collection to perform plasma biochemistry assays, hepatic oxidative stress assays, hepatic cholesterol and triglycerides measurements, liver histology and hepatic gene expression. Ethanol associated with low-protein diet induced hepatic oxidative stress, increased plasma transaminases and induced hepatic lipid accumulation. Many of these parameters were reversed by the administration of 6ECDCA, including amelioration of lipid accumulation and lipoperoxidation, and reduction of reactive oxygen species. These effects were possibly mediated by regulation of Srebpf1 and FAS gene expression, both reduced by the FXR agonist. Our data demonstrated that 6ECDCA reverses the accumulation of lipids in the liver and decreases the oxidative stress induced by ethanol and low-protein diet. This FXR agonist is promising as a potential therapy for alcoholic liver steatosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid

    NARCIS (Netherlands)

    Ijssennagger, N.; Janssen, A.W.; Milona, A.; Ramos Pittol, J.M.; Hollman, D.A.; Mokry, M.; Betzel, B; Berends, F.J.; Janssen, IM; Mil, S.W. van; Kersten, S.

    2016-01-01

    BACKGROUND & AIMS: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies

  15. Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid

    NARCIS (Netherlands)

    IJssennagger, Noortje; Janssen, A.W.F.; Milona, Alexandra; Ramos Pittol, J.M.; Hollman, D.A.A.; Mokry, Michal; Betzel, Bark; Berends, F.J.; Janssen, I.M.; Mil, van S.W.C.; Kersten, Sander

    2016-01-01

    Background & Aims: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse

  16. Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid [human

    NARCIS (Netherlands)

    IJssennagger, Noortje; Janssen, Aafke; Mil, van Saskia; Kersten, Sander

    2016-01-01

    Background: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6α-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH)

  17. Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid [mouse

    NARCIS (Netherlands)

    IJssennagger, Noortje; Janssen, Aafke; Kersten, Sander; Mil, van S.W.C.

    2016-01-01

    Background: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6α-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH)

  18. Cardiopulmonary protective effects of the selective FXR agonist obeticholic acid in the rat model of monocrotaline-induced pulmonary hypertension.

    Science.gov (United States)

    Vignozzi, Linda; Morelli, Annamaria; Cellai, Ilaria; Filippi, Sandra; Comeglio, Paolo; Sarchielli, Erica; Maneschi, Elena; Vannelli, Gabriella Barbara; Adorini, Luciano; Maggi, Mario

    2017-01-01

    Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development and even induce fibrosis regression in liver, kidney and intestine in multiple disease models. OCA also inhibits liver fibrosis in nonalcoholic steatohepatitis patients. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the effects of OCA treatment (3, 10 or 30mg/kg, daily for 5days a week, for 7 and/or 28 days) on inflammation, tissue remodeling and fibrosis in the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) rat model. Treatment with OCA attenuated MCT-induced increased pulmonary arterial wall thickness and right ventricular hypertrophy, by i) blunting pathogenic inflammatory mechanisms (downregulation of interleukin 6, IL-6, and monocyte chemoattractant protein-1, MCP-1) and ii) enhancing protective mechanisms counteracting fibrosis and endothelial/mesenchymal transition. MCT-injected rats also showed a marked decrease of pulmonary artery responsiveness to both endothelium-dependent and independent relaxant stimuli, such as acetylcholine and a nitric oxide donor, sodium nitroprusside. Administration of OCA (30mg/kg) normalized this decreased responsiveness. Accordingly, OCA treatment induced profound beneficial effects on lung histology. In particular, both OCA doses markedly reduced the MCT-induced medial wall thickness increase in small pulmonary arteries. To evaluate the objective functional improvement by OCA treatment of MCT-induced PAH, we performed a treadmill test and measured duration of exercise. MCT significantly reduced, and OCA normalized treadmill endurance. Results with OCA were similar, or even superior, to those obtained with tadalafil, a well-established treatment of PAH. In conclusion, OCA treatment demonstrates cardiopulmonary protective effects, modulating lung vascular remodeling, reducing

  19. Farnesoid X receptor (FXR activation and FXR genetic variation in inflammatory bowel disease.

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    Rian M Nijmeijer

    Full Text Available BACKGROUND: We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD. METHODS: mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15 and ulcerative colitis (UC; n = 12, all in clinical remission, and healthy controls (n = 17. Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD and 1193 UC and in 853 healthy controls. RESULTS: mRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD. CONCLUSIONS: FXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients.

  20. Farnesoid X Receptor (FXR) from normal to malignant state.

    Science.gov (United States)

    Koutsounas, Ioannis; Giaginis, Constantinos; Theocharis, Stamatios

    2012-07-01

    The Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors, which plays crucial role in bile acid, cholesterol, lipid and glucose metabolism, as well as in the development of atherosclerosis, intestinal bacterial growth and liver regeneration. FXR is also involved in the pathogenesis of cholestatic diseases, non-alcoholic fatty liver disease and inflammatory bowel disease. Recent evidence further suggests a key role for FXR in apoptosis and cancer. Notably, FXR deficiency promoted intestinal inflammation and tumorigenesis, suggesting that FXR activation might be a promising strategy in the treatment of colon cancer. FXR deficiency in mice led to the development of spontaneous hepatocarcinomas, while FXR inhibition might represent a novel therapeutic approach in Barett's esophagus. In breast cancer cell lines, FXR agonists down-regulated the breast cancer target gene aromatase. FXR inhibited Leydig tumor growth and progression, supporting evidence that FXR may be an important regulator of androgen homoeostasis. Further studies are required in order to establish possible antitumor effects of this nuclear receptor. Either reactivating or inhibiting FXR expression may represent promising therapeutic strategies in the treatment of certain types of human cancer.

  1. An extract from date palm fruit (Phoenix dactylifera) acts as a co-agonist ligand for the nuclear receptor FXR and differentially modulates FXR target-gene expression in vitro

    OpenAIRE

    Alfaro-Viquez, Emilia; Roling, Brent F.; Krueger, Christian G.; Rainey, Charlene J.; Reed, Jess D.; Ricketts, Marie-Louise

    2018-01-01

    Date palm fruit (Phoenix dactylifera) consumption reduces serum triglyceride levels in human subjects. The objective of this study was to prepare an extract from dates and determine whether it acts as a ligand for the farnesoid x receptor (FXR), a nuclear receptor important for maintaining triglyceride and cholesterol homeostasis. Freeze-dried extracts were isolated from California-grown dates (Deglet Noor and Medjool) from the 2014 and 2015 harvests, by means of liquid extraction and solid p...

  2. Activation of the farnesoid-X receptor protects against gastrointestinal injury caused by non-steroidal anti-inflammatory drugs in mice.

    Science.gov (United States)

    Fiorucci, Stefano; Mencarelli, Andrea; Cipriani, Sabrina; Renga, Barbara; Palladino, Giuseppe; Santucci, Luca; Distrutti, Eleonora

    2011-12-01

    Low doses of acetyl salicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage. The farnesoid X receptor (FXR) is a bile acid sensor essential for maintenance of intestinal homeostasis. Here, we have investigated whether FXR is required for mucosal protection in models of gastrointestinal injury caused by ASA and NSAIDs and if FXR activation has potential in the treatment or prevention of gastrointestinal injury caused by these agents. FXR(+/+) and FXR(-/-) mice were given ASA (10 to 100 mg·kg(-1) ) or NSAIDs. Gastric and intestinal mucosal damage assessed by measuring lesion scores. FXR were activated by giving mice natural (chenodeoxycholic acid; CDCA) or synthetic (GW4064) FXR agonists. FXR, mRNA and protein, was detected in human and mouse stomach. FXR(-/-) mice were more prone to develop severe gastric and intestinal injury in response to ASA and NSAIDs and showed a severe reduction in the gastrointestinal expression of cystathionine-γ-lyase (CSE), an enzyme required for generation of hydrogen sulphide. CSE expression was reduced by ≈50% in wild-type mice challenged with ASA. Treating wild-type mice but not FXR(-/-) mice with CDCA or GW4064 protected against gastric injury caused by ASA and NSAIDs, by a CSE-dependent and cycloxygenase- and NO-independent, mechanism. FXR activation by GW4064 rescued mice from intestinal injury caused by naproxen. FXR was essential to maintain gastric and intestinal mucosal barriers. FXR agonists protected against gastric injury caused by ASA and NSAIDs by a CSE-mediated mechanism. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  3. Genome-wide binding and transcriptome analysis of human farnesoid X receptor in primary human hepatocytes.

    Directory of Open Access Journals (Sweden)

    Le Zhan

    Full Text Available Farnesoid X receptor (FXR, NR1H4 is a ligand-activated transcription factor, belonging to the nuclear receptor superfamily. FXR is highly expressed in the liver and is essential in regulating bile acid homeostasis. FXR deficiency is implicated in numerous liver diseases and mice with modulation of FXR have been used as animal models to study liver physiology and pathology. We have reported genome-wide binding of FXR in mice by chromatin immunoprecipitation - deep sequencing (ChIP-seq, with results indicating that FXR may be involved in regulating diverse pathways in liver. However, limited information exists for the functions of human FXR and the suitability of using murine models to study human FXR functions.In the current study, we performed ChIP-seq in primary human hepatocytes (PHHs treated with a synthetic FXR agonist, GW4064 or DMSO control. In parallel, RNA deep sequencing (RNA-seq and RNA microarray were performed for GW4064 or control treated PHHs and wild type mouse livers, respectively.ChIP-seq showed similar profiles of genome-wide FXR binding in humans and mice in terms of motif analysis and pathway prediction. However, RNA-seq and microarray showed more different transcriptome profiles between PHHs and mouse livers upon GW4064 treatment.In summary, we have established genome-wide human FXR binding and transcriptome profiles. These results will aid in determining the human FXR functions, as well as judging to what level the mouse models could be used to study human FXR functions.

  4. Anti-fibrotic effects of chronic treatment with the selective FXR agonist obeticholic acid in the bleomycin-induced rat model of pulmonary fibrosis.

    Science.gov (United States)

    Comeglio, Paolo; Filippi, Sandra; Sarchielli, Erica; Morelli, Annamaria; Cellai, Ilaria; Corcetto, Francesca; Corno, Chiara; Maneschi, Elena; Pini, Alessandro; Adorini, Luciano; Vannelli, Gabriella Barbara; Maggi, Mario; Vignozzi, Linda

    2017-04-01

    Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development in liver, kidney and intestine in multiple disease models. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the protective effects of OCA treatment (3 or 10mg/kg/day) on inflammation, tissue remodeling and fibrosis in the bleomycin-induced pulmonary fibrosis rat model. Effects of OCA treatment on morphological and molecular alterations of the lung, as well as remodeling of the alveoli and the right ventricle were also evaluated. Lung function was assessed by measuring airway resistance to inflation. In the acute phase (7days), bleomycin promoted an initial thickening and fibrosis of the lung interstitium, with upregulation of genes related to epithelial proliferation, tissue remodeling and hypoxia. At 28days, an evident increase in the deposition of collagen in the lungs was observed. This excessive deposition was accompanied by an upregulation of transcripts related to the extracellular matrix (TGFβ1, SNAI1 and SNAI2), indicating lung fibrosis. Administration of OCA protected against bleomycin-induced lung damage by suppressing molecular mechanisms related to epithelial-to-mesenchymal transition (EMT), inflammation and collagen deposition, with a dose-dependent reduction of proinflammatory cytokines such as IL-1β and IL-6, as well as TGF-β1 and SNAI1 expression. Pirfenidone, a recently approved treatment for idiopathic pulmonary fibrosis (IPF), significantly counteracted bleomycin-induced pro-fibrotic genes expression, but did not exert significant effects on IL-1β and IL-6. OCA treatment in bleomycin-challenged rats also improved pulmonary function, by effectively normalizing airway resistance to inflation and lung stiffness in vivo. Results with OCA were similar, or even superior, to those obtained with pirfenidone. In

  5. Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism

    Directory of Open Access Journals (Sweden)

    Jorge C. Correia

    2015-12-01

    Conclusions: Our results show that the main FXR variants in human liver (α1 and α2 reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and therapeutic efficacy of FXR agonists.

  6. Farnesoid-X Receptor (FXR) as a Promising Pharmaceutical Target in Atherosclerosis.

    Science.gov (United States)

    Moris, Demetrios; Giaginis, Constantinos; Tsourouflis, Gerasimos; Theocharis, Stamatios

    2017-05-31

    Atherosclerosis (AS) is a major cause of death and morbidity in Western world and is strongly connected with atherogenic lipoproteins and inflammation. Bile acids (BA) act as activating signals of endogenous ligands such as Farnesoid-X receptor (FXR). Primary data indicate a potential role of FXR in AS. The therapeutic value of FXR ligands in AS is unknown. With the present review, we analyzed the efficacy of FXR agonists as a therapeutic modalities against AS. In this aspect, we performed an electronic search through Pub- Med/MEDLINE database by using the key terms: FXR*, Farnesoid X receptor*, atherosclerosis*, bile acids* and agonism*. According to our analysis, the FXR seems to be a promising therapeutic target in the atherosclerosis natural history. FXR agonism could exert protective effects in the development and evolution of AS. However, concomitant side effects such as the reduction of plasma HDL have been reported. Finally, results from undergoing clinical trials with synthetic FXR agonists will shed more light to the precise role of FXR agonism in AS treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2

    Science.gov (United States)

    Rifai, Eko Aditya; van Dijk, Marc; Vermeulen, Nico P. E.; Geerke, Daan P.

    2018-01-01

    Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds. Using our recently introduced reliability estimation metrics, we could classify predictions with higher confidence by featuring an applicability domain (AD) analysis in combination with protein-ligand interaction profiling. The outcomes of and agreement between our AD and interaction-profile analyses to distinguish and rationalize the performance of our predictions highlighted the relevance of sufficiently exploring protein-ligand interactions during training and it demonstrated the possibility to quantitatively and efficiently evaluate if this is achieved by using simulation data only.

  8. Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2.

    Science.gov (United States)

    Rifai, Eko Aditya; van Dijk, Marc; Vermeulen, Nico P E; Geerke, Daan P

    2018-01-01

    Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds. Using our recently introduced reliability estimation metrics, we could classify predictions with higher confidence by featuring an applicability domain (AD) analysis in combination with protein-ligand interaction profiling. The outcomes of and agreement between our AD and interaction-profile analyses to distinguish and rationalize the performance of our predictions highlighted the relevance of sufficiently exploring protein-ligand interactions during training and it demonstrated the possibility to quantitatively and efficiently evaluate if this is achieved by using simulation data only.

  9. Two farnesoid X receptor alpha isoforms in Japanese medaka (Oryzias latipes) are differentially activated in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Howarth, Deanna L. [Integrated Toxicology and Environmental Health Program and Nicholas School of the Environment and Earth Sciences, Duke University, Durham, NC 27708 (United States); Hagey, Lee R. [Department of Medicine, University of California at San Diego, La Jolla, CA 92093 (United States); Law, Sheran H.W. [Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695 (United States); Ai, Ni [Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854 (United States); Krasowski, Matthew D. [Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA (United States); Ekins, Sean [Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854 (United States); Collaboration in Chemistry, Jenkintown, PA 19046 (United States); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201 (United States); Moore, John T. [GlaxoSmithKline Discovery Research, Research Triangle Park, NC 27709 (United States); Kollitz, Erin M. [Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695 (United States); Hinton, David E. [Integrated Toxicology and Environmental Health Program and Nicholas School of the Environment and Earth Sciences, Duke University, Durham, NC 27708 (United States); Kullman, Seth W., E-mail: swkullma@ncsu.edu [Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695 (United States)

    2010-07-01

    The nuclear receptor farnesoid X receptor alpha (FXR{alpha}, NR1H4) is activated by bile acids in multiple species including mouse, rat, and human and in this study we have identified two isoforms of Fxr{alpha} in Japanese medaka (Oryzias latipes), a small freshwater teleost. Both isoforms share a high amino acid sequence identity to mammalian FXR{alpha} ({approx}70% in the ligand-binding domain). Fxr{alpha}1 and Fxr{alpha}2 differ within the AF1 domain due to alternative splicing at the fourth intron-exon boundary. This process results in Fxr{alpha}1 having an extended N-terminus compared to Fxr{alpha}2. A Gal4DBD-Fxr{alpha}LBD fusion construct was activated by chenodeoxycholic, cholic, deoxycholic and lithocholic acids, and the synthetic agonist GW4064 in transient transactivation assays. Activation of the Gal4DBD-Fxr{alpha}LBD fusion construct was enhanced by addition of PGC-1{alpha}, as demonstrated through titration assays. Surprisingly, when the full-length versions of the two Fxr{alpha} isoforms were compared in transient transfection assays, Fxr{alpha}2 was activated by C{sub 24} bile acids and GW4064, while Fxr{alpha}1 was not significantly activated by any of the compounds tested. Since the only significant difference between the full-length constructs was sequence in the AF1 domain, these experiments highlight a key functional region in the Fxr{alpha} AF1 domain. Furthermore, mammalian two-hybrid studies demonstrated the ability of Fxr{alpha}2, but not Fxr{alpha}1, to interact with PGC-1{alpha} and SRC-1, and supported our results from the transient transfection reporter gene activation assays. These data demonstrate that both mammalian and teleost FXR (Fxr{alpha}2 isoform) are activated by primary and secondary bile acids.

  10. Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands.

    Science.gov (United States)

    Finamore, Claudia; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Carino, Adriana; Masullo, Dario; Biagioli, Michele; Marchianò, Silvia; Capolupo, Angela; Monti, Maria Chiara; Fiorucci, Stefano; Zampella, Angela

    2016-07-06

    Bile acids are signaling molecules interacting with nuclear receptors and membrane G-protein-coupled receptors. Among these receptors, the farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) have gained increasing consideration as druggable receptors and their exogenous dual regulation represents an attractive strategy in the treatment of enterohepatic and metabolic disorders. However, the therapeutic use of dual modulators could be associated to severe side effects and therefore the discovery of selective GPBAR1 and FXR agonists is an essential step in the medicinal chemistry optimization of bile acid scaffold. In this study, a new series of 6-ethylcholane derivatives modified on the tetracyclic core and on the side chain has been designed and synthesized and their in vitro activities on FXR and GPBAR1 were assayed. This speculation resulted in the identification of compound 7 as a potent and selective GPBAR1 agonist and of several derivatives showing potent dual agonistic activity.

  11. Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Chen, Bi; You, Wen-Jie; Xue, Shan; Qin, Hui; Zhao, Xu-Ji; Zhang, Miao; Liu, Xue-Qing; Zhu, Shu-Yang; Jiang, Han-Dong

    2016-11-01

    Epithelial-mesenchymal transition (EMT) and cyclooxygenase-2 (COX-2) contribute to airway remodelling and inflammation in chronic obstructive pulmonary disease (COPD). Recent data suggest that the farnesoid X receptor (FXR), a nuclear receptor traditionally considered as bile acid-activated receptor, is also expressed in non-classical bile acids target tissues with novel functions beyond regulating bile acid homeostasis. This study aimed to investigate the potential role of FXR in the development of COPD, as well as factors that affect FXR expression. Expression of FXR, EMT biomarkers and COX-2 was examined by immunohistochemistry in lung tissues from non-smokers, smokers, and smokers with COPD. The role of FXR in TGF-β1-induced EMT and COX-2 expression in human bronchial epithelial (HBE) cells was evaluated in vitro . Factors regulating FXR expression were assessed in cultured HBE cells and a cigarette smoke-induced rat model of COPD. Expression of FXR, EMT markers and COX-2 was significantly elevated in small airway epithelium of COPD patients compared with controls. The staining scores of FXR in small airway epithelium were negatively related with FEV 1 % of predicted of smokers without and with COPD. FXR agonist GW4064 remarkably enhanced and FXR antagonist Z-Guggulsterone significantly inhibited EMT changes in TGF-β1-treated HBE cells. Both chenodeoxycholic acid (CDCA) and GW4064 increased COX-2 expression in HBE cells, whereas Z-Guggulsterone dramatically restrained CDCA-induced COX-2 expression. Finally, FXR expression is induced by IL-4 and IL-13 in HBE cells, as well as by cigarette smoke exposure in a rat model of COPD. Overexpression of FXR in small airway may contribute to airway remodelling and inflammation in COPD by regulating EMT and COX-2 expression.

  12. Statins and transcriptional regulation: The FXR connection

    International Nuclear Information System (INIS)

    Habeos, Ioannis; Ziros, Panos G.; Psyrogiannis, Agathoklis; Vagenakis, Apostolos G.; Papavassiliou, Athanasios G.

    2005-01-01

    Farnesoid X receptor (FXR) is a nuclear receptor involved in lipoprotein as well as glucose metabolism. Statins are widely used hypolipidemic agents with many pleiotropic actions. It is known that statins affect other nuclear hormone receptors, but no reports are available on the effect of these drugs on FXR. Employing an animal model (Syrian hamsters), we hereby present evidence to demonstrate that Simvastatin, a broadly prescribed statin, decreases the expression of FXR at both the RNA and protein levels and down-regulates its DNA-binding activity. This novel property may have important implications on the mode statins influence on lipoprotein and carbohydrate homeostasis in the organism

  13. FXR-deficiency confers increased susceptibility to torpor

    NARCIS (Netherlands)

    Cariou, Bertrand; Bouchaert, Emmanuel; Abdelkarim, Mouaadh; Dumont, Julie; Caron, Sandrine; Fruchart, Jean-Charles; Burcelin, Remy; Kuipers, Folkert; Staels, Bart

    2007-01-01

    The role of the nuclear receptor FXR in adaptive thermogenesis was investigated using FXR-deficient mice. Despite elevated serum bile acid concentrations and increased mRNA expression profiles of thermogenic genes in brown adipose tissue, FXR-deficiency did not alter energy expenditure under basal

  14. An Intestinal Farnesoid X Receptor–Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice

    Science.gov (United States)

    Xie, Cen; Shi, Jingmin; Gao, Xiaoxia; Sun, Dongxue; Sun, Lulu; Wang, Ting; Takahashi, Shogo; Anitha, Mallappa; Krausz, Kristopher W.; Patterson, Andrew D.

    2017-01-01

    Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut microbiota–FXR signaling axis was reported to significantly impact glucose intolerance, but the precise molecular mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-β-muricholic acid, which selectively suppresses intestinal FXR signaling. Intestinal FXR inhibition decreased ceramide levels by suppressing expression of genes involved in ceramide synthesis specifically in the intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase (PC) activities and attenuated hepatic gluconeogenesis, independent of body weight change and hepatic insulin signaling in vivo; this was reversed by treatment of mice with ceramides or the FXR agonist GW4064. Ceramides substantially attenuated mitochondrial citrate synthase activities primarily through the induction of endoplasmic reticulum stress, which triggers increased hepatic mitochondrial acetyl-CoA levels and PC activities. These results reveal a mechanism by which the dietary supplement CAPE and intestinal FXR regulates hepatic gluconeogenesis and suggest that inhibiting intestinal FXR is a strategy for treating hyperglycemia. PMID:28223344

  15. Fatty liver diseases, bile acids, and FXR

    Directory of Open Access Journals (Sweden)

    Yan Zhu

    2016-09-01

    Full Text Available The prevalence of nonalcoholic fatty liver disease (NAFLD worldwide has increased at an alarming rate, which will likely result in enormous medical and economic burden. NAFLD presents as a spectrum of liver diseases ranging from simple steatosis, nonalcoholic steatohepatitis (NASH, fibrosis, cirrhosis, and even to hepatocellular carcinoma (HCC. A comprehensive understanding of the mechanism(s of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved. An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH. Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury. The bile acid homeostasis is critically regulated by the farnesoid X receptor (FXR that is activated by bile acids. FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport. Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver. Therefore, the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD.

  16. Activation of farnesoid X receptor increases the expression of cytokine inducible SH2-containing protein in HepG2 cells.

    Science.gov (United States)

    Xu, Zhizhen; Huang, Gang; Gong, Wei; Zhao, Yuanyin; Zhou, Peng; Zeng, Yijun; He, Fengtian

    2012-11-01

    Cytokine inducible SH2-containing protein (CISH), which negatively regulates cytokine signaling by inhibiting JAK2/STAT5 activity, is regarded as a therapeutic target for inflammatory diseases. Farnesoid X receptor (FXR), a ligand-activated transcription factor, has been proposed to play a protective function in the inflammatory responses. However, the role of FXR in modulation of CISH expression is unknown. In the present study, we for the first time identified that in human hepatoma cell line HepG2 the activation of FXR by the natural agonist chenodeoxycholic acid (CDCA) and the synthetic specific agonist GW4064 upregulated CISH at both transcriptional and translational levels, and inhibited interleukin (IL)6-induced STAT5 activation. Moreover, the in vivo experiment demonstrated that gavaging mice with CDCA increased CISH expression and reduced basal STAT5 phosphorylation in liver tissues. Reporter assay showed that FXR agonists enhanced the transcriptional activity of CISH promoter. These data suggest that FXR may serve as a novel molecular target for manipulating CISH expression in hepatocytes. FXR-mediated upregulation of CISH may play an important role in the homeostasis of cytokine signal networks and be beneficial to control cytokine-associated inflammatory diseases.

  17. Transient impairment of the adaptive response to fasting in FXR-deficient mice

    NARCIS (Netherlands)

    Cariou, B; van Harmelen, K; Duran-Sandoval, D; van Dijk, T; Grefhorst, A; Bouchaert, E; Fruchart, JC; Gonzalez, FJ; Kuipers, F; Staels, B

    2005-01-01

    The farnesoid X receptor (FXR) has been suggested to play a role in gluconeogenesis. To determine whether FXR modulates the response to fasting in vivo, FXR-deficient (FXR-/-) and wild-type mice were submitted to fasting for 48 h. Our results demonstrate that FXR modulates the kinetics of

  18. Farnesoid X receptor up-regulates expression of Lipid transfer inhibitor protein in liver cells and mice

    Energy Technology Data Exchange (ETDEWEB)

    Li, Liangpeng [Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Third Military Medical University, Chongqing 400038 (China); Liu, Hong [Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037 (China); Peng, Jiahe; Wang, Yongchao; Zhang, Yan; Dong, Jinyu; Liu, Xiaohua; Guo, Dongmei [Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Third Military Medical University, Chongqing 400038 (China); Jiang, Yu, E-mail: yujiang61@gmail.com [Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Third Military Medical University, Chongqing 400038 (China)

    2013-11-29

    Highlights: •FXR up-regulates apoF. •It binds to ER1 element. •It activates apoF gene promoter. -- Abstract: Apolipoprotein F is a component protein mainly secreted by liver and resides on several lipoprotein classes. It can inhibit lipids transfer between different lipoproteins. FXR is a member of the nuclear receptor superfamily which is also highly expressed in the liver. It modulates bile acids synthesis and lipids metabolism by transcriptional regulation. We aimed to determine whether apoF can be regulated by FXR. The FXR agonist Chenodeoxycholic acid (CDCA) and GW4064 both can activate the expression of apoF in liver cell lines and in C57/BL6 mouse liver. This is dependent on the binding of FXR to the FXR element ER1 (−2904 to −2892 bp) in the apoF gene promoter. Taken together, we have identified apoF as likely another target gene of FXR.

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

    Directory of Open Access Journals (Sweden)

    Eva Hambruch

    2016-06-01

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

  20. Structural Studies of the Tandem Tudor Domains of Fragile X Mental Retardation Related Proteins FXR1 and FXR2

    Energy Technology Data Exchange (ETDEWEB)

    Adams-Cioaba, Melanie A.; Guo, Yahong; Bian, ChuanBing; Amaya, Maria F.; Lam, Robert; Wasney, Gregory A.; Vedadi, Masoud; Xu, Chao; Min, Jinrong (Toronto)

    2011-11-23

    Expansion of the CGG trinucleotide repeat in the 5'-untranslated region of the FMR1, fragile X mental retardation 1, gene results in suppression of protein expression for this gene and is the underlying cause of Fragile X syndrome. In unaffected individuals, the FMRP protein, together with two additional paralogues (Fragile X Mental Retardation Syndrome-related Protein 1 and 2), associates with mRNA to form a ribonucleoprotein complex in the nucleus that is transported to dendrites and spines of neuronal cells. It is thought that the fragile X family of proteins contributes to the regulation of protein synthesis at sites where mRNAs are locally translated in response to stimuli. Here, we report the X-ray crystal structures of the non-canonical nuclear localization signals of the FXR1 and FXR2 autosomal paralogues of FMRP, which were determined at 2.50 and 1.92 {angstrom}, respectively. The nuclear localization signals of the FXR1 and FXR2 comprise tandem Tudor domain architectures, closely resembling that of UHRF1, which is proposed to bind methylated histone H3K9. The FMRP, FXR1 and FXR2 proteins comprise a small family of highly conserved proteins that appear to be important in translational regulation, particularly in neuronal cells. The crystal structures of the N-terminal tandem Tudor domains of FXR1 and FXR2 revealed a conserved architecture with that of FMRP. Biochemical analysis of the tandem Tudor doamins reveals their ability to preferentially recognize trimethylated peptides in a sequence-specific manner.

  1. DAX1 suppresses FXR transactivity as a novel co-repressor

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jin; Lu, Yan; Liu, Ruya; Xiong, Xuelian; Zhang, Zhijian; Zhang, Xianfeng [Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025 (China); Ning, Guang, E-mail: guangning@gmail.com.cn [Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025 (China); The Key Laboratory of Endocrine Tumors and The Division of Endocrine and Metabolic Diseases, E-Institute of Shanghai Universities, Shanghai 200025 (China); Li, Xiaoying, E-mail: lixy@sibs.ac.cn [Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025 (China); The Key Laboratory of Endocrine Tumors and The Division of Endocrine and Metabolic Diseases, E-Institute of Shanghai Universities, Shanghai 200025 (China)

    2011-09-09

    Highlights: {yields} DAX1 is co-localized with FXR and interacts with FXR. {yields} DAX1 acts as a negative regulator of FXR. {yields} Three LXXLL motifs in the N-terminus of DAX1 were required. {yields} DAX1 suppresses FXR transactivation by competing with co-activators. -- Abstract: Bile acid receptor FXR (farnesoid X receptor) is a key regulator of hepatic bile acid, glucose and lipid homeostasis through regulation of numerous genes involved in the process of bile acid, triglyceride and glucose metabolism. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains and acts primarily as a co-repressor of many nuclear receptors. Here, we demonstrated that DAX1 is co-localized with FXR in the nucleus and acted as a negative regulator of FXR through a physical interaction with FXR. Our study showed that over-expression of DAX1 down-regulated the expression of FXR target genes, whereas knockdown of DAX1 led to their up-regulation. Furthermore, three LXXLL motifs in the N-terminus of DAX1 were required for the full repression of FXR transactivation. In addition, our study characterized that DAX1 suppresses FXR transactivation via competing with co-activators such as SRC-1 and PGC-1{alpha}. In conclusion, DAX1 acts as a co-repressor to negatively modulate FXR transactivity.

  2. DAX1 suppresses FXR transactivity as a novel co-repressor

    International Nuclear Information System (INIS)

    Li, Jin; Lu, Yan; Liu, Ruya; Xiong, Xuelian; Zhang, Zhijian; Zhang, Xianfeng; Ning, Guang; Li, Xiaoying

    2011-01-01

    Highlights: → DAX1 is co-localized with FXR and interacts with FXR. → DAX1 acts as a negative regulator of FXR. → Three LXXLL motifs in the N-terminus of DAX1 were required. → DAX1 suppresses FXR transactivation by competing with co-activators. -- Abstract: Bile acid receptor FXR (farnesoid X receptor) is a key regulator of hepatic bile acid, glucose and lipid homeostasis through regulation of numerous genes involved in the process of bile acid, triglyceride and glucose metabolism. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains and acts primarily as a co-repressor of many nuclear receptors. Here, we demonstrated that DAX1 is co-localized with FXR in the nucleus and acted as a negative regulator of FXR through a physical interaction with FXR. Our study showed that over-expression of DAX1 down-regulated the expression of FXR target genes, whereas knockdown of DAX1 led to their up-regulation. Furthermore, three LXXLL motifs in the N-terminus of DAX1 were required for the full repression of FXR transactivation. In addition, our study characterized that DAX1 suppresses FXR transactivation via competing with co-activators such as SRC-1 and PGC-1α. In conclusion, DAX1 acts as a co-repressor to negatively modulate FXR transactivity.

  3. Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes.

    Directory of Open Access Journals (Sweden)

    Yunwon Moon

    Full Text Available This study evaluated HIF-1α inhibitors under different hypoxic conditions, physiological hypoxia (5% O2 and severe hypoxia (0.1% O2. We found that chenodeoxy cholic acid (CDCA reduced the amount of HIF-1α protein only under physiological hypoxia but not under severe hypoxia without decreasing its mRNA level. By using a proteasome inhibitor MG132 and a translation inhibitor cyclohexamide, we showed that CDCA reduced HIF-1α protein by decreasing its translation but not by enhancing its degradation. The following findings indicated that farnesoid X receptor (FXR, a CDCA receptor and its target gene, Small heterodimer partner (SHP are not involved in this effect of CDCA. Distinctly from CDCA, MG132 prevented SHP and an exogenous FXR agonist, GW4064 from reducing HIF-1α protein. Furthermore a FXR antagonist, guggulsterone failed to prevent CDCA from decreasing HIF-1α protein. Furthermore, guggulsterone by itself reduced HIF-1α protein even in the presence of MG132. These findings suggested that CDCA and guggulsterone reduced the translation of HIF-1α in a mechanism which FXR and SHP are not involved. This study reveals novel therapeutic functions of traditional nontoxic drugs, CDCA and guggulsterone, as inhibitors of HIF-1α protein.

  4. Agonist of farnesoid X receptor protects against bile acid induced damage and oxidative stress in mouse placenta--a study on maternal cholestasis model.

    Science.gov (United States)

    Wu, W B; Xu, Y Y; Cheng, W W; Wang, Y X; Liu, Y; Huang, D; Zhang, H J

    2015-05-01

    Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which is characterized by raised serum bile acid level and potential adverse fetal outcome. Farnesoid X receptor (FXR), also known as a bile acid receptor, was found to be expressed in placenta with low level. Whether activation of FXR by specific agonists could regulate the pathogenesis of ICP is still unclear. A model of maternal cholestasis was induced by administration of 17α-ethynylestradiol (E2) in pregnant mice for 6 days. We explored the regulatory effect of WAY-362450 (W450), a highly selective and potent FXR agonist on placenta. In this study, we demonstrated that administration of E2 increased bile acid levels in mouse serum, liver and amniotic fluid. Bile acid levels were significantly decreased after W450 treatment. W450 protected against the impairment of placentas induced by E2, including severe intracellular edema and apoptosis of trophoblasts. Moreover, W450 significantly induced the expressions of FXR target bile acid transport gene ATP-binding cassette, sub-family B (MDR/TAP), member 11 (Abcb11;Bsep) in placenta. W450 could also attenuate placental oxidative stress and increase the expressions of antioxidant enzymes Prdx1 and Prdx3. In conclusion, our data demonstrated that FXR agonist W450 modulated bile acid balance and protected against placental oxidative stress. Thus, our results support that potent FXR agonists might represent promising drugs for the treatment of ICP. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Molecular mechanism for the involvement of nuclear receptor FXR in HBV-associated hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Yong-dong Niu

    2011-08-01

    Full Text Available Farnesoid X receptor (FXR, also termed nuclear receptor NR1H4 is critically involved in the regulation of nascent bile formation and bile acid enterohepatic circulation. FXR and bile acids have been shown to play roles in liver regeneration and inflammatory responses. There is increasing evidence suggesting that FXR and the FXR signaling pathway are involved in the pathophysiology of a wide range of liver diseases, such as viral hepatitis, cirrhosis, and hepatocellular carcinoma (HCC. Here we discuss the latest discoveries of FXR functions with relevance to bile acid metabolism and HBV-associated HCC. More specifically, the goal of this review is to discuss the roles of FXR and bile acids in regulating HBV replication and how disregulation of the FXR-bile acid signaling pathway is involved in HBV-associated hepatocarcinogenesis.

  6. Impact of global Fxr deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis

    NARCIS (Netherlands)

    Nijmeijer, Rian M.; Schaap, Frank G.; Smits, Alexander J. J.; Kremer, Andreas E.; Akkermans, Louis M. A.; Kroese, Alfons B. A.; Rijkers, Ger T.; Schipper, Marguerite E. I.; Verheem, André; Wijmenga, Cisca; Gooszen, Hein G.; van Erpecum, Karel J.

    2014-01-01

    Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the

  7. Impact of Global Fxr Deficiency on Experimental Acute Pancreatitis and Genetic Variation in the FXR Locus in Human Acute Pancreatitis

    NARCIS (Netherlands)

    Nijmeijer, Rian M.; Schaap, Frank G.; Smits, Alexander J. J.; Kremer, Andreas E.; Akkermans, Louis M. A.; Kroese, Alfons B. A.; Rijkers, Ger. T.; Schipper, Marguerite E. I.; Verheem, Andre; Wijmenga, Cisca; Gooszen, Hein G.; van Erpecum, Karel J.

    2014-01-01

    Background: Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs

  8. Impact of Global Fxr Deficiency on Experimental Acute Pancreatitis and Genetic Variation in the FXR Locus in Human Acute Pancreatitis

    NARCIS (Netherlands)

    Nijmeijer, R.M.; Schaap, F.G.; Smits, A.J.A.; Kremer, A.E.; Akkermans, L.M.; Kroese, A.B.A.; Rijkers, G.T.; Schipper, M.E.; Verheem, A.; Wijmenga, C.; Gooszen, H.G.; Erpecum, K.J. van

    2014-01-01

    BACKGROUND: Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs

  9. Immunohistochemical Expression of FXR1 in Canine Normal Tissues and Melanomas.

    Science.gov (United States)

    Nordio, Laura; Marques, Andreia T; Lecchi, Cristina; Luciano, Alberto M; Stefanello, Damiano; Giudice, Chiara

    2018-04-01

    Fragile X mental retardation-related protein 1 (FXR1) is a cytoplasmic RNA-binding protein highly conserved among vertebrates. It has been studied for its role in muscle development, inflammation, and tumorigenesis, being related, for example, to metastasizing behavior in human and canine uveal melanoma. Anti-FXR1 antibodies have never been validated in the canine species. To investigate FXR1 expression in canine melanocytic tumors, the present study tested two commercially available polyclonal anti-human FXR1 antibodies, raised in goat and rabbit, respectively. The cross-reactivity of the anti-FXR1 antibodies was assessed by Western blot analysis, and the protein was localized by IHC in a set of normal canine tissues and in canine melanocytic tumors (10 uveal and 10 oral). Western blot results demonstrated that the antibody raised in rabbit specifically recognized the canine FXR1, while the antibody raised in goat did not cross-react with this canine protein. FXR1 protein was immunodetected using rabbit anti-FXR1 antibody, in canine normal tissues with different levels of intensity and distribution. It was also detected in 10/10 uveal and 9/10 oral melanocytic tumors. The present study validated for the first time the use of anti-FXR1 antibody in dogs and highlighted different FXR1 protein expression in canine melanocytic tumors, the significance of which is undergoing further investigations.

  10. FXR silencing in human colon cancer by DNA methylation and KRAS signaling.

    Science.gov (United States)

    Bailey, Ann M; Zhan, Le; Maru, Dipen; Shureiqi, Imad; Pickering, Curtis R; Kiriakova, Galina; Izzo, Julie; He, Nan; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Liang, Han; Kopetz, Scott; Powis, Garth; Guo, Grace L

    2014-01-01

    Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue (n = 238), polyps (n = 32), and adenocarcinomas, staged I-IV (n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ~12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

  11. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior

    Directory of Open Access Journals (Sweden)

    Fei eHuang

    2015-03-01

    Full Text Available Farnesoid X receptor (FXR is a nuclear hormone receptor involved in bile acid synthesis and homeostasis. Dysfunction of FXR is involved in cholestasis and atherosclerosis. FXR is prevalent in liver, gallbladder, and intestine, but it is not yet clear whether it modulates neurobehavior. In the current study, we tested the hypothesis that mouse FXR deficiency affects a specific subset of neurotransmitters and results in a unique behavioral phenotype. The FXR knockout mice showed less depressive-like and anxiety-related behavior, but increased motor activity. They had impaired memory and reduced motor coordination. There were changes of glutamatergic, GABAergic, serotoninergic and norepinephrinergic neurotransmission in either hippocampus or cerebellum. FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex. FXR deletion increased serum concentrations of many bile acids, including taurodehydrocholic acid, taurocholic acid, deoxycholic acid, glycocholic acid, tauro-α-muricholic acid, tauro-ω-muricholic acid, and hyodeoxycholic acid. There were also changes in brain concentrations of taurocholic acid, taurodehydrocholic acid, tauro-ω-muricholic acid, tauro-β-muricholic acid, deoxycholic acid, and lithocholic acid. Taken together, the results from studies with FXR knockout mice suggest that FXR contributes to the homeostasis of multiple neurotransmitter systems in different brain regions and modulates neurobehavior. The effect appears to be at least partially mediated by bile acids that are known to cross the blood-brain barrier inducing potential neurotoxicity.

  12. Development of cable fed flash X-ray (FXR) system

    Science.gov (United States)

    Menon, Rakhee; Mitra, S.; Patel, A. S.; Kumar, R.; Singh, G.; Senthil, K.; Kumar, Ranjeet; Kolge, T. S.; Roy, Amitava; Acharya, S.; Biswas, D.; Sharma, Archana

    2017-08-01

    Flash X-ray sources driven by pulsed power find applications in industrial radiography, and a portable X-ray source is ideal where the radiography needs to be taken at the test site. A compact and portable flash X-ray (FXR) system based on a Marx generator has been developed with the high voltage fed to the FXR tube via a cable feed-through arrangement. Hard bremsstrahlung X-rays of few tens of nanosecond duration are generated by impinging intense electron beams on an anode target of high Z material. An industrial X-ray source is developed with source size as low as 1 mm. The system can be operated from 150 kV to 450 kV peak voltages and a dose of 10 mR has been measured at 1 m distance from the source window. The modeling of the FXR source has been carried out using particle-in-cell and Monte Carlo simulations for the electron beam dynamics and X-ray generation, respectively. The angular dose profile of X-ray has been measured and compared with the simulation.

  13. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

    Directory of Open Access Journals (Sweden)

    Mikael Bjursell

    Full Text Available Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1, the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

  14. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

    Science.gov (United States)

    Bjursell, Mikael; Wedin, Marianne; Admyre, Therése; Hermansson, Majlis; Böttcher, Gerhard; Göransson, Melker; Lindén, Daniel; Bamberg, Krister; Oscarsson, Jan; Bohlooly-Y, Mohammad

    2013-01-01

    Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH) and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

  15. Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists.

    Science.gov (United States)

    Zhang, Guoning; Liu, Shuainan; Tan, Wenjuan; Verma, Ruchi; Chen, Yuan; Sun, Deyang; Huan, Yi; Jiang, Qian; Wang, Xing; Wang, Na; Xu, Yang; Wong, Chiwai; Shen, Zhufang; Deng, Ruitang; Liu, Jinsong; Zhang, Yanqiao; Fang, Weishuo

    2017-03-31

    Farnesoid X receptor (FXR), a nuclear receptor mainly distributed in liver and intestine, has been regarded as a potential target for the treatment of various metabolic diseases, cancer and infectious diseases related to liver. Starting from two previously identified chalcone-based FXR antagonists, we tried to increase the activity through the design and synthesis of a library containing chalcones, flavones and chromenes, based on substitution manipulation and conformation (ring closure) restriction strategy. Many chalcones and four chromenes were identified as microM potent FXR antagonists, among which chromene 11c significantly decreased the plasma and hepatic triglyceride level in KKay mice. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery

    Directory of Open Access Journals (Sweden)

    Olivier F. Noel

    2016-01-01

    Full Text Available Overweight and obesity represent major risk factors for diabetes and related metabolic diseases. Obesity is associated with a chronic and progressive inflammatory response leading to the development of insulin resistance and type 2 diabetes (T2D mellitus, although the precise mechanism mediating this inflammatory process remains poorly understood. The most effective intervention for the treatment of obesity, bariatric surgery, leads to glucose normalization and remission of T2D. Recent work in both clinical studies and animal models supports bile acids (BAs as key mediators of these effects. BAs are involved in lipid and glucose homeostasis primarily via the farnesoid X receptor (FXR transcription factor. BAs are also involved in regulating genes involved in inflammation, obesity, and lipid metabolism. Here, we review the novel role of BAs in bariatric surgery and the intersection between BAs and immune, obesity, weight loss, and lipid metabolism genes.

  17. Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance.

    Science.gov (United States)

    Preidis, Geoffrey A; Kim, Kang Ho; Moore, David D

    2017-04-03

    The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.

  18. FXR blocks the growth of liver cancer cells through inhibiting mTOR-s6K pathway

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Xiongfei, E-mail: xiongfeihuang@hotmail.com [Department of Pathology and Institute of Oncology, Preclinical School, Fujian Medical University, Fuzhou 350108, Fujian (China); Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350108, Fujian (China); Zeng, Yeting [Department of Pathology and Institute of Oncology, Preclinical School, Fujian Medical University, Fuzhou 350108, Fujian (China); Wang, Xinrui [Department of Biochemistry and Molecular Biology, Fujian Medical University, Fuzhou 350108, Fujian (China); Ma, Xiaoxiao [Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, CA 91010 (United States); Li, Qianqian; Li, Ningbo; Su, Hongying [Department of Pathology and Institute of Oncology, Preclinical School, Fujian Medical University, Fuzhou 350108, Fujian (China); Huang, Wendong [Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, CA 91010 (United States)

    2016-05-27

    The nuclear receptor Farnesoid X Receptor (FXR) is likely a tumor suppressor in liver tissue but its molecular mechanism of suppression is not well understood. In this study, the gene expression profile of human liver cancer cells was investigated by microarray. Bioinformatics analysis of these data revealed that FXR might regulate the mTOR/S6K signaling pathway. This was confirmed by altering the expression level of FXR in liver cancer cells. Overexpression of FXR prevented the growth of cells and induced cell cycle arrest, which was enhanced by the mTOR/S6K inhibitor rapamycin. FXR upregulation also intensified the inhibition of cell growth by rapamycin. Downregulation of FXR produced the opposite effect. Finally, we found that ectopic expression of FXR in SK-Hep-1 xenografts inhibits tumor growth and reduces expression of the phosphorylated protein S6K. Taken together, our data provide the first evidence that FXR suppresses proliferation of human liver cancer cells via the inhibition of the mTOR/S6K signaling pathway. FXR expression can be used as a biomarker of personalized mTOR inhibitor treatment assessment for liver cancer patients. -- Highlights: •FXR inhibits the proliferation of liver cancer cells by prolonging G0/G1 phase. •Microarray results indicate that mTOR-S6k signaling is involved in cellular processes in which FXR plays an important role. •FXR blocks the growth of liver cancer cells via the inhibition of the mTOR/S6K signaling pathway in vitro and in vivo.

  19. The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.

    Directory of Open Access Journals (Sweden)

    Barbara Renga

    Full Text Available BACKGROUND: Toll like receptors (TLRs sense the intestinal microbiota and regulate the innate immune response. A dysregulation of TLRs function participates into intestinal inflammation. Farnesoid X Receptor (FXR is a nuclear receptor and bile acid sensor highly expressed in entero-hepatic tissues. FXR regulates lipid metabolism and innate immunity. METHODOLOGY/PRINCIPAL FINDINGS: In this study we have investigated whether FXR gene expression/function in the intestine is modulated by TLRs. We found that in human monocytes activation of membrane TLRs (i.e. TLR2, 4, 5 and 6 downregulates, while activation of intracellular TLRs (i.e. TLR3, 7, 8 and 9 upregulates the expression of FXR and its target gene SHP, small heterodimer partner. This effect was TLR9-dependent and TNFα independent. Intestinal inflammation induced in mice by TNBS downregulates the intestinal expression of FXR in a TLR9-dependent manner. Protection against TNBS colitis by CpG, a TLR-9 ligand, was lost in FXR(-/- mice. In contrast, activation of FXR rescued TLR9(-/- and MyD88(-/- mice from colitis. A putative IRF7 response element was detected in the FXR promoter and its functional characterization revealed that IRF7 is recruited on the FXR promoter under TLR9 stimulation. CONCLUSIONS/SIGNIFICANCE: Intestinal expression of FXR is selectively modulated by TLR9. In addition to its role in regulating type-I interferons and innate antiviral immunity, IRF-7 a TLR9-dependent factor, regulates the expression of FXR, linking microbiota-sensing receptors to host's immune and metabolic signaling.

  20. Splenic dendritic cell involvement in FXR-mediated amelioration of DSS colitis

    NARCIS (Netherlands)

    Massafra, Vittoria; Ijssennagger, Noortje; Plantinga, Maud; Milona, Alexandra; Ramos Pittol, José M.; Boes, Marianne; van Mil, Saskia W C

    2016-01-01

    Inflammatory Bowel Disease (IBD) is a multifactorial disorder involving dysregulation of the immune response and bacterial translocation through the intestinal mucosal barrier. Previously, we have shown that activation of the bile acid sensor Farnesoid X Receptor (FXR), which belongs to the family

  1. FXR-Gankyrin axis is involved in development of pediatric liver cancer.

    Science.gov (United States)

    Valanejad, Leila; Lewis, Kyle; Wright, Mary; Jiang, Yanjun; D'Souza, Amber; Karns, Rebekah; Sheridan, Rachel; Gupta, Anita; Bove, Kevin; Witte, David; Geller, James; Tiao, Gregory; Nelson, David L; Timchenko, Lubov; Timchenko, Nikolai

    2017-07-01

    The development of hepatoblastoma (HBL) is associated with failure of hepatic stem cells (HSC) to differentiate into hepatocytes. Despite intensive investigations, mechanisms of the failure of HSC to differentiate are not known. We found that oncogene Gankyrin (Gank) is involved in the inhibition of differentiation of HSC via triggering degradation of tumor suppressor proteins (TSPs) Rb, p53, C/EBPα and HNF4α. Our data show that the activation of a repressor of Gank, farnesoid X receptor, FXR, after initiation of liver cancer by Diethylnitrosamine (DEN) prevents the development of liver cancer by inhibiting Gank and rescuing tumor suppressor proteins. We next analyzed FXR-Gank-Tumor suppressor pathways in a large cohort of HBL patients which include 6 controls and 53 HBL samples. Systemic analysis of these samples and RNA-Seq approach revealed that the FXR-Gank axis is activated; markers of hepatic stem cells are dramatically elevated and hepatocyte markers are reduced in HBL samples. In the course of these studies, we found that RNA binding protein CUGBP1 is a new tumor suppressor protein which is reduced in all HBL samples. Therefore, we generated CUGBP1 KO mice and examined HBL signatures in the liver of these mice. Micro-array studies revealed that the HBL-specific molecular signature is developed in livers of CUGBP1 KO mice at very early ages. Thus, we conclude that FXR-Gank-TSPs-Stem cells pathway is a key determinant of liver cancer in animal models and in pediatric liver cancer. Our data provide a strong basis for development of FXR-Gank-based therapy for treatment of patients with hepatoblastoma. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Validation of anti-FXR1 antibodies in the canine species and application to an immunohistochemical study of canine oral melanomas

    Directory of Open Access Journals (Sweden)

    Laura Nordio

    2017-05-01

    Full Text Available FXR1 (Fragile X mental retardation-related protein 1 is a cytoplasmic RNA binding protein, which genetic expression has been related to metastatic potential in human melanoma. The aims of the present study were: the validation of two commercially available clones of polyclonal anti-human FXR1 antibody in dogs; their application to investigate FXR1 expression in a group of canine oral melanomas. Anti-FXR1 antibody was not previously validated in the canine species. Two different commercially available polyclonal anti-FXR1 antibodies (respectively made in goat and in rabbit were used. FXR1 protein in canine serum was identified by western blot after SDS-PAGE, using human serum as control. FXR1 immunohistochemical expression was tested in a series of normal tissues, that are expected to express FXR1, and in 31 cases of oral melanomas. The final immunohistochemical protocol used heat-induced unmasking and overnight incubation. FXR1 protein bands in canine serum were detected by tested antibodies, in a more specific way by the rabbit antibody. FXR1 immunohistochemical staining was positive in all tested organs, with different levels of expression. FXR1 was also expressed in 31/31 tested melanomas, with variable intensity and percentage of positive cells (Figure 1. Equal results were achieved with the two antibodies in 8 cases of melanoma, whereas there were variable differences in 22, and one case stained only with goat antibody. The rabbit antibody gave less background staining. This study validated anti-FXR1 antibodies for use in the canine species. This protein was expressed in various normal tissues, as well as in the tested neoplasms. Significance of different level of expression is undergoing evaluation with further studies.

  3. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

    Science.gov (United States)

    Gomez-Ospina, Natalia; Potter, Carol J.; Xiao, Rui; Manickam, Kandamurugu; Kim, Mi-Sun; Kim, Kang Ho; Shneider, Benjamin L.; Picarsic, Jennifer L.; Jacobson, Theodora A.; Zhang, Jing; He, Weimin; Liu, Pengfei; Knisely, A. S.; Finegold, Milton J.; Muzny, Donna M.; Boerwinkle, Eric; Lupski, James R.; Plon, Sharon E.; Gibbs, Richard A.; Eng, Christine M.; Yang, Yaping; Washington, Gabriel C.; Porteus, Matthew H.; Berquist, William E.; Kambham, Neeraja; Singh, Ravinder J.; Xia, Fan; Enns, Gregory M.; Moore, David D.

    2016-01-01

    Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection. PMID:26888176

  4. Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands

    OpenAIRE

    Claudia Finamore; Carmen Festa; Barbara Renga; Valentina Sepe; Adriana Carino; Dario Masullo; Michele Biagioli; Silvia Marchianò; Angela Capolupo; Maria Chiara Monti; Stefano Fiorucci; Angela Zampella

    2016-01-01

    Bile acids are signaling molecules interacting with nuclear receptors and membrane G-protein-coupled receptors. Among these receptors, the farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) have gained increasing consideration as druggable receptors and their exogenous dual regulation represents an attractive strategy in the treatment of enterohepatic and metabolic disorders. However, the therapeutic use of dual modulators could be associated to severe side effects and th...

  5. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach

    Science.gov (United States)

    Lu, Weiqiang; Cheng, Feixiong; Jiang, Jing; Zhang, Chen; Deng, Xiaokang; Xu, Zhongyu; Zou, Shien; Shen, Xu; Tang, Yun; Huang, Jin

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are worldwide used drugs for analgesic, antipyretic, and anti-inflammatory therapeutics. However, NSAIDs often cause several serious liver injuries, such as drug-induced liver injury (DILI), and the molecular mechanisms of DILI have not been clearly elucidated. In this study, we developed a systems pharmacology approach to explore the mechanism-of-action of NSAIDs. We found that the Farnesoid X Receptor (FXR) antagonism of NSAIDs is a potential molecular mechanism of DILI through systematic network analysis and in vitro assays. Specially, the quantitative real-time PCR assay reveals that indomethacin and ibuprofen regulate FXR downstream target gene expression in HepG2 cells. Furthermore, the western blot shows that FXR antagonism by indomethacin induces the phosphorylation of STAT3 (signal transducer and activator of transcription 3), promotes the activation of caspase9, and finally causes DILI. In summary, our systems pharmacology approach provided novel insights into molecular mechanisms of DILI for NSAIDs, which may propel the ways toward the design of novel anti-inflammatory pharmacotherapeutics. PMID:25631039

  6. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach.

    Science.gov (United States)

    Lu, Weiqiang; Cheng, Feixiong; Jiang, Jing; Zhang, Chen; Deng, Xiaokang; Xu, Zhongyu; Zou, Shien; Shen, Xu; Tang, Yun; Huang, Jin

    2015-01-29

    Non-steroidal anti-inflammatory drugs (NSAIDs) are worldwide used drugs for analgesic, antipyretic, and anti-inflammatory therapeutics. However, NSAIDs often cause several serious liver injuries, such as drug-induced liver injury (DILI), and the molecular mechanisms of DILI have not been clearly elucidated. In this study, we developed a systems pharmacology approach to explore the mechanism-of-action of NSAIDs. We found that the Farnesoid X Receptor (FXR) antagonism of NSAIDs is a potential molecular mechanism of DILI through systematic network analysis and in vitro assays. Specially, the quantitative real-time PCR assay reveals that indomethacin and ibuprofen regulate FXR downstream target gene expression in HepG2 cells. Furthermore, the western blot shows that FXR antagonism by indomethacin induces the phosphorylation of STAT3 (signal transducer and activator of transcription 3), promotes the activation of caspase9, and finally causes DILI. In summary, our systems pharmacology approach provided novel insights into molecular mechanisms of DILI for NSAIDs, which may propel the ways toward the design of novel anti-inflammatory pharmacotherapeutics.

  7. O-GlcNAcylation links ChREBP and FXR to glucose-sensing

    Directory of Open Access Journals (Sweden)

    Fadila eBenhamed

    2015-01-01

    Full Text Available Accumulating evidence suggests that O-GlcNAc transferase (OGT, an enzyme responsible for O-GlcNAc post-translational modification acts as a nutrient sensor that links glucose and the hexosamine biosynthetic pathway to the regulation of transcriptional factors involved in energy homeostasis. In liver, glucose signaling is mediated by ChREBP (carbohydrate response element binding protein which stimulates glycolytic and lipogenic gene expression through its binding on a specific ChoRE DNA sequence. Modulation of ChREBP by O-GlcNAcylation increases its DNA binding affinity and its activity. ChREBP transcriptional activity also depends on the presence of several other co-factors and transcriptional factors. Among them, the nuclear Farnesoid X Receptor (FXR, a key transcription factor of bile acid metabolism involved in the gut-liver axis homeostasis was recently shown to directly interact with ChREBP, acting as a repressor on the ChoRE of glycolytic genes. Interestingly, similarly to ChREBP, FXR is O-GlcNAcylated in response to glucose. This review discusses the importance of ChREBP and FXR modification through O-GlcNAcylation in liver and how glucose can modify their mutual affinity and transcriptional activity.

  8. RNA-Binding Protein FXR1 Regulates p21 and TERC RNA to Bypass p53-Mediated Cellular Senescence in OSCC.

    Directory of Open Access Journals (Sweden)

    Mrinmoyee Majumder

    2016-09-01

    Full Text Available RNA-binding proteins (RBP regulate numerous aspects of co- and post-transcriptional gene expression in cancer cells. Here, we demonstrate that RBP, fragile X-related protein 1 (FXR1, plays an essential role in cellular senescence by utilizing mRNA turnover pathway. We report that overexpressed FXR1 in head and neck squamous cell carcinoma targets (G-quadruplex (G4 RNA structure within both mRNA encoding p21 (Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A, Cip1 and the non-coding RNA Telomerase RNA Component (TERC, and regulates their turnover to avoid senescence. Silencing of FXR1 in cancer cells triggers the activation of Cyclin-Dependent Kinase Inhibitors, p53, increases DNA damage, and ultimately, cellular senescence. Overexpressed FXR1 binds and destabilizes p21 mRNA, subsequently reduces p21 protein expression in oral cancer cells. In addition, FXR1 also binds and stabilizes TERC RNA and suppresses the cellular senescence possibly through telomerase activity. Finally, we report that FXR1-regulated senescence is irreversible and FXR1-depleted cells fail to form colonies to re-enter cellular proliferation. Collectively, FXR1 displays a novel mechanism of controlling the expression of p21 through p53-dependent manner to bypass cellular senescence in oral cancer cells.

  9. Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei

    Directory of Open Access Journals (Sweden)

    Stefano Fiorucci

    2012-11-01

    Full Text Available Using theonellasterol as a novel FXR antagonist hit, we prepared a series of semi-synthetic derivatives in order to gain insight into the structural requirements for exhibiting antagonistic activity. These derivatives are characterized by modification at the exocyclic carbon-carbon double bond at C-4 and at the hydroxyl group at C-3 and were prepared from theonellasterol using simple reactions. Pharmacological investigation showed that the introduction of a hydroxyl group at C-4 as well as the oxidation at C-3 with or without concomitant modification at the exomethylene functionality preserve the ability of theonellasterol to inhibit FXR transactivation caused by CDCA. Docking analysis showed that the placement of these molecules in the FXR-LBD is well stabilized when on ring A functional groups, able to form hydrogen bonds and π interactions, are present.

  10. FXR is a molecular target for the effects of vertical sleeve gastrectomy

    DEFF Research Database (Denmark)

    Ryan, Karen K; Tremaroli, Valentina; Clemmensen, Christoffer

    2014-01-01

    Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing......-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG...... molecular underpinning for the beneficial effects of this weight-loss surgery....

  11. Design and performance of the 1.5 MV injector for FXR

    International Nuclear Information System (INIS)

    Kulke, B.; Ravenscroft, D.S.; Vogtlin, G.E.

    1981-01-01

    The new flash x-ray machine (FXR) at LLNL is scheduled for completion in late 1981. This is a 54 module, linear induction accelerator, designed to deliver 500 Roentgen at 1 m as bremsstrahlung from a 20 MeV, 4 kA, 60 ns pulsed electron beam. The 1.5 MV, cold cathode injector makes use of six accelerator modules as voltage sources. High voltage testing of the accelerator modules and their associated pulse forming lines and Marx banks has been completed, and beam tests of the complete injector assembly are in progress. Design information and preliminary test results are presented

  12. Waltonitone inhibits proliferation of hepatoma cells and tumorigenesis via FXR-miR-22-CCNA2 signaling pathway.

    Science.gov (United States)

    Yang, Fan; Gong, Junting; Wang, Guangyun; Chen, Peng; Yang, Li; Wang, Zhengtao

    2016-11-15

    Waltonitone (WA), an ursane-type pentacyclic triterpene extracted from Gentiana waltonii Burkill, was recently appeared to exert anti-tumor effect. However, the biological underpinnings underlying the role of WA in hepatocellular carcinoma (HCC) cells have not been completely elucidated. Our previous report indicated that the FXR-regulated miR-22-CCNA2 pathway contributed to the progression and development of HCC. Besides, a wide spectrum of microRNAs (miRNAs) could be up- or down-regulated upon WA treatment, including miR-22. Hence, we aimed to determine whether WA inhibited HCC cell proliferation via the FXR-miR-22-CCNA2 axis. In this study, we observed a significant downregulation of FXR and miR-22, along with upregulation of CCNA2 in 80 paired tumors relative to adjacent normal tissues of HCC subjects, which were obtained from the available GEO database in NCBI (GSE22058). Furthermore, we validated the expression patterns of these three targets in another set of HCC samples and found the highly correlation within each other. Additionally, our data demonstrated that WA induced miR-22 and repressed CCNA2 in HCC cells, which contributed to the cell proliferation arrest. In addition, evidence suggested that either miR-22 silencing or FXR knockdown reversed the diminished CCNA2 expression as well as cell proliferation inhibition caused by WA treatment and WA inhibited tumor masses in vivo in a subcutaneous xenograft mouse model of HCC. Overall, our data indicated that WA inhibited HCC cell proliferation and tumorigenesis through miR-22-regulated CCNA2 repression, which was at least partially through FXR modulation.

  13. Glutamate receptor agonists

    DEFF Research Database (Denmark)

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

    2011-01-01

    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...

  14. Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms

    Directory of Open Access Journals (Sweden)

    Weixiang Guo

    2015-06-01

    Full Text Available Fragile X mental retardation protein (FMRP and its autosomal paralog FXR2P are selective neuronal RNA-binding proteins, and mice that lack either protein exhibit cognitive deficits. Although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. In the present study, we discovered that FXR2P (also known as FXR2 is important for neuronal dendritic development. FMRP and FXR2P additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GluA1, but they do so via distinct mechanisms: FXR2P binds and stabilizes GluA1 mRNA and enhances subsequent protein expression, whereas FMRP promotes GluA1 membrane delivery. Our findings unveil important roles for FXR2P and GluA1 in neuronal development, uncover a regulatory mechanism of GluA1, and reveal a functional convergence between fragile X proteins in neuronal development.

  15. 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...

  16. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.

    Science.gov (United States)

    Sayin, Sama I; Wahlström, Annika; Felin, Jenny; Jäntti, Sirkku; Marschall, Hanns-Ulrich; Bamberg, Krister; Angelin, Bo; Hyötyläinen, Tuulia; Orešič, Matej; Bäckhed, Fredrik

    2013-02-05

    Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Waltonitone inhibits proliferation of hepatoma cells and tumorigenesis via FXR-miR-22-CCNA2 signaling pathway

    OpenAIRE

    Yang, Fan; Gong, Junting; Wang, Guangyun; Chen, Peng; Yang, Li; Wang, Zhengtao

    2016-01-01

    Waltonitone (WA), an ursane-type pentacyclic triterpene extracted from Gentiana waltonii Burkill, was recently appeared to exert anti-tumor effect. However, the biological underpinnings underlying the role of WA in hepatocellular carcinoma (HCC) cells have not been completely elucidated. Our previous report indicated that the FXR-regulated miR-22-CCNA2 pathway contributed to the progression and development of HCC. Besides, a wide spectrum of microRNAs (miRNAs) could be up- or down-regulated u...

  18. A novel role for the RNA-binding protein FXR1P in myoblasts cell-cycle progression by modulating p21/Cdkn1a/Cip1/Waf1 mRNA stability.

    Directory of Open Access Journals (Sweden)

    Laetitia Davidovic

    2013-03-01

    Full Text Available The Fragile X-Related 1 gene (FXR1 is a paralog of the Fragile X Mental Retardation 1 gene (FMR1, whose absence causes the Fragile X syndrome, the most common form of inherited intellectual disability. FXR1P plays an important role in normal muscle development, and its absence causes muscular abnormalities in mice, frog, and zebrafish. Seven alternatively spliced FXR1 transcripts have been identified and two of them are skeletal muscle-specific. A reduction of these isoforms is found in myoblasts from Facio-Scapulo Humeral Dystrophy (FSHD patients. FXR1P is an RNA-binding protein involved in translational control; however, so far, no mRNA target of FXR1P has been linked to the drastic muscular phenotypes caused by its absence. In this study, gene expression profiling of C2C12 myoblasts reveals that transcripts involved in cell cycle and muscular development pathways are modulated by Fxr1-depletion. We observed an increase of p21--a regulator of cell-cycle progression--in Fxr1-knocked-down mouse C2C12 and FSHD human myoblasts. Rescue of this molecular phenotype is possible by re-expressing human FXR1P in Fxr1-depleted C2C12 cells. FXR1P muscle-specific isoforms bind p21 mRNA via direct interaction with a conserved G-quadruplex located in its 3' untranslated region. The FXR1P/G-quadruplex complex reduces the half-life of p21 mRNA. In the absence of FXR1P, the upregulation of p21 mRNA determines the elevated level of its protein product that affects cell-cycle progression inducing a premature cell-cycle exit and generating a pool of cells blocked at G0. Our study describes a novel role of FXR1P that has crucial implications for the understanding of its role during myogenesis and muscle development, since we show here that in its absence a reduced number of myoblasts will be available for muscle formation/regeneration, shedding new light into the pathophysiology of FSHD.

  19. Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells.

    Science.gov (United States)

    Selmin, Ornella I; Fang, Changming; Lyon, Adam M; Doetschman, Tom C; Thompson, Patricia A; Martinez, Jesse D; Smith, Jeffrey W; Lance, Peter M; Romagnolo, Donato F

    2016-02-01

    The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention. We investigated how APC inactivation influences the regulation of FXR expression in colonic mucosal cells. We hypothesized that APC inactivation would epigenetically repress nuclear receptor subfamily 1, group H, member 4 (FXR gene name) expression through increased CpG methylation. Normal proximal colonic mucosa and normal-appearing adjacent colonic mucosa and colon tumors were collected from wild-type C57BL/6J and Apc-deficient (Apc(Min) (/+)) male mice, respectively. The expression of Fxr, ileal bile acid-binding protein (Ibabp), small heterodimer partner (Shp), and cyclooxygenase-2 (Cox-2) were determined by real-time polymerase chain reaction. In both normal and adjacent colonic mucosa and colon tumors, we measured CpG methylation of Fxr in bisulfonated genomic DNA. In vitro, we measured the impact of APC inactivation and deoxycholic acid (DCA) treatment on FXR expression in human colon cancer HCT-116 cells transfected with silencing RNA for APC and HT-29 cells carrying inactivated APC. In Apc(Min) (/+) mice, constitutive CpG methylation of the Fxrα3/4 promoter was linked to reduced (60-90%) baseline Fxr, Ibabp, and Shp and increased Cox-2 expression in apparently normal adjacent mucosa and colon tumors. Apc knockdown in HCT-116 cells increased cellular myelocytomatosis (c-MYC) and lowered (∼50%) FXR expression, which was further reduced (∼80%) by DCA. In human HCT-116 but not HT-29 colon cancer cells, DCA induced FXR expression and lowered CpG methylation of FXR. We conclude that the loss of APC function favors the silencing of FXR expression through CpG hypermethylation in mouse colonic mucosa and human colon cells

  20. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Qiang; Chen, Xin-li; Wang, Chang-yuan; Liu, Qi; Sun, Hui-jun; Sun, Peng-yuan; Huo, Xiao-kui; Liu, Zhi-hao; Yao, Ji-hong; Liu, Ke-xin, E-mail: kexinliu@dlmedu.edu.cn

    2015-03-15

    Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes. - Highlights: • AB23A has at least three roles in protection against ANIT-induced liver injury. • AB23A decreases Ntcp, and increases Bsep, Mrp2 and Mdr2 expression. • AB23A represses Cyp7a1 and Cyp8b1 through inducing Shp and Fgf15 expression. • AB23A increases bile acid metabolism through inducing Sult2a1 expression. • FXR activation is involved

  1. 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

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

    International Nuclear Information System (INIS)

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

    2014-01-01

    Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various 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. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  4. Dopamine agonists and Othello's syndrome

    Science.gov (United States)

    Graff-Radford, Jonathan; Ahlskog, J Eric.; Bower, James H.; Josephs, Keith A.

    2014-01-01

    Background Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists. Methods We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities. Results Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions. Conclusions OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option. PMID:20829092

  5. Apolipoprotein M regulates the orphan nuclear receptor LRH-1 gene expression through binding to its promoter region in HepG2 cells

    Directory of Open Access Journals (Sweden)

    Pan Y

    2015-04-01

    Full Text Available Yi Pan,1,2,* Hou-gang Zhou,1,* Hui Zhou,3 Min Hu,1 Li-jun Tang2 1Clinical Laboratory, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 2Molecular Biology Research Center, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China; 3Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China *These authors contributed equally to this work Abstract: Apolipoprotein M (ApoM is predominantly located in the high-density lipoprotein in human plasma. It has been demonstrated that ApoM expression could be regulated by several crucial nuclear receptors that are involved in the bile acid metabolism. In the present study, by combining gene-silencing experiments, overexpression studies, and chromatin immunoprecipitation assays, we showed that ApoM positively regulated liver receptor homolog-1 (LRH-1 gene expression via direct binding to an LRH-1 promoter region (nucleotides -406/-197. In addition, we investigated the effects of farnesoid X receptor agonist GW4064 on hepatic ApoM expression in vitro. In HepG2 cell cultures, both mRNA and protein levels of ApoM and LRH-1 were decreased in a time-dependent manner in the presence of 1 µM GW4064, and the inhibition effect was gradually attenuated after 24 hours. In conclusion, our findings present supportive evidence that ApoM is a regulator of human LRH-1 transcription, and further reveal the importance of ApoM as a critical regulator of bile acids metabolism. Keywords: bile acids, chromatin immunoprecipitation assay, farnesoid X receptor, GW4064, high-density lipoprotein 

  6. Hormones and β-Agonists

    NARCIS (Netherlands)

    Ginkel, van L.A.; Bovee, T.F.H.; Blokland, M.H.; Sterk, S.S.; Smits, N.G.E.; Pleadin, Jelka; Vulić, Ana

    2016-01-01

    This chapter provides some updated information on contemporary methods for hormone and β-agonist analyses. It deals with the classical approaches for the effective detection and identification of exogenous hormones. The chapter examines specific problems related to control strategies for natural

  7. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

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

    2011-01-01

    and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  8. 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...

  9. 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......, including virtually complete prevention of ovarian hyperstimulation syndrome (OHSS), the introduction of a surge of FSH in addition to the LH surge and finally the possibility to individualize luteal-phase supplementation based on ovarian response to stimulation. We maintain that the automatic HCG...... 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...

  10. Small Molecule Fluoride Toxicity Agonists

    Science.gov (United States)

    Nelson1, James W.; Plummer, Mark S.; Blount, Kenneth F.; Ames, Tyler D.; Breaker, Ronald R.

    2015-01-01

    SUMMARY Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch-reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID:25910244

  11. 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.

  12. 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.

  13. Using physics-based pose predictions and free energy perturbation calculations to predict binding poses and relative binding affinities for FXR ligands in the D3R Grand Challenge 2

    Science.gov (United States)

    Athanasiou, Christina; Vasilakaki, Sofia; Dellis, Dimitris; Cournia, Zoe

    2018-01-01

    Computer-aided drug design has become an integral part of drug discovery and development in the pharmaceutical and biotechnology industry, and is nowadays extensively used in the lead identification and lead optimization phases. The drug design data resource (D3R) organizes challenges against blinded experimental data to prospectively test computational methodologies as an opportunity for improved methods and algorithms to emerge. We participated in Grand Challenge 2 to predict the crystallographic poses of 36 Farnesoid X Receptor (FXR)-bound ligands and the relative binding affinities for two designated subsets of 18 and 15 FXR-bound ligands. Here, we present our methodology for pose and affinity predictions and its evaluation after the release of the experimental data. For predicting the crystallographic poses, we used docking and physics-based pose prediction methods guided by the binding poses of native ligands. For FXR ligands with known chemotypes in the PDB, we accurately predicted their binding modes, while for those with unknown chemotypes the predictions were more challenging. Our group ranked #1st (based on the median RMSD) out of 46 groups, which submitted complete entries for the binding pose prediction challenge. For the relative binding affinity prediction challenge, we performed free energy perturbation (FEP) calculations coupled with molecular dynamics (MD) simulations. FEP/MD calculations displayed a high success rate in identifying compounds with better or worse binding affinity than the reference (parent) compound. Our studies suggest that when ligands with chemical precedent are available in the literature, binding pose predictions using docking and physics-based methods are reliable; however, predictions are challenging for ligands with completely unknown chemotypes. We also show that FEP/MD calculations hold predictive value and can nowadays be used in a high throughput mode in a lead optimization project provided that crystal structures of

  14. Using physics-based pose predictions and free energy perturbation calculations to predict binding poses and relative binding affinities for FXR ligands in the D3R Grand Challenge 2.

    Science.gov (United States)

    Athanasiou, Christina; Vasilakaki, Sofia; Dellis, Dimitris; Cournia, Zoe

    2018-01-01

    Computer-aided drug design has become an integral part of drug discovery and development in the pharmaceutical and biotechnology industry, and is nowadays extensively used in the lead identification and lead optimization phases. The drug design data resource (D3R) organizes challenges against blinded experimental data to prospectively test computational methodologies as an opportunity for improved methods and algorithms to emerge. We participated in Grand Challenge 2 to predict the crystallographic poses of 36 Farnesoid X Receptor (FXR)-bound ligands and the relative binding affinities for two designated subsets of 18 and 15 FXR-bound ligands. Here, we present our methodology for pose and affinity predictions and its evaluation after the release of the experimental data. For predicting the crystallographic poses, we used docking and physics-based pose prediction methods guided by the binding poses of native ligands. For FXR ligands with known chemotypes in the PDB, we accurately predicted their binding modes, while for those with unknown chemotypes the predictions were more challenging. Our group ranked #1st (based on the median RMSD) out of 46 groups, which submitted complete entries for the binding pose prediction challenge. For the relative binding affinity prediction challenge, we performed free energy perturbation (FEP) calculations coupled with molecular dynamics (MD) simulations. FEP/MD calculations displayed a high success rate in identifying compounds with better or worse binding affinity than the reference (parent) compound. Our studies suggest that when ligands with chemical precedent are available in the literature, binding pose predictions using docking and physics-based methods are reliable; however, predictions are challenging for ligands with completely unknown chemotypes. We also show that FEP/MD calculations hold predictive value and can nowadays be used in a high throughput mode in a lead optimization project provided that crystal structures of

  15. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels

    2015-01-01

    to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...... antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site...... and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR...

  16. 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.

  17. Sports doping: Emerging designer and therapeutic B2-agonists

    NARCIS (Netherlands)

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

    2013-01-01

    Beta2-adrenergic agonists, or ß2-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 ß2-agonists is prohibited in sports by the World Anti-Doping

  18. 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...

  19. Adverse Effects of GLP-1 Receptor Agonists

    OpenAIRE

    Filippatos, Theodosios D.; Panagiotopoulou, Thalia V.; Elisaf, Moses S.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of ...

  20. 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.)...

  1. 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. © 2013.

  2. GLP-1 agonists for type 2 diabetes

    DEFF Research Database (Denmark)

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

    2013-01-01

    and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches...... and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable...

  3. 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.

  4. Neurotensin agonists block the prepulse inhibition deficits produced by a 5-HT2A and an alpha1 agonist.

    Science.gov (United States)

    Shilling, P D; Melendez, G; Priebe, K; Richelson, E; Feifel, D

    2004-09-01

    Neurotensin (NT) agonists have been proposed as potential antipsychotics based exclusively upon their ability to inhibit dopamine-2 (D2) receptor transmission. Several other pharmacological mechanisms have been implicated in enhancing the antipsychotic profile produced by D2 inhibition alone. These include inhibition of 5-HT2A and alpha1-adrenoceptors. Recently, we reported that systemic administration of the neurotensin agonist PD149163 blocks deficits in prepulse inhibition (PPI) of the startle reflex produced by the 5-HT2A receptor agonist DOI. This suggested that NT agonists could inhibit 5-HT2A modulation of neurotransmission. To determine if other peripherally administered NT agonists shared this effect, we examined the effects of NT69L, another NT agonist, on DOI-induced PPI deficits. In addition, to determine if NT agonists also inhibit alpha1-adrenoceptor neurotransmission, we examined the effects of PD149163 and NT69L on PPI deficits induced by the alpha1-adrenoceptor agonist, cirazoline. In the NT69L/DOI study, rats received subcutaneous (SC) injections of NT69L (0, 0.1, 1, or 2 mg/kg) followed 30 min later by SC saline or DOI (0.5 mg/kg). In the NT agonist/cirazoline studies, animals received SC injections of either PD149163 (0, 0.01, 0.1, or 1 mg/kg) or NT69L (0, 0.01, 0.1, or 1 mg/kg) followed 30 min later by SC saline or cirazoline (0.7 mg/kg). Animals were tested in startle chambers 20 min later. In all three experiments the PPI disruption produced by DOI and cirazoline was blocked by the NT agonists. These findings provide strong evidence that NT agonists inhibit 5-HT2A and alpha1-adrenoceptor modulation of neurotransmission, pharmacological effects that, in conjunction with their known inhibition of dopamine transmission, strengthen the antipsychotic potential of NT agonists.

  5. The importance of β2-agonists in myocardial infarction

    DEFF Research Database (Denmark)

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

    2016-01-01

    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...

  6. Agonist induction, conformational selection, and mutant receptors.

    Science.gov (United States)

    Giraldo, Jesús

    2004-01-02

    Current models of receptor activation are based on either of two basic mechanisms: agonist induction or conformational selection. The importance of one pathway relative to the other is controversial. In this article, the impossibility of distinguishing between the two mechanisms under a thermodynamic approach is shown. The effect of receptor mutation on the constants governing ligand-receptor equilibria is discussed. The two-state model of agonism both in its original formulation (one cycle) and including multiple active states (multiple cycles) is used. Pharmacological equations for the double (two cycles) two-state model are derived. The simulations performed suggest that the double two-state model of agonism can be a useful model for assessing quantitatively the changes in pharmacological activity following receptor mutation.

  7. Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

    DEFF Research Database (Denmark)

    Maolanon, Alex R.; Risgaard, Rune; Wang, Shuang Yan

    2017-01-01

    A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist...... efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit......-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission....

  8. Adenosine receptor agonists modulate visceral hyperalgesia in the rat.

    Science.gov (United States)

    Sohn, Chong-Il; Park, Hyo Jin; Gebhart, G F

    2008-06-01

    Adenosine is an endogenous modulator of nociception. Its role in visceral nociception, particularly in visceral hyperalgesia, has not been studied. The aim of this study was to determine the effects of adenosine receptor agonists in a model of visceral hyperalgesia. The visceromotor response (VMR) in rats to colorectal distension (CRD; 80 mmHg, 20 seconds) was quantified by electromyographic recordings from the abdominal musculature. Three hours after the intracolonic administration of zymosan (25 mg/mL, 1 mL), VMRs to CRD were measured before and after either subcutaneous or intrathecal administration of an adenosine receptor agonist. Subcutaneous injection of 5'-N-ethylcarboxyamidoadenosine (NECA; an A1 and A2 receptor agonist), R(-)-N6-(2-phenylisopropyl)-adenosine (R-PIA; a selective A1 receptor agonist), or CGS-21680 hydrochloride (a selective A2a receptor agonist) dose-dependently (10-100 mg/kg) attenuated the VMR to CRD, although hindlimb weakness occurred at the higher doses tested. Intrathecal administration of NECA or R-PIA dose-dependently (0.1-1.0 microg/kg) decreased the VMR, whereas CGS-21680 hydrochloride was ineffective over the same concentration range. Higher intrathecal doses of the A1/A2 receptor agonist NECA produced motor weakness. Adenosine receptor agonists are antihyperalgesic, but also produce motor weakness at high doses. However, activation of the spinal A1 receptor significantly attenuates the VMR to CRD without producing motor weakness.

  9. Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity

    Science.gov (United States)

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don; Hurd, Alexander; Aicher, Thomas D.; Toogood, Peter L.; Glick, Gary D.; Paulos, Chrystal M.; Zou, Weiping; Carter, Laura L.

    2016-01-01

    ABSTRACT RORγt is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ−/− T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer. PMID:28123897

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

    Science.gov (United States)

    Nirenberg, Melissa J

    2013-08-01

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

  11. Synthetic ROR? agonists regulate multiple pathways to enhance antitumor immunity

    OpenAIRE

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don

    2016-01-01

    ABSTRACT ROR?t is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are ROR?+ cells. To evaluate the role of ROR? in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate ROR? to a greater extent than the endogenous agonist desmosterol. These ROR? agonists enhance effector function of Type 17...

  12. Problematic gambling on dopamine agonists: Not such a rarity.

    Science.gov (United States)

    Grosset, Katherine A; Macphee, Graeme; Pal, Guru; Stewart, David; Watt, Andrew; Davie, Jim; Grosset, D G

    2006-12-01

    Excessive gambling is recognized with dopamine agonist therapy, but the prevalence is unknown. We assessed the prevalence of excess gambling by specific prospective enquiry in Parkinson's disease patients attending six West Scotland movement disorder clinics. Of 388 patients taking anti-Parkinson medication, 17 (4.4%) developed pathological gambling, all of whom were prescribed dopamine agonists. Thus, 8% of patients taking dopamine agonists had pathological gambling. Pathological gambling is not uncommon, and patients should be made aware of this potential adverse effect. Copyright 2006 Movement Disorder Society.

  13. Nicotine receptor partial agonists for smoking cessation.

    Science.gov (United States)

    Cahill, Kate; Stead, Lindsay F; Lancaster, Tim

    2012-04-18

    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). 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. 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 specialised register was in December 2011. We also searched online clinical trials registers. 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. 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. Two recent cytisine trials (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled RR of

  14. Albiglutide: a unique GLP-1 receptor agonist.

    Science.gov (United States)

    Rendell, Marc S

    2016-12-01

    Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection. Area covered: The pharmacokinetic and pharmacodynamic properties of albiglutide and its clinical effects are discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents. Expert opinion: Albiglutide has a chemical structure quite distinct from that of other marketed GLP-1 RAs. The agent has less gastrointestinal side effects than other comparable GLP-1 RAs and is safe in patients with renal failure. As a sole treatment for diabetes and used with other hypoglycemic agents, it achieves a lowering of HbA1c of up to 1%, less than several competitor GLP-1 RAs. The benefit on weight reduction is minimal compared to other GLP-1 RAs. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long term study now underway will determine if albiglutide, with its lower level of GI intolerance, has a place in the treatment of patients with increased risk of cardiovascular events.

  15. 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

  16. Development of a radioreceptor assay for β2 adrenergic agonists

    International Nuclear Information System (INIS)

    Helbo, V.; Vandenbroeck, M.; Maghuin-Rogister, G.

    1994-01-01

    Several β 2 adrenergic agonists are illegally used as growth promoters in meat production. We have developed and evaluated a radioreceptor assay for the multianalyte detection of these compounds. The method is based on a competition for binding with receptors (plasma membranes prepared from bovine teat muscles) between a radioactive tracer ( 3 H-dihydroalprenolol) and β 2 agonist residues present in the samples. The method has been validated for three β 2 agonists (clenbuterol, mabuterol and cimaterol) in bovine urine samples. The detection limit (mean of ''blank'' values + 3 SEM) in urine was 2.4 ppb clenbuterol. Using this procedure, samples containing at least 5 ppb of clenbuterol, mabuterol or cimaterol could be identified as positive for the presence of β 2 agonists. (orig.) [de

  17. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    Directory of Open Access Journals (Sweden)

    Akinori Hirashima

    2003-04-01

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

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

    Science.gov (United States)

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

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. © 2010 American Academy of Forensic Sciences.

  19. 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.  

  20. Sleep attacks in patients taking dopamine agonists: review.

    Science.gov (United States)

    Homann, Carl Nikolaus; Wenzel, Karoline; Suppan, Klaudia; Ivanic, Gerd; Kriechbaum, Norbert; Crevenna, Richard; Ott, Erwin

    2002-06-22

    To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information.

  1. A step ahead of PPARγ full agonists to PPARγ partial agonists: therapeutic perspectives in the management of diabetic insulin resistance.

    Science.gov (United States)

    Chigurupati, Sridevi; Dhanaraj, Sokkalingam A; Balakumar, Pitchai

    2015-05-15

    Described since long as a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptors (PPARs) regulate the gene expression of proteins involved in glucose and lipid metabolism. PPARs indeed regulate several physiologic processes, including lipid homeostasis, adipogenesis, inflammation, and wound healing. PPARs bind natural or synthetic PPAR ligands can function as cellular sensors to regulate the gene transcription. Dyslipidemia, and type 2 diabetes mellitus (T2DM) with insulin resistance are treated using agonists of PPARα and PPARγ, respectively. The PPARγ is a key regulator of insulin sensitization and glucose metabolism, and therefore is considered as an imperative pharmacological target to combat diabetic metabolic disease and insulin resistance. Of note, currently available PPARγ full agonists like rosiglitazone display serious adverse effects such as fluid retention/oedema, weight gain, and increased incidence of cardiovascular events. On the other hand, PPARγ partial agonists are being suggested to devoid or having less incidence of these undesirable events, and are under developmental stages. Current research is on the way for the development of novel PPARγ partial agonists with enhanced therapeutic efficacy and reduced adverse effects. This review sheds lights on the current status of development of PPARγ partial agonists, for the management of T2DM, having comparatively less or no adverse effects to that of PPARγ full agonists. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Activation of farnesoid X receptor induces RECK expression in mouse liver

    International Nuclear Information System (INIS)

    Peng, Xiaomin; Wu, Weibin; Zhu, Bo; Sun, Zhichao; Ji, Lingling; Ruan, Yuanyuan; Zhou, Meiling; Zhou, Lei; Gu, Jianxin

    2014-01-01

    Highlights: •RECK is a novel transcriptional target gene of FXR in mouse liver. •The FXR response element is located within the intron 1 of RECK gene. •FXR agonist reverses the down-regulation of RECK in the liver in mouse NASH model. -- Abstract: Farnesoid X receptor (FXR) belongs to the ligand-activated nuclear receptor superfamily, and functions as a transcription factor regulating the transcription of numerous genes involved in bile acid homeostasis, lipoprotein and glucose metabolism. In the present study, we identified RECK, a membrane-anchored inhibitor of matrix metalloproteinases, as a novel target gene of FXR in mouse liver. We found that FXR agonist substantially augmented hepatic RECK mRNA and protein expression in vivo and in vitro. FXR regulated the transcription of RECK through directly binding to FXR response element located within intron 1 of the mouse RECK gene. Moreover, FXR agonist reversed the down-regulation of RECK in the livers from mice fed a methionine and choline deficient diet. In summary, our data suggest that RECK is a novel transcriptional target of FXR in mouse liver, and provide clues to better understanding the function of FXR in liver

  3. Activation of farnesoid X receptor induces RECK expression in mouse liver

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Xiaomin [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Wu, Weibin [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Sciences, Fudan University, Shanghai 200032 (China); Zhu, Bo; Sun, Zhichao; Ji, Lingling; Ruan, Yuanyuan [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Zhou, Meiling, E-mail: meilingzhou2012@gmail.com [Department of Radiology, Zhongshan Hospital of Fudan University and Shanghai Institute of Medical Imaging, Shanghai 200032 (China); Zhou, Lei, E-mail: yhchloech@gmail.com [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Sciences, Fudan University, Shanghai 200032 (China)

    2014-01-03

    Highlights: •RECK is a novel transcriptional target gene of FXR in mouse liver. •The FXR response element is located within the intron 1 of RECK gene. •FXR agonist reverses the down-regulation of RECK in the liver in mouse NASH model. -- Abstract: Farnesoid X receptor (FXR) belongs to the ligand-activated nuclear receptor superfamily, and functions as a transcription factor regulating the transcription of numerous genes involved in bile acid homeostasis, lipoprotein and glucose metabolism. In the present study, we identified RECK, a membrane-anchored inhibitor of matrix metalloproteinases, as a novel target gene of FXR in mouse liver. We found that FXR agonist substantially augmented hepatic RECK mRNA and protein expression in vivo and in vitro. FXR regulated the transcription of RECK through directly binding to FXR response element located within intron 1 of the mouse RECK gene. Moreover, FXR agonist reversed the down-regulation of RECK in the livers from mice fed a methionine and choline deficient diet. In summary, our data suggest that RECK is a novel transcriptional target of FXR in mouse liver, and provide clues to better understanding the function of FXR in liver.

  4. Ecdysone Agonist: New Insecticides with Novel Mode of Action

    Directory of Open Access Journals (Sweden)

    Y. Andi Trisyono

    2002-12-01

    Full Text Available Development of insect resistance to insecticide has been the major driving force for the development of new insecticides. Awareness and demand from public for more environmentally friendly insecticides have contributed in shifting the trend from using broad spectrum to selective insecticides. As a result, scientists have looked for new target sites beyond the nervous system. Insect growth regulators (IGRs are more selective insecticides than conventional insecticides, and ecdysone agonists are the newest IGRs being commercialized, e.g. tebufenozide, methoxyfenozide, and halofenozide. Ecdysone agonists bind to the ecdysteroid receptors, and they act similarly to the molting hormone 20-hydroxyecdysone. The binding provides larvae or nymphs with a signal to enter a premature and lethal molting cycle. In addition, the ecdysone agonists cause a reduction in the number of eggs laid by female insects. The ecdysone agonists are being developed as selective biorational insecticides. Tebufenozide and methoxyfenozide are used to control lepidopteran insect pests, whereas halofenozide is being used to control coleopteran insect pests. Their selectivity is due to differences in the binding affinity between these compounds to the receptors in insects from different orders. The selectivity of these compounds makes them candidates to be used in combinations with other control strategies to develop integrated pest management programs in agricultural ecosystems. Key words: new insecticides, selectivity, ecdysone agonists

  5. Modification of opiate agonist binding by pertussis toxin

    Energy Technology Data Exchange (ETDEWEB)

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  6. Agonistic behavior enhances adult neurogenesis in male Acheta domesticus crickets.

    Science.gov (United States)

    Ghosal, Kaushik; Gupta, Mohit; Killian, Kathleen A

    2009-07-01

    We examined the effect of agonistic behavior on cell proliferation and neurogenesis in the central nervous system (CNS) of adult male Acheta domesticus crickets. We combined 5-bromo,2'deoxyuridine (BrdU)-labeling of dividing cells with immunocytochemical detection of the neuronal marker horseradish peroxidase to examine the proliferation of progenitor cells and the survival of newborn neurons. In crickets, the mushroom bodies of the brain contain clusters of proliferative cells that divide and generate new neurons in adulthood. Pairs of male crickets were allowed to fight and establish social rank and were then injected with BrdU. Proliferation of mushroom body neurogenic cluster cells was unaffected by agonistic interactions; 24 h after a fight, the number of BrdU positive cells in fought and un-fought males did not significantly differ. However, agonistic interactions did influence cell survival. Two weeks after an agonistic interaction, fought males had more newborn neurons than males that did not fight. There was also a rank-specific effect because dominant males had significantly more new neurons than subordinates. We also report for the first time that neurogenesis in adult crickets can occur in other regions of the brain and in other CNS ganglia, including the terminal abdominal ganglion (TAG). Agonistic interactions enhanced the proliferation of these distributed precursor cells but did not increase the survival of the newborn neurons generated by these cells.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    Based on the conformationally constrained D-Trp-Phe-D-Trp (wFw) core of the prototype inverse agonist [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]substance P, a series of novel, small, peptide-mimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers...... connecting the D-Trp-Phe-D-Trp motif with the important C-terminal carboxyamide group, 40 nm agonism potency was obtained and also in one case (wFw-Isn-NH(2), where Isn is isonipecotic acid) ~80% efficacy. However, in contrast to all previously reported ghrelin receptor agonists, the piperidine-constrained w......Fw-Isn-NH(2) was found to be a functionally biased agonist. Thus, wFw-Isn-NH(2) mediated potent and efficacious signaling through the Ga(q) and ERK1/2 signaling pathways, but in contrast to all previous ghrelin receptor agonists it did not signal through the serum response element, conceivably the Ga(12...

  8. Modification of opiate agonist binding by pertussis toxin

    International Nuclear Information System (INIS)

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-01-01

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in 3 (H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding

  9. Tactical Approaches to Interconverting GPCR Agonists and Antagonists.

    Science.gov (United States)

    Dosa, Peter I; Amin, Elizabeth Ambrose

    2016-02-11

    There are many reported examples of small structural modifications to GPCR-targeted ligands leading to major changes in their functional activity, converting agonists into antagonists or vice versa. These shifts in functional activity are often accompanied by negligible changes in binding affinity. The current perspective focuses on outlining and analyzing various approaches that have been used to interconvert GPCR agonists, partial agonists, and antagonists in order to achieve the intended functional activity at a GPCR of therapeutic interest. An improved understanding of specific structural modifications that are likely to alter the functional activity of a GPCR ligand may be of use to researchers designing GPCR-targeted drugs and/or probe compounds, specifically in cases where a particular ligand exhibits good potency but not the preferred functional activity at the GPCR of choice.

  10. 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

    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......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...

  11. 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.

  12. GnRH antagonist versus long agonist protocols in IVF

    DEFF Research Database (Denmark)

    Lambalk, C B; Banga, F R; Huirne, J A

    2017-01-01

    was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH......BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist...... METHODS: The Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials and Pubmed and Embase databases were searched from inception until June 2016. Eligible trials were those that compared GnRH antagonist protocols and standard long GnRH agonist protocols...

  13. TPO receptor agonist for chronic idiopathic thrombocytopenic purpura.

    Science.gov (United States)

    Zeng, Yan; Duan, Xin; Xu, Jiajun; Ni, Xun

    2011-07-06

    Chronic idiopathic thrombocytopenic purpura (ITP) is an acquired autoimmune disorder that is characterized predominantly by a low platelet count. Thrombopoietin (TPO) receptor agonists increase production of platelets by stimulating the TPO receptor in people with chronic ITP. To determine the efficacy and safety of TPO receptor agonists in chronic ITP patients. We searched MEDLINE (from 1950 to March 2011), EMBASE (from 1974 to March 2011), and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3) to identify all randomized trials in chronic ITP. We also contacted authors of included studies and TPO receptor agonists manufacturers. Randomized controlled trials (RCTs) comparing TPO receptor agonists alone, or in combination with other drugs, to placebo, no treatment, other drugs, splenectomy or another TPO receptor agonist in patients with chronic ITP. Two review authors independently screened papers, extracted data and assessed the risk of bias in the included studies. Six trials with 808 patients were included. Five studies compared TPO receptor agonists with placebo (romiplostim: 100, eltrombopag: 299, placebo: 175); one study compared TPO receptor agonists with standard of care (SOC) (romiplostim: 157; SOC: 77). SOC included a variety of therapies, such as glucocorticoid, anti-D immune globulin, intravenous immune globulin, rituximab, azathioprine, and so on. Overall survival, one of our primary outcomes, was not studied by these RCTs and we could not estimate number needed to treat (NNT). Another primary outcome, improving significant bleeding events, did not reveal any significant differences between the TPO receptor agonists group and the control group (placebo or SOC) (versus placebo risk ratio (RR) 0.48, 95% confidence interval (CI) 0.20 to 1.15; versus SOC RR 0.49, 95% CI 0.15 to 1.63).For secondary outcomes, TPO receptor agonists statistically significantly improved overall platelet response (versus placebo RR

  14. [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. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  15. 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...

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  17. 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...

  18. Beta2-adrenoceptors: mechanisms of action of beta2-agonists.

    Science.gov (United States)

    Johnson, M

    2001-03-01

    The human beta2-adrenoceptor is a member of the 7 transmembrane family of receptors. It is encoded by a gene on chromosome 5 and is widely distributed in the respiratory tract. Following beta2-adrenoceptor activation, intracellular signalling is mainly produced by inducing cyclic AMP. This produces airway relaxation through phosphorylation of muscle regulatory proteins and modification of cellular Ca2+concentrations. Beta2-agonists have been characterised into those which directly activate the receptor (salbutamol/terbutaline), those which are taken up into a membrane depot (formoterol) and those which interact with a receptor-specific, auxiliary binding site (salmeterol). These differences in mechanism of action are reflected in the kinetics of airway smooth muscle relaxation and bronchodilation in asthmatic patients. Beta-adrenoceptor desensitisation is associated with beta2-agonist activation and differs depending on the cell type. It is reflected in the different profiles of clinical tolerance to chronic beta2-agonist therapy. A number of polymorphisms of the beta2-receptor have been described which appear to alter the behaviour of the receptor, including the degree of downregulation and response to beta2-agonists.

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

    NARCIS (Netherlands)

    Haasen, Christian; van den Brink, Wim

    2006-01-01

    PURPOSE OF REVIEW: To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. RECENT FINDINGS: The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid

  20. The elusive endogenous adipogenic PPARγ agonists: Lining up the suspects

    DEFF Research Database (Denmark)

    Hallenborg, Philip; Petersen, Rasmus K.; Kouskoumvekaki, Irene

    2016-01-01

    and their derivatives are known to bind to and activate PPARγ, the identity of the ligand(s) responsible for initiating adipocyte differentiation is still a matter of debate. Here we review recent data on pathways involved in ligand production as well as possible endogenous, adipogenic PPARγ agonists....

  1. Dopamine agonists and risk: impulse control disorders in Parkinson's disease.

    Science.gov (United States)

    Voon, Valerie; Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J; Hallett, Mark

    2011-05-01

    Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.

  2. Dopamine agonists and risk: impulse control disorders in Parkinson's; disease

    Science.gov (United States)

    Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J.; Hallett, Mark

    2011-01-01

    Impulse control disorders are common in Parkinson's; disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's; disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a ‘Sure’ choice and a ‘Gamble’ choice of moderate risk. To commence each trial, in the ‘Gain’ condition, individuals started at $0 and in the ‘Loss’ condition individuals started at −$50 below the ‘Sure’ amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk (‘Gamble Risk’). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's; disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the ‘Gain’ relative to the ‘Loss’ condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's; disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's; disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals. PMID:21596771

  3. Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Zarnke, Allison L; Laine, Muriel; Al Abosy, Rose; Chang, Ya-Fang; Dembo, Anna G; Schoenfelt, Kelly; Vadhi, Raga; Qiu, Xintao; Rao, Prakash; Santhamma, Bindu; Nair, Hareesh B; Nickisch, Klaus J; Long, Henry W; Becker, Lev; Brown, Myles; Greene, Geoffrey L

    2018-01-12

    Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR

  4. Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E.; Zarnke, Allison L.; Laine, Muriel; Al Abosy, Rose; Chang, Ya-Fang; Dembo, Anna G.; Schoenfelt, Kelly; Vadhi, Raga; Qiu, Xintao; Rao, Prakash; Santhamma, Bindu; Nair, Hareesh B.; Nickisch, Klaus J.; Long, Henry W.; Becker, Lev; Brown, Myles; Greene, Geoffrey L.

    2018-01-01

    Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR

  5. Bile acid receptor agonists. INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice

    NARCIS (Netherlands)

    de Oliveira, Monique C.; Gilglioni, Eduardo H.; de Boer, Bouke A.; Runge, Jurgen H.; de Waart, Dirk R.; Salgueiro, Clairce L.; Ishii-Iwamoto, Emy L.; Oude Elferink, Ronald P. J.; Gaemers, Ingrid C.

    2016-01-01

    Menopause is often followed by obesity and, related to this, non-alcoholic fatty liver disease (NAFLD). Two bile acid (BA) receptors, farnesoid X receptor (FXR) and G-protein-coupled receptor TGR5, have emerged as putative therapeutic targets for obesity and NAFLD. Aim of this study: to evaluate the

  6. 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

    , 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...

  7. Agonist signalling properties of radiotracers used for imaging of dopamine D2/3 receptors

    NARCIS (Netherlands)

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

    2014-01-01

    Dopamine D2/3 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 are more

  8. 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

  9. Agonists and partial agonists of rhodopsin: retinal polyene methylation affects receptor activation.

    Science.gov (United States)

    Vogel, Reiner; Lüdeke, Steffen; Siebert, Friedrich; Sakmar, Thomas P; Hirshfeld, Amiram; Sheves, Mordechai

    2006-02-14

    Using Fourier transform infrared (FTIR) difference spectroscopy, we have studied the impact of sites and extent of methylation of the retinal polyene with respect to position and thermodynamic parameters of the conformational equilibrium between the Meta I and Meta II photoproducts of rhodopsin. Deletion of methyl groups to form 9-demethyl and 13-demethyl analogues, as well as addition of a methyl group at C10 or C12, shifted the Meta I/Meta II equilibrium toward Meta I, such that the retinal analogues behaved like partial agonists. This equilibrium shift resulted from an apparent reduction of the entropy gain of the transition of up to 65%, which was only partially offset by a concomitant reduction of the enthalpy increase. The analogues produced Meta II photoproducts with relatively small alterations, while their Meta I states were significantly altered, which accounted for the aberrant transitions to Meta II. Addition of a methyl group at C14 influenced the thermodynamic parameters but had little impact on the position of the Meta I/Meta II equilibrium. Neutralization of the residue 134 in the E134Q opsin mutant increased the Meta II content of the 13-demethyl analogue, but not of the 9-demethyl analogue, indicating a severe impairment of the allosteric coupling between the conserved cytoplasmic ERY motif involved in proton uptake and the Schiff base/Glu 113 microdomain in the 9-demethyl analogue. The 9-methyl group appears therefore essential for the correct positioning of retinal to link protonation of the cytoplasmic motif with protonation of Glu 113 during receptor activation.

  10. Medical treatment in Cushing's syndrome: dopamine agonists and cabergoline.

    Science.gov (United States)

    Petrossians, Patrick; Thonnard, Anne-Sophie; Beckers, Albert

    2010-01-01

    Dopamine (DA) is a catecholamine with a wide range of functions and whose five subtype receptors are found in different organs where they exert a mainly inhibitory action. Since this action may also appear in a number of secretory tumors in various locations, DA agonists have elicited some interest as a medical treatment for hypercorticism. Non-iatrogenic Cushing's syndromes are due in 70% of the cases to a pituitary adrenocorticotropic hormone (ACTH)-producing adenoma, and, less frequently, to an adrenal adenoma or an ectopic ACTH secretion by a neuroendocrine tumor. First-line treatment in Cushing's syndrome consists of the surgical removal of the secreting tumor. However, surgery may not achieve a complete cure in a number of cases, hence emphasizing the potential benefit of a medical complementary treatment, which could also benefit patients as an alternative approach, either when waiting for, or when the patient is not eligible for surgery. Studies of corticotropic adenomas have shown that 80% of these tumors express D2 receptors. Clinical trials of DA agonists in Cushing's disease have shown an inhibitory effect of these drugs with an inhibition of ACTH secretion and/or a decrease of tumor size. There are only a few cases of documented use of DA agonists in ectopic ACTH secretion, but when the tumor expresses DA receptors, DA agonists may represent a useful complementary treatment. DA receptors are also expressed in normal and tumoral adrenals, suggesting a potential use of DA agonists in Cushing's syndrome secondary to adrenal tumors. However, clinical data regarding this specific situation are very scarce, maybe due to the relatively high rate of surgical cure of adrenal adenomas. In conclusion, DA agonists represent a potential preparatory or complementary treatment for endogenous Cushing's syndrome, especially in Cushing's disease. These compounds may be underused as suggested by the scarce number of publication and case reports in the literature. In the

  11. Modulation of farnesoid X receptor results in post-translational modification of poly (ADP-ribose) polymerase 1 in the liver

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Yan [Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing (China); Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Li, Guodong [Department of Surgical Oncology, Cancer Treatment Center, Fourth Affiliated Hospital of Harbin Medical University, Harbin (China); Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Dong, Yafeng; Zhou, Helen H. [Department of Obstetrics and Gynecologic, University of Kansas Medical Center, Kansas City, KS (United States); Kong, Bo; Aleksunes, Lauren M. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Richardson, Jason R. [Environmental and Occupational Medicine, UMDNJ—Robert Wood Johnson Medical School, Piscataway, NJ (United States); Li, Fei, E-mail: xw_lifei@yahoo.com.cn [Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing (China); Guo, Grace L., E-mail: guo@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States)

    2013-01-15

    The farnesoid X receptor (FXR) is a bile acid-activated transcription factor belonging to the nuclear receptor superfamily. FXR deficiency in mice results in cholestasis, metabolic disorders, and tumorigenesis in liver and intestine. FXR is known to contribute to pathogenesis by regulating gene transcription; however, changes in the post-transcriptional modification of proteins associated with FXR modulation have not been determined. In the current study, proteomic analysis of the livers of wild-type (WT) and FXR knockout (FXR-KO) mice treated with a FXR synthetic ligand or vehicle was performed. The results identified five proteins as novel FXR targets. Since FXR deficiency in mice leads to liver tumorigenesis, poly (ADP-ribose) polymerase family, member 1 (Parp1) that is important for DNA repair, was validated in the current study by quantitative real-time PCR, and 1- and 2-dimensional gel electrophoresis/western blot. The results showed that Parp1 mRNA levels were not altered by FXR genetic status or by agonist treatment. However, total Parp1 protein levels were increased in FXR-KO mice as early as 3 month old. Interestingly, total Parp1 protein levels were increased in WT mice in an age-dependent manner (from 3 to 18 months), but not in FXR-KO mice. Finally, activation of FXR in WT mice resulted in reduction of phosporylated Parp1 protein in the liver without affecting total Parp1 protein levels. In conclusion, this study reveals that FXR genetic status and agonist treatment affects basal levels and phosphorylation state of Parp1, respectively. These alterations, in turn, may be associated with the hepatobiliary alterations observed in FXR-KO mice and participate in FXR agonist-induced protection in the liver. -- Highlights: ► Proteomic analysis identified novel FXR targets. ► FXR modification altered post-translational modification of the Parp1 protein. ► Altered Parp1 function may contribute to mechanisms of FXR regulation of liver functions.

  12. Beta-adrenergic agonists as additive in beef cattle

    Directory of Open Access Journals (Sweden)

    Marcelo Vedovatto

    2014-10-01

    Full Text Available The agonists receptor beta-adrenergic (β-AA are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fully understood, these may cause morphological and physiological changes such as increased blood flow decrease in plasma insulin, decreased lipogenesis, and muscle hypertrophy mainly in type II fibers. We also observed changes in motility and secretions grastointestinal tract, beyond the direct influence on the rumen bacteria, altering the digestibility of the diet. The β-AA agonists released in some countries for use in beef cattle are ractopamine hydrochloride and zilpaterol hydrochloride. According to literature data, the inclusion of these additives in the diet of feedlot cattle has been associated with an increase infeed efficiency with the increase in daily weight gain and with equal or lower feed intake. Carcass characteristics improvement was verified in carcass weight, and increased loin eye area, but with the possibility to decrease the subcutaneous fat thickness and marbling. Reviews in sensory panel of meat from animals consuming β-AA agonists showed decreased tenderness and juiciness. Thus β-AA improve performance and carcass characteristics, but more studies are needed to confirm whether they have negative influence on the organoleptic characteristics of the meat.

  13. Newspapers and Newspaper Ink Contain Agonists for the Ah Receptor

    Science.gov (United States)

    Bohonowych, Jessica E. S.; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T.; Denison, Michael S.

    2010-01-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [3H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  14. Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

    Science.gov (United States)

    2010-05-01

    agents histamine and cowhage activate separate populations of Ko and Naughtonto antinociceptive effects of spinally administered mor- phine or/and NOP...similar to other opioid receptor agonists at the cellular level (Meunier et al., 1995; Rizzi et al., 2007). However, the effects of NOP receptor...the hypotheses that in the non-human primate (1) the functions and behavioral effects of the NOP receptor are independent of classical opioid receptors

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

    Energy Technology Data Exchange (ETDEWEB)

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K. (GSKPA)

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  16. GnRH agonist for triggering of final oocyte maturation

    DEFF Research Database (Denmark)

    Al Humaidan, Peter Samir Heskjær; Kol, S; Papanikolaou, E G

    2011-01-01

    GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase...... deficiency. Therefore, the challenge has been to rescue the luteal phase. Studies now report a luteal phase rescue, with a reproductive outcome comparable to that seen after hCG triggering....

  17. State Estimation For An Agonistic-Antagonistic Muscle System

    OpenAIRE

    Nguyen, Thang; Warner, Holly; La, Hung; Mohammadi, Hanieh; Simon, Dan; Richter, Hanz

    2017-01-01

    Research on assistive technology, rehabilitation, and prosthesis requires the understanding of human machine interaction, in which human muscular properties play a pivotal role. This paper studies a nonlinear agonistic-antagonistic muscle system based on the Hill muscle model. To investigate the characteristics of the muscle model, the problem of estimating the state variables and activation signals of the dual muscle system is considered. In this work, parameter uncertainty and unknown input...

  18. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    Science.gov (United States)

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline.

  19. 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

  20. Structure of the agonist-bound neurotensin receptor.

    Science.gov (United States)

    White, Jim F; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G; Grisshammer, Reinhard

    2012-10-25

    Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.

  1. Pyrazolodiazepine derivatives with agonist activity toward Drosophila RYamide receptor.

    Science.gov (United States)

    Yoon, Yeu Kyung; Kim, Jung Ha; Kim, Jeong-Hyun; Kwon, Jae-Young; Kim, Yong-Chul; Kim, Young-Joon; Park, Zee-Yong

    2016-10-15

    The neuropeptide Y (NPY)-like signaling is conserved broadly in many animal species, and implicated in diverse biological functions, particularly those associated with feeding and metabolism. In Drosophila, three G protein coupled receptors (GPCRs) are closely related to the vertebrate NPY receptors: RYamide receptor (RYa-R) CG5811, neuropeptide F receptor (NPFR) CG1147 and short neuropeptide F receptor (sNPF-R) CG7395. Here, we screened 442 compounds of the pyrazolodiazepine analogs library, and identified four synthetic small compounds that activate the RYa-R, but not other two receptors. Their maximum activity is about 40% of the endogenous ligand, Drosophila RYamide-1, indicating they are partial agonists. Structural comparisons of these agonists identified an active core structure, characterized by phenylalanine and lysine fused pyrazolodiazepine skeletons, which can be utilized as a lead structure for further development of more potent drugs active on mammalian NPYRs. Identification of small compound agonists selective on RYa-R of the genetically amenable insect model will facilitate future efforts to understand biological functions of RYa-R, a GPCR conserved in many species. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Suppression of atherosclerosis by synthetic REV-ERB agonist

    International Nuclear Information System (INIS)

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-01-01

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - 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

  3. 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.

  4. Fluorescent agonists for the Torpedo nicotinic acetylcholine receptor.

    Science.gov (United States)

    Krieger, Florian; Mourot, Alexandre; Araoz, Romulo; Kotzyba-Hibert, Florence; Molgó, Jordi; Bamberg, Ernst; Goeldner, Maurice

    2008-05-05

    We have synthesized a series of fluorescent acylcholine derivatives carrying different linkers that vary in length and structure and connect the acylcholine unit to the environment-sensitive fluorophores 7-(diethylamino)coumarin-3-carbonyl (DEAC) or N-(7-nitrobenz-2-oxa-1,3-diazol-yl) (NBD). The pharmacological properties of the fluorescent analogues were investigated on heterologously expressed nicotinic acetylcholine receptor (nAChR) from Torpedo californica and on oocytes transplanted with nAChR-rich Torpedo marmorata membranes. Agonist action strongly depends on the length and the structure of the linker. One particular analogue, DEAC-Gly-C6-choline, showed partial agonist behavior with about half of the maximum response of acetylcholine, which is at least 20 times higher than those observed with previously described fluorescent dansyl- and NBD-acylcholine analogues. Binding of DEAC-Gly-C6-choline to Torpedo nAChR induces a strong enhancement of fluorescence intensity. Association and displacement kinetic experiments revealed dissociation constants of 0.5 nM for the alphadelta-binding site and 15.0 nM for the alphagamma-binding site. Both the pharmacological and the spectroscopic properties of this agonist show great promise for characterizing the allosteric mechanism behind the function of the Torpedo nAChR, as well as for drug-screening studies.

  5. Development of specific dopamine D-1 agonists and antagonists

    International Nuclear Information System (INIS)

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo[a,d]cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo[1,2]cyclohepta[3,4,5d,e]isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC 50 of compound 11 for displacement of 3 H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of 3 H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor

  6. PPAR Agonists and Metabolic Syndrome: An Established Role?

    Directory of Open Access Journals (Sweden)

    Margherita Botta

    2018-04-01

    Full Text Available Therapeutic approaches to metabolic syndrome (MetS are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs, blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C. PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil and myopathy should also be acknowledged.

  7. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    Science.gov (United States)

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes. Copyright © 2013 John Wiley & Sons, Ltd.

  8. Computer models in the design of FXR

    Energy Technology Data Exchange (ETDEWEB)

    Vogtlin, G.; Kuenning, R.

    1980-01-01

    Lawrence Livermore National Laboratory is developing a 15 to 20 MeV electron accelerator with a beam current goal of 4 kA. This accelerator will be used for flash radiography and has a requirement of high reliability. Components being developed include spark gaps, Marx generators, water Blumleins and oil insulation systems. A SCEPTRE model was developed that takes into consideration the non-linearity of the ferrite and the time dependency of the emission from a field emitter cathode. This model was used to predict an optimum charge time to obtain maximum magnetic flux change from the ferrite. This model and its application will be discussed. JASON was used extensively to determine optimum locations and shapes of supports and insulators. It was also used to determine stress within bubbles adjacent to walls in oil. Computer results will be shown and bubble breakdown will be related to bubble size.

  9. Computer models in the design of FXR

    International Nuclear Information System (INIS)

    Vogtlin, G.; Kuenning, R.

    1980-01-01

    Lawrence Livermore National Laboratory is developing a 15 to 20 MeV electron accelerator with a beam current goal of 4 kA. This accelerator will be used for flash radiography and has a requirement of high reliability. Components being developed include spark gaps, Marx generators, water Blumleins and oil insulation systems. A SCEPTRE model was developed that takes into consideration the non-linearity of the ferrite and the time dependency of the emission from a field emitter cathode. This model was used to predict an optimum charge time to obtain maximum magnetic flux change from the ferrite. This model and its application will be discussed. JASON was used extensively to determine optimum locations and shapes of supports and insulators. It was also used to determine stress within bubbles adjacent to walls in oil. Computer results will be shown and bubble breakdown will be related to bubble size

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    secretagogue GHRP-6) plus four nonpeptide agonists-the original benzolactam L-692,429 [3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5-yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamide], the spiroindoline sulfonamide MK-677 [N-[1(R)-1, 2-dihydro-1-ethanesulfonylspiro-3H...

  11. Problems of normative strenght and critique within the concept of agonistic participation: Towards the complementarity of agonistic and participatory democracy

    Directory of Open Access Journals (Sweden)

    Đorđević Biljana

    2014-01-01

    Full Text Available In this article I argue that there are grounds for considering agonistic democracy and participatory democracy complementarity in order to institutionalize agonism which has thus far lacked an elaborate articulation of its institutional dimension. The two democratic theories share a commitment toward widening the scope of the political as a way of inclusion of citizens and their subsequent political subjectivation and empowerment. Furthermore, there are authors on both sides who think democracy does not need foundations. Agonistic participation and contestation, on the one hand, and the broadening and strengthening of various sectors of political participation, on the other, both open up new possibilities for critique and change, but also create new risks. Building on a redefinition of agonisitic participation, I aim to attenuate an objection that agonism is normatively weak in terms of lacking resources to motivate citizens and justify their critique of practices of domination and oppression. The article concludes that we need to embrace agonistic participation as a means towards the development of democratic political judgement, as there are no other guarantees, i.e. secure foundations, for our ability to distinguish between democratic and non-democratic agon. [Projekat Ministarstva nauke Republike Srbije, br. 47026: Konstitucionalizam i vladavina prava u izgradnji nacionalne države - slučaj Srbije

  12. 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

  13. Synthetic and computer assisted analysis of the pharmacophore for agonists at benzodiazepine receptors.

    Science.gov (United States)

    Diaz-Arauzo, H; Koehler, K F; Hagen, T J; Cook, J M

    1991-01-01

    In order to employ rational drug design in the discovery of selective benzodiazepine receptor agonists and inverse agonists, pharmacophore/receptor models for both these activities must first be established. Recently, a pharmacophore for the inverse agonist site has been formulated employing the most recent receptor mapping techniques (22). The continuation of this approach to the pharmacophore for agonist ligands has permitted a definition of this site independently of the inverse agonist model. The agonist pharmacophore/receptor contains two hydrogen bond donating sites of interaction (H1 and H2) located about 6.5 A from each other, as well as three areas of lipophilic interaction (L1-L3). The areas L1 and L2 are critical for agonist activity; moreover, some ligands also require an interaction in a third lipophilic area termed L3. This is in agreement with previous work (12-23). In addition, an area of negative steric interaction (S1) between the ligand and receptor-binding protein is defined. In regard to the pharmacophore, it was established that the alignment rule for agonist beta-carbolines is different from that which elicits inverse agonist activity. Consideration of the pharmacophore has resulted in the synthesis of a new beta-carboline 16 which elicits agonist activity. This ligand 16 not only satisfied the requirements of the pharmacophore, but more importantly it elicited both anticonvulsant and anxiolytic activity, but was devoid of the myorelaxant/ataxic properties associated with the benzodiazepines.

  14. Lipid- and polyion complex-based micelles as agonist platforms for TNFR superfamily receptors.

    Science.gov (United States)

    Gilbreth, Ryan N; Novarra, Shabazz; Wetzel, Leslie; Florinas, Stelios; Cabral, Horacio; Kataoka, Kazunori; Rios-Doria, Jonathan; Christie, Ronald J; Baca, Manuel

    2016-07-28

    Receptor clustering is important for signaling among the therapeutically relevant TNFR superfamily of receptors. In nature, this clustering is driven by trimeric ligands often presented in large numbers as cell surface proteins. Molecules capable of driving similar levels of clustering could make good agonists and hold therapeutic value. However, recapitulating such extensive clustering using typical biotherapeutic formats, such as antibodies, is difficult. Consequently, generating effective agonists of TNFR superfamily receptors is challenging. Toward addressing this challenge we have used lipid- and polyion complex-based micelles as platforms for presenting receptor-binding biologics in a multivalent format that facilitates receptor clustering and imparts strong agonist activity. We show that receptor-binding scFvs or small antibody mimetics that have no agonist activity on their own can be transformed into potent agonists through multivalent presentation on a micelle surface and that the activity of already active multivalent agonists can be enhanced. Using this strategy, we generated potent agonists against two different TNFR superfamily receptors and mouse tumor model studies demonstrate that these micellar agonists have therapeutic efficacy in vivo. Due to its ease of implementation and applicability independent of agonist molecular format, we anticipate that this strategy could be useful for developing agonists to a variety of receptors that rely on clustering to signal. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. α7 nicotinic receptor agonist reactivates neurogenesis in adult brain.

    Science.gov (United States)

    Narla, Sridhar; Klejbor, Ilona; Birkaya, Barbara; Lee, Yu-Wei; Morys, Janusz; Stachowiak, Ewa K; Terranova, Christopher; Bencherif, Merouane; Stachowiak, Michal K

    2013-10-15

    Reactivation of neurogenesis by endogenous Neural Stem/Progenitor Cells (NS/PC) in the adult brain or spinal cord holds the key for treatment of CNS injuries as well as neurodegenerative disorders, which are major healthcare issues for the world's aging population. Recent studies show that targeting the α7 nicotinic acetylcholine receptors (α7nAChR) with a specific TC-7020 agonist inhibits proliferation and stimulates neuronal differentiation of NS/PC in subventricular zone (SVZ) in the adult mouse brain. TC-7020-induced neuronogenesis is observed in different brain regions, including: (1) βIII Tubulin-expressing cortical neurons, (2) calretinin expressing hippocampal neurons and (3) cells in substantia nigra (SN) expressing predopaminergic Nurr1+phenotype. Reactivation of developmental integrative nuclear FGFR1 signaling (INFS), via gene transfection reinstates neurogenesis in the adult brain by promoting neuronal differentiation of brain NS/PC. TC-7020 neuronogenic effect is associated with a robust accumulation of endogenous FGFR1 in the nuclei of differentiating cells. Furthermore, direct in vitro stimulation of neural stem/progenitor cells with α7nAChR agonist activates INFS and neuronal-like differentiation and activation of neuronal genes. The α7nAChR upregulation of early neuronal βIII-Tubulin gene involves neurogenic FGFR1-Nur signaling and direct FGFR1 interaction with the gene promoter. The reactivation of developmental INFS and neurogenesis in adult brain by the α7nAChR agonist may offer new strategy to treat brain injuries, neurodegenerative and neurodevelopmental diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

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

    DEFF Research Database (Denmark)

    Kalsen, Anders

    2015-01-01

    athletes. The present PhD thesis is based on four manuscripts in which the acute effects of beta2-agonists on exercise performance were investigated. The aims were 1) to investigate whether supratherapeutic inhalation of beta2-agonists enhances muscle strength, anaerobic performance and aerobic performance...... that supratherapeutic inhalation of beta2-agonists increases muscle strength and improves performance during maximal sprinting lasting up to ~ 60 s, whereas no effect was observed on exercise lasting more than ~ 180 s. The ergogenic effects of beta2-agonists on power output during maximal sprinting requires......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...

  17. 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...... athletes. The present PhD thesis is based on four manuscripts in which the acute effects of beta2-agonists on exercise performance were investigated. The aims were 1) to investigate whether supratherapeutic inhalation of beta2-agonists enhances muscle strength, anaerobic performance and aerobic performance...... that supratherapeutic inhalation of beta2-agonists increases muscle strength and improves performance during maximal sprinting lasting up to ~ 60 s, whereas no effect was observed on exercise lasting more than ~ 180 s. The ergogenic effects of beta2-agonists on power output during maximal sprinting requires...

  18. Cardiovascular safety and benefits of GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Dalsgaard, Niels B; Brønden, Andreas; Lauritsen, Tina Vilsbøll

    2017-01-01

    INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss...... and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients...

  19. Potent small molecule Hedgehog agonists induce VEGF expression in vitro.

    Science.gov (United States)

    Seifert, Katrin; Büttner, Anita; Rigol, Stephan; Eilert, Nicole; Wandel, Elke; Giannis, Athanassios

    2012-11-01

    Here, we describe the synthesis, SAR studies as well as biological investigations of the known Hedgehog signaling agonist SAG and a small library of its analogues. The SAG and its derivatives were analyzed for their potency to activate the expression of the Hh target gene Gli1 in a reporter gene assay. By analyzing SAR important molecular descriptors for Gli1 activation have been identified. SAG as well as compound 10c proven to be potent activators of VEGF expression in cultivated dermal fibroblasts. Importantly and in contrast to SAG, derivative 10c displayed no toxicity in concentrations up to 250 μm. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    Science.gov (United States)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  1. Long-acting β2-agonists in asthma

    DEFF Research Database (Denmark)

    Jacobson, Glenn A; Raidal, Sharanne; Hostrup, Morten

    2018-01-01

    Long-acting β2-agonists (LABAs) such as formoterol and salmeterol are used for prolonged bronchodilatation in asthma, usually in combination with inhaled corticosteroids (ICSs). Unexplained paradoxical asthma exacerbations and deaths have been associated with LABAs, particularly when used without...... ICS. LABAs clearly demonstrate effective bronchodilatation and steroid-sparing activity, but long-term treatment can lead to tolerance of their bronchodilator effects. There are also concerns with regard to the effects of LABAs on bronchial hyperresponsiveness (BHR), where long-term use is associated...

  2. Innate Immune Responses to TLR2 and TLR4 Agonists Differ between Baboons, Chimpanzees and Humans

    Science.gov (United States)

    Brinkworth, Jessica F.; Pechenkina, Ekaterina A.; Silver, Jack; Goyert, Sanna M.

    2012-01-01

    Background African catarrhine primates differ in bacterial disease susceptibility. Methods Human, chimpanzee, and baboon blood was stimulated with TLR-detected bacterial agonists and cytokine/chemokine induction assessed by real-time pcr. Results Humans and chimpanzees shared similar cytokine/chemokine responses, while baboon cytokine/chemokine induction differed. Generally, responses were agonist-independent. Conclusions These primates tend to generate species rather than agonist–specific responses to bacterial agonists. PMID:22978822

  3. Glucagon-Like Peptide-1 Receptor Agonists: Beta-Cell Protection or Exhaustion?

    Science.gov (United States)

    van Raalte, Daniël H; Verchere, C Bruce

    2016-07-01

    Glucagon-like peptide (GLP)-1 receptor agonists enhance insulin secretion and may improve pancreatic islet cell function. However, GLP-1 receptor (GLP-1R) agonist treatment may have more complex, and sometimes deleterious, effects on beta cells. We discuss the concepts of beta cell protection versus exhaustion for different GLP-1R agonists based on recent data. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. 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....... The BALaglitazone glucose Lowering Efficacy Trial aimed to establish the glucose-lowering effects and safety parameters of the perioxisome proliferator-activated receptor-¿ partial agonist balaglitazone in diabetic patients on stable insulin therapy....

  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. Agonist signalling properties of radiotracers used for imaging of dopamine D2/3 receptors.

    Science.gov (United States)

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

    2014-01-01

    Dopamine D2/3 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 are more sensitive to detect dopamine release than antagonist radiopharmaceuticals, but this theory has been challenged. Interestingly, not all agonists similarly activate the classic cyclic adenosine mono phosphate (cAMP) and the ?-arrestin-2 pathway, some stimulate preferentially one of these pathways; a phenomenon called biased agonism. Because these pathways can be affected separately by pathologies or drugs (including dopamine releasers), it is important to know how agonist radiotracers act on these pathways. Therefore, we characterized the intracellular signalling of the well-known D2/3R agonist radiopharmaceuticals NPA and PHNO and of several novel D2/3R agonists. cAMP accumulation and ?-arrestin-2 recruitment were measured on cells expressing human D2R. All tested agonists showed (almost) full agonism in both pathways. The tested D2/3R agonist radiopharmaceuticals did not exhibit biased agonism in vitro. Consequently, it is likely that drugs (including psychostimulants like amphetamines) and/or pathologies that influence the cAMP and/or the ?-arrestin-2 pathway may influence the binding of these radiopharmaceuticals.

  7. 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...

  8. How does agonistic behaviour differ in albino and pigmented fish?

    Science.gov (United States)

    Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  9. 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.

  10. Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists

    Directory of Open Access Journals (Sweden)

    M.A. Quera Salva

    2012-04-01

    Full Text Available Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC. Melatonin (N-acetyl-5-hydroxytryptamine is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.

  11. 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.

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

    Science.gov (United States)

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

    2010-01-01

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

  13. 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.

  14. 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.

  15. Toll-Like Receptor 9 Agonists for Cancer Therapy.

    Science.gov (United States)

    Melisi, Davide; Frizziero, Melissa; Tamburrino, Anna; Zanotto, Marco; Carbone, Carmine; Piro, Geny; Tortora, Giampaolo

    2014-08-04

    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.

  16. Cannabidiol, a novel inverse agonist for GPR12.

    Science.gov (United States)

    Brown, Kevin J; Laun, Alyssa S; Song, Zhao-Hui

    2017-11-04

    GPR12 is a constitutively active, G s protein-coupled receptor that currently has no confirmed endogenous ligands. GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. In this study, the potential effects of various classes of cannabinoids on GPR12 were tested using a cAMP accumulation assay. Our data demonstrate that cannabidiol (CBD), a major non-psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD. The structure-activity relationship studies of CBD indicate that both the free hydroxyl and the pentyl side chain are crucial for the effects of CBD on GPR12. Furthermore, studies using cholera toxin, which blocks G s protein and pertussis toxin, which blocks G i protein, revealed that G s , but not G i is involved in the inverse agonism of CBD on GPR12. CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter viscoelasticity of metastatic cancer cells. Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. 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.

  18. NKT-cell glycolipid agonist as adjuvant in synthetic vaccine.

    Science.gov (United States)

    Liu, Zheng; Guo, Jun

    2017-11-27

    NKT cells are CD1d-restricted, glycolipid antigen-reactive, immunoregulatory T lymphocytes that can serve as a bridge between the innate and adaptive immunities. NKT cells have a wide range of therapeutic application in autoimmunity, transplant biology, infectious disease, cancer, and vaccinology. Rather than triggering "danger signal" and eliciting an innate immune response, αGalCer-based NKT-cell agonist act via a unique mechanism, recruiting NKT cells which play a T helper-like role even without peptide as Th epitope. Importantly, the non-polymorphism of CD1d render glycolipid a universal helper epitope, offering the potential to simplify the vaccine construct capable of eliciting consistent immune response in different individuals. This review details recent advances in the design of synthetic vaccines using NKT-cell agonist as adjuvant, highlighting the role of organic synthesis and conjugation technique to enhance the immunological actives and to simplify the vaccine constructs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    International Nuclear Information System (INIS)

    Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.

    1985-01-01

    The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with [ 3 H]-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT 2 antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT 2 type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures

  20. Effect of obeticholic acid on liver regeneration following portal vein embolization in an experimental model

    NARCIS (Netherlands)

    Olthof, P. B.; Huisman, F.; Schaap, F. G.; van Lienden, K. P.; Bennink, R. J.; van Golen, R. F.; Heger, M.; Verheij, J.; Jansen, P. L.; Olde Damink, S. W.; van Gulik, T. M.

    2017-01-01

    The bile salt-activated transcription factor farnesoid X receptor (FXR) is a key mediator of proliferative bile salt signalling, which is assumed to play a role in the early phase of compensatory liver growth. The aim of this study was to evaluate the effect of a potent FXR agonist (obeticholic

  1. Do β-adrenoceptor agonists induce homologous or heterologous desensitization in rat urinary bladder?

    Science.gov (United States)

    Michel, Martin C

    2014-03-01

    β3-Adrenoceptor agonists have recently been introduced for the symptomatic treatment of the overactive bladder syndrome. As such treatment is not curative, long-term treatment is anticipated to be required. As the susceptibility of β3-adrenoceptors to undergo agonist-induced desensitization is cell type- and tissue-dependent, we have explored whether pre-treatment with a β-adrenoceptor agonist will attenuate subsequent relaxation responses to freshly added agonist using rat urinary bladder as a model. We have used the prototypical β-adrenoceptor agonist isoprenaline, the β2-selective fenoterol and the β3-selective CL 316,243 and mirabegron as well as the receptor-independent bladder relaxant forskolin. We show that a 6-h pre-treatment with agonist can significantly reduce subsequent relaxation against KCl-induced smooth muscle tone, but agonist-induced desensitization was also observed with longer pre-treatments or against passive tension. The agonist-induced desensitization was prominent for the β2 component of rat bladder relaxation but much weaker or even absent for the β3 component. Moreover, β-adrenoceptor agonist pre-treatment reduced contractile responses to the muscarinic agonist carbachol and the receptor-independent stimulus KCl. Taken together these data do not support the hypothesis that the long-term clinical efficacy of β3-adrenoceptor agonists in the treatment of the overactive bladder syndrome will be limited by receptor desensitization. Rather they raise the possibility that such treatment may not only cause smooth muscle relaxation but also may attenuate hyper-contractility of the bladder.

  2. 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

  3. 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...

  4. Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists

    DEFF Research Database (Denmark)

    Palmer, Daniel; Gonçalves, Juliana P.L.; Hansen, Louise V.

    2017-01-01

    were synthesized by solid phase click chemistry to develop novel, potent, selective MC4R agonists. Using cAMP measurements and a transcriptional reporter assay, we observed that several constrained agonists generated by a cycloaddition reaction displayed high selectivity (223- to 467-fold) toward MC4R...

  5. Low-dose add-back therapy during postoperative GnRH agonist treatment

    Directory of Open Access Journals (Sweden)

    Hsiao-Wen Tsai

    2016-02-01

    Conclusion: Low dose add-back therapy could effectively ameliorate hypoestrogenic side effects and simultaneously maintain the therapeutic response of GnRH agonist treatment. The treatment dropout was lower compared with a regular dose. Therefore, low dose add-back therapy can be considered a treatment choice during postoperative GnRH agonist treatment.

  6. 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

  7. Major drawbacks and additional benefits of agonist trigger--not ovarian hyperstimulation syndrome related

    DEFF Research Database (Denmark)

    Shapiro, Bruce S; Andersen, Claus Yding

    2015-01-01

    The GnRH agonist trigger alters traditional IVF paradigms when compared with hCG-only triggers. The agonist trigger induces rapid luteolysis and therefore separates the oocyte maturation aspect of LH from the luteal support previously afforded by lingering hCG. This might allow customized and mor...

  8. 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...

  9. Effects of â2-agonist therapy on blood pressure, glycaemic control ...

    African Journals Online (AJOL)

    Introduction: the blood pressure, glycaemic control and electrolyte concentrations are influenced by autonomic nervous system and are expected to be affected by beta-2 agonist medications commonly used by asthmatic patients. Objective:The objective of this study is to detect the possible effects of beta-2 agonist ...

  10. Structure and function of an irreversible agonist-β(2) adrenoceptor complex

    DEFF Research Database (Denmark)

    Rosenbaum, Daniel M; Zhang, Cheng; Lyons, Joseph A

    2011-01-01

    G-protein-coupled receptors (GPCRs) are eukaryotic integral membrane proteins that modulate biological function by initiating cellular signalling in response to chemically diverse agonists. Despite recent progress in the structural biology of GPCRs, the molecular basis for agonist binding and all...

  11. PPAR Agonists: Potential as Therapeutics for Neovascular Retinopathies

    Directory of Open Access Journals (Sweden)

    Harrihar A. Pershadsingh

    2008-01-01

    Full Text Available The angiogenic, neovascular proliferative retinopathies, proliferative diabetic retinopathy (PDR, and age-dependent macular degeneration (AMD complicated by choroidal neovascularization (CNV, also termed exudative or “wet” AMD, are common causes of blindness. The antidiabetic thiazolidinediones (TZDs, rosiglitazone, and troglitazone are PPAR agonists with demonstrable antiproliferative, and anti-inflammatory effects, in vivo, were shown to ameliorate PDR and CNV in rodent models, implying the potential efficacy of TZDs for treating proliferative retinopathies in humans. Activation of the angiotensin II type 1 receptor (AT1-R propagates proinflammatory and proliferative pathogenic determinants underlying PDR and CNV. The antihypertensive dual AT1-R blocker (ARB, telmisartan, recently was shown to activate PPAR and improve glucose and lipid metabolism and to clinically improve PDR and CNV in rodent models. Therefore, the TZDs and telmisartan, clinically approved antidiabetic and antihypertensive drugs, respectively, may be efficacious for treating and attenuating PDR and CNV humans. Clinical trials are needed to test these possibilities.

  12. Emerging corticosteroid agonists for the treatment of asthma

    DEFF Research Database (Denmark)

    Westergaard, Christian G; Porsbjerg, Celeste; Backer, Vibeke

    2015-01-01

    approved ICS show improved pharmocodynamic properties. Nevertheless, emerging drugs acting on the same receptor as the ICS, glucocorticoid receptor agonists (GRAs), are under current research. These drugs exhibit selective action on the glucocorticoid receptor (GR), which may improve their adverse effect...... profile, compared to the currently approved ICS that act unselectively on the GR. AREAS COVERED: The present article reviews emerging GRAs for the treatment of asthma. Furthermore, the more recently approved ICS with improved safety profiles are reviewed. EXPERT OPINION: Compared with drugs acting...... on other pathological pathways, research in GRAs for asthma is sparse. However, a few promising agents acting selectively on the GR are currently under investigation and may reach approval for asthma treatment. These drugs exhibit improved pharmacodynamic properties due to selectivity in the mechanism...

  13. Use of thrombopoietin receptor agonists in childhood immune thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Angelica Maria Garzon

    2015-08-01

    Full Text Available Most children with immune thrombocytopenia (ITP will have spontaneous remission regardless of therapy, while about 20% will go on to have chronic ITP. In those children with chronic ITP who need treatment, standard therapies for acute ITP may have adverse effects that complicate their long term use. Thus, alternative treatment options are needed for children with chronic ITP. Thrombopoietin receptor agonists (TPO-RA have been shown to be safe and efficacious in adults with ITP, and represent a new treatment option for children with chronic ITP. One TPO-RA, eltrombopag, is now approved for children. Clinical trials in children are ongoing and data is emerging on safety and efficacy. This review will focus on the physiology of TPO-RA, their clinical use in children, as well as the long term safety issues that need to be considered when using these agents

  14. [Safety and tolerability of GLP-1 receptor agonists].

    Science.gov (United States)

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  15. Inverse agonistic activity of antihistamines and suppression of histamine H1 receptor gene expression.

    Science.gov (United States)

    Mizuguchi, Hiroyuki; Ono, Shohei; Hattori, Masashi; Fukui, Hiroyuki

    2012-01-01

    Histamine H(1) receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R gene expression. Two inverse agonists (carebastine and mepyramine), but not the neutral antagonist oxatomide, decreased inositol phosphate accumulation. The inverse agonists also decreased H1R gene expression and down-regulated H1R mRNA below basal expression, while basal H1R mRNA expression was maintained after oxatomide treatment. These results suggest that inverse agonists more potently alleviate allergy symptoms by not only inhibiting stimulus-induced up-regulation of H1R gene expression but also by suppressing basal histamine signaling through their inverse agonistic activity.

  16. 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.

  17. 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.

    2012-01-01

    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 A1 receptor (A1R). In contrast, AMP only activated the adenosine A2B receptor (A2BR) after hydrolysis to adenosine by ecto-5′-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A1R 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 A1R. 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 A1R 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 A1R. 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. PMID:22215671

  18. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Science.gov (United States)

    Frank, Guido K. W.

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  19. Theory of partial agonist activity of steroid hormones

    Directory of Open Access Journals (Sweden)

    Carson C. Chow

    2015-04-01

    Full Text Available The different amounts of residual partial agonist activity (PAA of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS, which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists.

  20. 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.

  1. Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

    Science.gov (United States)

    Gill, JasKiran K.; Savolainen, Mari; Young, Gareth T.; Zwart, Ruud; Sher, Emanuele; Millar, Neil S.

    2011-01-01

    Conventional nicotinic acetylcholine receptor (nAChR) agonists, such as acetylcholine, act at an extracellular “orthosteric” binding site located at the interface between two adjacent subunits. Here, we present evidence of potent activation of α7 nAChRs via an allosteric transmembrane site. Previous studies have identified a series of nAChR-positive allosteric modulators (PAMs) that lack agonist activity but are able to potentiate responses to orthosteric agonists, such as acetylcholine. It has been shown, for example, that TQS acts as a conventional α7 nAChR PAM. In contrast, we have found that a compound with close chemical similarity to TQS (4BP-TQS) is a potent allosteric agonist of α7 nAChRs. Whereas the α7 nAChR antagonist metyllycaconitine acts competitively with conventional nicotinic agonists, metyllycaconitine is a noncompetitive antagonist of 4BP-TQS. Mutation of an amino acid (M253L), located in a transmembrane cavity that has been proposed as being the binding site for PAMs, completely blocks agonist activation by 4BP-TQS. In contrast, this mutation had no significant effect on agonist activation by acetylcholine. Conversely, mutation of an amino acid located within the known orthosteric binding site (W148F) has a profound effect on agonist potency of acetylcholine (resulting in a shift of ∼200-fold in the acetylcholine dose-response curve), but had little effect on the agonist dose-response curve for 4BP-TQS. Computer docking studies with an α7 homology model provides evidence that both TQS and 4BP-TQS bind within an intrasubunit transmembrane cavity. Taken together, these findings provide evidence that agonist activation of nAChRs can occur via an allosteric transmembrane site. PMID:21436053

  2. Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations.

    Science.gov (United States)

    Carris, Nicholas W; Taylor, James R; Gums, John G

    2014-12-01

    Most patients with diabetes mellitus require multiple medications to achieve glycemic goals. Considering this and the increasing incidence of type 2 diabetes worldwide, the need for effective combination therapy is pressing. Basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. Though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. This review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin-GLP-1 receptor agonist regimen. Basal insulin added to a GLP-1 receptor agonist reduces hemoglobin A1c (HbA1c) without weight gain or significantly increased hypoglycemia. A GLP-1 receptor agonist added to basal insulin reduces HbA1c and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA1c, weight loss instead of weight gain, and less hypoglycemia. Gastrointestinal adverse events are common with GLP-1 receptor agonists, especially during initiation and titration. However, combination with basal insulin is not expected to augment expected adverse events that come with using a GLP-1 receptor agonist. Basal insulin can be added to a GLP-1 receptor agonist with a slow titration to target goal fasting plasma glucose. In patients starting a GLP-1 receptor agonist, the dose of basal insulin should be decreased by 20 % in patients with an HbA1c ≤8 %. The evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes.

  3. Association Between Benzodiazepine Receptor Agonists and Snoring Among Women in the Nurses' Health Study.

    Science.gov (United States)

    Lin, Brian M; Hu, Frank B; Curhan, Gary C

    2017-02-01

    Snoring is highly prevalent among adults. The use of benzodiazepine receptor agonists is also common, with higher prevalence of use with more advanced age. Benzodiazepine receptor agonists cause muscle relaxation, which may affect muscle tone and airway dynamics and thereby increase snoring. Previous studies examining the association between use of benzodiazepine receptor agonists and snoring were underpowered to detect clinically meaningful differences or did not report the magnitude of association. To investigate the association between use of benzodiazepine receptor agonists and snoring in women. Women aged 62 to 86 years provided information on snoring and covariates of interest in the 2008 survey of the Nurses' Health Study, a cross-sectional cohort study of female registered nurses in the United States. Potential effect modification of the association between use of benzodiazepine receptor agonists and snoring by age, body mass index, waist circumference, smoking, alcohol consumption, and physical activity was explored. Logistic regression was used to adjust for potential confounders. Data analysis was conducted from November 2015 to March 2016. Self-reported habitual snoring, defined as a few nights a week or more. Of 52 504 participants (mean [SD] age, 72.4 [6.7] years), 14 831 (28.2%) reported habitual snoring. There was a slightly higher prevalence of benzodiazepine receptor agonist use among habitual snorers (11.4%) compared with nonhabitual snorers (10.6%) (absolute difference, 0.8%; 95% CI, 0.2%-1.4%). After multivariable adjustment, use of benzodiazepine receptor agonists was not associated with snoring (odds ratio, 1.01; 95% CI, 0.95-1.07) compared with women who did not use benzodiazepine receptor agonists. Although there was no significant interaction with smoking, there were higher odds of snoring with use of benzodiazepine receptor agonists among current smokers (odds ratio, 1.34; 95% CI, 1.04-1.73). Use of benzodiazepine receptor agonists is

  4. Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.

    Science.gov (United States)

    Pan, Shi; Sharma, Pawan; Shah, Sushrut D; Deshpande, Deepak A

    2017-07-01

    Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases. Copyright © 2017 the American Physiological

  5. The emergence of devastating impulse control disorders during dopamine agonist therapy of the restless legs syndrome.

    Science.gov (United States)

    Dang, Dien; Cunnington, David; Swieca, John

    2011-01-01

    The Restless Legs Syndrome is a common sensorimotor disorder, typically amenable to treatment with dopamine agonist therapy. Dopamine agonists have been associated with emergent impulse control disorders (ICDs) when used in patients with Parkinson disease, and ICDs have now been reported in individuals with RLS on dopamine agonist therapy. Our aim was to characterize cases of emergent ICDs in Australian patients with focus on the dopamine agonists implicated and the social significance of ICDs. A series of RLS patients on dopamine agonist therapy were identified with ICDs over a 2-year period. Additional cases of ICDs were found using a mailout questionnaire designed to capture those with high impulsivity. These patients were assessed using the Barratt Impulsiveness Scale, Version 11, and a modified Minnesota Impulse Disorders Interview. Case records and medication schedules were evaluated. Twelve cases of patients with de novo ICDs were found with a range of impulsive behaviors including pathological gambling, kleptomania, compulsive shopping, and hypersexuality. Criminality, suicidality, and marital discord also were featured. These occurred over a wide range of latencies and l-dopa exposures. This group of Australian RLS patients with ICDs display high levels of impulsivity and is the first to use the BIS-11 questionnaire in this setting. Impulse control disorders can occur over a wide range of dopamine agonist therapy types and dose exposures. Impulse control disorder tendencies may persist, despite withdrawal of dopamine agonists. The emergence of ICDs needs careful consideration in light of their potentially devastating financial, social, and marital consequences.

  6. Association of dopamine agonist use with impulse control disorders in Parkinson disease.

    Science.gov (United States)

    Weintraub, Daniel; Siderowf, Andrew D; Potenza, Marc N; Goveas, Joseph; Morales, Knashawn H; Duda, John E; Moberg, Paul J; Stern, Matthew B

    2006-07-01

    To determine the frequency and correlates of impulse control disorders (ICDs) in Parkinson disease (PD). An unstructured screening interview for ICDs (compulsive gambling, buying, and sexual behavior) followed by a telephone-administered structured interview for screen-positive patients. Two university-affiliated movement disorders centers. A convenience sample of 272 patients with idiopathic PD who were screened for psychiatric complications. Presence of compulsive gambling, buying, or sexual behavior as assessed by the Minnesota Impulsive Disorders Interview. Eighteen patients (6.6%) with PD met criteria for an ICD at some point during the course of PD, including 11 (4.0%) with an active ICD. Compulsive gambling and compulsive sexual behavior were equally common. In a multivariate model, treatment with a dopamine agonist (P = .01) and a history of ICD symptoms prior to PD onset (P = .02) predicted current ICD. There were no differences between the dopamine agonists in their association with ICDs (P = .21), and daily doses of dopamine agonists were higher in patients with an ICD than in dopamine agonist-treated patients without an ICD (P < .001). Patients with PD treated with a dopamine agonist should be made aware of the risk of developing an ICD and monitored clinically. Because dopamine agonists are increasingly being used for other indications, future research should assess the dopamine agonist-associated risk for ICDs in other populations.

  7. Dopamine Agonist Use is Associated with Impulse Control Disorders in Parkinson’s Disease

    Science.gov (United States)

    Weintraub, Daniel; Siderowf, Andrew D.; Potenza, Marc N.; Goveas, Joseph; Morales, Knashawn H.; Duda, John E.; Moberg, Paul J.; Stern, Matthew B.

    2006-01-01

    Objective To determine the frequency and correlates of impulse control disorders (ICDs) in Parkinson’s disease (PD). Design An unstructured screening interview for ICDs (compulsive gambling, buying, and sexual behavior) followed by a telephone-administered structured interview for screen-positive patients. Setting Two university-affiliated movement disorders centers. Participants A convenience sample of 272 patients with idiopathic PD who were screened for psychiatric complications. Main Outcome Measures Presence of compulsive gambling, buying, or sexual behavior as assessed by the Minnesota Impulsive Disorders Interview. Results Eighteen (6.6%) PD patients met criteria for an ICD at some point during the course of PD, including 11 (4.0%) with an active ICD. Compulsive gambling and compulsive sexual behavior were equally common. In a multivariate model, treatment with a dopamine agonist (P = .01) and a history of ICD symptomatology prior to PD onset (P = .02) predicted current ICD. There were no differences between the dopamine agonists in their association with ICDs (P = .21), and daily doses of dopamine agonists were higher in patients with an ICD than in dopamine agonist-treated patients without an ICD (P < .001). Conclusions PD patients treated with a dopamine agonist should be made aware of the risk of developing an ICD and monitored clinically. As dopamine agonists are increasing being used for other indications, future research should assess the dopamine agonist-associated risk for ICDs in other populations. PMID:16831966

  8. Serotonin 2A receptor agonist binding in the human brain with [C]Cimbi-36

    DEFF Research Database (Denmark)

    Ettrup, A.; da Cunha-Bang, S.; McMahon, Barry P.

    2014-01-01

    [C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely ....... Thus, we here describe [C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT receptors in the human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 30 April 2014; doi:10.1038/jcbfm.2014.68.......[C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely...... than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT receptors with [C]Cimbi-36 PET. The two-tissue compartment model using arterial input...

  9. The Role of Agonistic Striving in the Association Between Cortisol and High Blood Pressure.

    Science.gov (United States)

    Ewart, Craig K; Elder, Gavin J; Jorgensen, Randall S; Fitzgerald, Sheila T

    2017-05-01

    A social action theory of chronic stress proposes that agonistic striving (seeking to influence or control others) impairs cardiovascular health by magnifying the impact of high adversity-induced cortisol levels on blood pressure. We tested three predictions of social action theory: (1) the social action theory taxonomy of regulatory strivings characterizes young adults from high-adversity neighborhoods; (2) high cortisol levels predict high blood pressure more reliably in the subgroup with the agonistic striving profile than in subgroups with other profiles; (3) the association of higher cortisol and higher blood pressure with agonistic striving is not explained by negative affect (depressive symptoms/dysphoria, anger, hostility). Participants were young adults (N = 198, mean [SD] age = 32 [3.4] years); 71% female; 65% black) from disadvantaged urban neighborhoods. Motive profiles (including agonistic strivings) were assessed using the Social Competence Interview. Cortisol levels were derived from saliva samples; blood pressure level was obtained during two days of ambulatory monitoring. Psychological measures of negative affect were assessed using questionnaires. The predicted taxonomy of regulatory strivings was replicated in this sample; the interaction between cortisol and motive profile was significant (F(2, 91) = 6.72, p = .002); analyses of simple effects disclosed that higher cortisol levels predicted higher ambulatory blood pressure only in individuals who exhibited agonistic striving. Depressive symptoms/dysphoria, trait anger, and hostility were not correlated with agonistic striving, cortisol, or blood pressure. Agonistic striving may represent a distinctive (and novel) social-cognitive mechanism of toxic stress and cardiovascular risk.

  10. The Effect of PPAR Agonists on the Migration of Mature and Immature Eosinophils

    Directory of Open Access Journals (Sweden)

    Steven G. Smith

    2012-01-01

    Full Text Available PPARγ agonists can either enhance or inhibit eosinophil migration, which is a sum of directional migration (chemotaxis and random cell movement (chemokinesis. To date, the effects of PPAR agonists on chemokinesis have not been examined. This study investigates the effects of PPARα, δ, and γ agonists on eosinophil migration and chemokinesis. Eosinophils purified from blood of atopic donors were preincubated with rosiglitazone (PPARγ agonist, GW9578 (PPARα agonist, GW501516 (PPARδ agonist, or diluent. The effects of PPAR agonists were examined on eosinophil chemokinesis, eotaxin-induced migration of eosinophils, and migration of IL-5Rα+ CD34+ cells. Expressions of CCR3, phospho-p38, phospho-ERK, and calcium release were also measured in eosinophils after rosiglitazone treatment. Low concentrations of rosiglitazone, but not GW9578 or GW501516, increased chemokinesis of eosinophils (P=0.0038, and SDF-1α-induced migration of immature eosinophils (P=0.0538. Rosiglitazone had an effect on eosinophil calcium flux but had no effect on expression of CCR3 or phosphorylation of p38 or ERK. In contrast, high concentrations of rosiglitazone inhibited eosinophil migration (P=0.0042. The effect of rosiglitazone on eosinophil migration and chemokinesis appears to be through modification of calcium signaling, which alludes to a novel PPAR-mediated mechanism to modulate eosinophil function.

  11. Ascorbic acid enables reversible dopamine receptor 3H-agonist binding

    International Nuclear Information System (INIS)

    Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.

    1981-01-01

    The effects of ascorbic acid on dopaminergic 3 H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the 3 H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total 3 H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable 3 H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable 3 H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of 3 H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific 3 H-agonist binding to dopamine receptors

  12. Usefulness of HeLa cells to evaluate inverse agonistic activity of antihistamines.

    Science.gov (United States)

    Mizuguchi, Hiroyuki; Ono, Shohei; Hattori, Masashi; Sasaki, Yohei; Fukui, Hiroyuki

    2013-03-01

    Antihistamines are thought to antagonize histamine and prevent it from binding to the histamine H1 receptor (H1R). However, recent studies indicate that antihistamines are classified into two groups, i.e., inverse agonists and neutral antagonists on the basis of their ability to down-regulate the constitutive activity of H1R. As H1R is an allergy-sensitive gene whose expression influences the severity of allergic symptoms, inverse agonists should more potently alleviate allergic symptoms than neutral antagonists by inhibiting H1R constitutive activity. Therefore, it is important to assess inverse agonistic activity of antihistamines. Here we report a novel assay method using HeLa cells expressing H1R endogenously for evaluation of inverse agonistic activity of antihistamines. Pretreatment with inverse agonists down-regulated H1R gene expression below to its basal level. On the other hand, basal H1R mRNA expression was unchanged by neutral antagonist pretreatment. Both inverse agonists and neutral antagonists suppressed histamine-induced H1R mRNA elevation. Classification of antihistamines on the basis of their suppressive activity of basal H1R gene expression was consistent with that of inositol phosphate accumulation in H1R-overexpressed cells. Our data suggest that the assay method using HeLa cells is more convenient and useful than the existing methods and may contribute to develop new antihistamines with inverse agonistic activity. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    Energy Technology Data Exchange (ETDEWEB)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail: kumamote@cc.saga-u.ac.jp

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  14. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    International Nuclear Information System (INIS)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-01-01

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC 50 values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC 50 = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other

  15. Regulation of ventilation and oxygen consumption by delta- and mu-opioid receptor agonists.

    Science.gov (United States)

    Schaeffer, J I; Haddad, G G

    1985-09-01

    To study the effect of endorphins on metabolic rate and on the relationship between O2 consumption (VO2) and ventilation, we administered enkephalin analogues (relatively selective delta-receptor agonists) and a morphiceptin analogue (a highly selective mu-receptor agonist) intracisternally in nine unanesthetized chronically instrumented adult dogs. Both delta- and mu-agonists decreased VO2 by 40-60%. delta-Agonists induced a dose-dependent decrease in mean instantaneous minute ventilation (VT/TT) associated with periodic breathing. The decrease in VT/TT started and resolved prior to the decrease and returned to baseline of VO2, respectively. In contrast, the mu-agonists induced an increase in VT/TT associated with rapid shallow breathing. Arterial PCO2 increased and arterial PO2 decreased after both delta- and mu-agonists. Low doses of intracisternal naloxone (0.002-2.0 micrograms/kg) reversed the opioid effect on VT/TT but not on VO2; higher doses of naloxone (5-25 micrograms/kg) reversed both. Naloxone administered alone had no effect on VT/TT or VO2. These data suggest that 1) both delta- and mu-agonists induce alveolar hypoventilation despite a decrease in VO2, 2) this hypoventilation results from a decrease in VT/TT after delta-agonists but an increase in dead space ventilation after mu-agonists, and 3) endorphins do not modulate ventilation and metabolic rate tonically, but we speculate that they may do so in response to stressful stimulation.

  16. TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors

    Directory of Open Access Journals (Sweden)

    Teagan R. Wall

    2017-09-01

    Full Text Available (E-5-(Pyrimidin-5-yl-1,2,3,4,7,8-hexahydroazocine (TC299423 is a novel agonist for nicotinic acetylcholine receptors (nAChRs. We examined its efficacy, affinity, and potency for α6β2∗ (α6β2-containing, α4β2∗, and α3β4∗ nAChRs, using [125I]-epibatidine binding, whole-cell patch-clamp recordings, synaptosomal 86Rb+ efflux, [3H]-dopamine release, and [3H]-acetylcholine release. TC299423 displayed an EC50 of 30–60 nM for α6β2∗ nAChRs in patch-clamp recordings and [3H]-dopamine release assays. Its potency for α6β2∗ in these assays was 2.5-fold greater than that for α4β2∗, and much greater than that for α3β4∗-mediated [3H]-acetylcholine release. We observed no major off-target binding on 70 diverse molecular targets. TC299423 was bioavailable after intraperitoneal or oral administration. Locomotor assays, measured with gain-of-function, mutant α6 (α6L9′S nAChR mice, show that TC299423 elicits α6β2∗ nAChR-mediated responses at low doses. Conditioned place preference assays show that low-dose TC299423 also produces significant reward in α6L9′S mice, and modest reward in WT mice, through a mechanism that probably involves α6(non-α4β2∗ nAChRs. However, TC299423 did not suppress nicotine self-administration in rats, indicating that it did not block nicotine reinforcement in the dosage range that was tested. In a hot-plate test, TC299423 evoked antinociceptive responses in mice similar to those of nicotine. TC299423 and nicotine similarly inhibited mouse marble burying as a measure of anxiolytic effects. Taken together, our data suggest that TC299423 will be a useful small-molecule agonist for future in vitro and in vivo studies of nAChR function and physiology.

  17. Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization

    Directory of Open Access Journals (Sweden)

    Paul Fredrickson

    2014-01-01

    Full Text Available Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a “gateway drug”. Neurotensin (NT is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13 analog, blocks behavioral sensitization (an animal model for psychostimulant addiction to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

  18. Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

    Directory of Open Access Journals (Sweden)

    Fabrizio Fierro

    2017-09-01

    Full Text Available Human G-protein coupled receptors (hGPCRs constitute a large and highly pharmaceutically relevant membrane receptor superfamily. About half of the hGPCRs' family members are chemosensory receptors, involved in bitter taste and olfaction, along with a variety of other physiological processes. Hence these receptors constitute promising targets for pharmaceutical intervention. Molecular modeling has been so far the most important tool to get insights on agonist binding and receptor activation. Here we investigate both aspects by bioinformatics-based predictions across all bitter taste and odorant receptors for which site-directed mutagenesis data are available. First, we observe that state-of-the-art homology modeling combined with previously used docking procedures turned out to reproduce only a limited fraction of ligand/receptor interactions inferred by experiments. This is most probably caused by the low sequence identity with available structural templates, which limits the accuracy of the protein model and in particular of the side-chains' orientations. Methods which transcend the limited sampling of the conformational space of docking may improve the predictions. As an example corroborating this, we review here multi-scale simulations from our lab and show that, for the three complexes studied so far, they significantly enhance the predictive power of the computational approach. Second, our bioinformatics analysis provides support to previous claims that several residues, including those at positions 1.50, 2.50, and 7.52, are involved in receptor activation.

  19. PPAR and Agonists against Cancer: Rational Design of Complementation Treatments

    Directory of Open Access Journals (Sweden)

    Dorina Veliceasa

    2008-01-01

    Full Text Available PPAR is a member of the ligand-activated nuclear receptor superfamily: its ligands act as insulin sensitizers and some are approved for the treatment of metabolic disorders in humans. PPAR has pleiotropic effects on survival and proliferation of multiple cell types, including cancer cells, and is now subject of intensive preclinical cancer research. Studies of the recent decade highlighted PPAR role as a potential modulator of angiogenesis in vitro and in vivo. These observations provide an additional facet to the PPAR image as potential anticancer drug. Currently PPAR is regarded as an important target for the therapies against angiogenesis-dependent pathological states including cancer and vascular complications of diabetes. Some of the studies, however, identify pro-angiogenic and tumor-promoting effects of PPAR and its ligands pointing out the need for further studies. Below, we summarize current knowledge of PPAR regulatory mechanisms and molecular targets, and discuss ways to maximize the beneficial activity of the PPAR agonists.

  20. PPAR agonists, - Could tissue targeting pave the way?

    Science.gov (United States)

    Bugge, Anne; Holst, Dorte

    2017-05-01

    Over the last couple of decades, the PPAR family of transcription factors has received much attention from the pharmaceutical industry due to their profound ability to improve glucose and lipid metabolism upon agonist activation. However, more recently the interest in these nuclear receptors has faded because several clinical trials have shown that it is difficult to develop a ligand that significantly ameliorates glucose and lipid metabolism disorders without concomitantly inducing unacceptable side-effects. Nevertheless, the data also suggests that tissue specific targeting could pave the way to renewed interest and clinical use of PPAR ligands. In this review we summarize the results and learnings from the clinical trials on PPAR agonism and discuss the possibilities for tissue targeting of PPAR ligands by using state of the art technology to fuse them to peptides homing selectively to tissues expressing the cognate surface receptor. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  1. Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist.

    Science.gov (United States)

    Bandholtz, Sebastian; Erdmann, Sarah; von Hacht, Jan Lennart; Exner, Samantha; Krause, Gerd; Kleinau, Gunnar; Grötzinger, Carsten

    2016-11-23

    This study investigated the role of individual U-II amino acid positions and side chain characteristics important for U-IIR activation. A complete permutation library of 209 U-II variants was studied in an activity screen that contained single substitution variants of each position with one of the other 19 proteinogenic amino acids. Receptor activation was measured using a cell-based high-throughput fluorescence calcium mobilization assay. We generated the first complete U-II substitution map for U-II receptor activation, resulting in a detailed view into the structural features required for receptor activation, accompanied by complementary information from receptor modeling and ligand docking studies. On the basis of the systematic SAR study of U-II, we created 33 further short and linear U-II variants from eight to three amino acids in length, including d- and other non-natural amino acids. We identified the first high-potency linear U-II analogues. Urolinin, a linear U-II agonist (nWWK-Tyr(3-NO 2 )-Abu), shows low nanomolar potency as well as improved metabolic stability.

  2. Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin-1 receptor in the grey squirrel (Sciurus carolinensis).

    Science.gov (United States)

    McRobie, Helen R; King, Linda M; Fanutti, Cristina; Symmons, Martyn F; Coussons, Peter J

    2014-06-27

    The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RΔ24) variant. We demonstrate that the MC1RΔ24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RΔ24. We conclude that the deletion in the MC1RΔ24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  3. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

    Science.gov (United States)

    Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

    2013-01-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

  4. Comparison of Agonist vs. Antagonist Stimulation on Triceps Surae Spasticity in Spinal Cord

    Directory of Open Access Journals (Sweden)

    Sneha Khanna

    2017-06-01

    Discussion: This study provides evidence that both agonist electrical stimulation and antagonist electrical stimulations are equally effective in reducing spasticity in triceps surae muscle in patients with spinal cord injury.

  5. Minimal_Set_of_In_Vitro_ER_Agonist_Assays_Selection_RegToxPharm_Data

    Data.gov (United States)

    U.S. Environmental Protection Agency — A dataset for the manuscript which demonstrates that it is possible to achieve levels of performance equivalent to the full 16 assay ER agonist model against both in...

  6. Agonists of fibroblast growth factor receptor induce neurite outgrowth and survival of cerebellar granule neurons

    DEFF Research Database (Denmark)

    Li, Shizhong; Christensen, Claus; Køhler, Lene B

    2009-01-01

    Fibroblast growth factor receptor (FGFR) signaling is pivotal in the regulation of neurogenesis, neuronal differentiation and survival, and synaptic plasticity both during development and in adulthood. In order to develop low molecular weight agonists of FGFR, seven peptides, termed hexafins...

  7. Crystal structure of the GLP-1 receptor bound to a peptide agonist.

    Science.gov (United States)

    Jazayeri, Ali; Rappas, Mathieu; Brown, Alastair J H; Kean, James; Errey, James C; Robertson, Nathan J; Fiez-Vandal, Cédric; Andrews, Stephen P; Congreve, Miles; Bortolato, Andrea; Mason, Jonathan S; Baig, Asma H; Teobald, Iryna; Doré, Andrew S; Weir, Malcolm; Cooke, Robert M; Marshall, Fiona H

    2017-06-08

    Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an α-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.

  8. Structure and biological activity of endogenous and synthetic agonists of GPR119

    Science.gov (United States)

    Tyurenkov, I. N.; Ozerov, A. A.; Kurkin, D. V.; Logvinova, E. O.; Bakulin, D. A.; Volotova, E. V.; Borodin, D. D.

    2018-02-01

    A G-protein-coupled receptor, GPR119, is a promising pharmacological target for a new class of hypoglycaemic drugs with an original mechanism of action, namely, increase in the glucose-dependent incretin and insulin secretion. In 2005, the first ligands were found and in the subsequent years, a large number of GPR119 agonists were synthesized in laboratories in various countries; the safest and most promising agonists have entered phase I and II clinical trials as agents for the treatment of type 2 diabetes mellitus and obesity. The review describes the major endogenous GPR119 agonists and the main trends in the design and modification of synthetic structures for increasing the hypoglycaemic activity. The data on synthetic agonists are arranged according to the type of the central core of the molecules. The bibliography includes 104 references.

  9. The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor.

    Science.gov (United States)

    Westaway, Susan M; Brown, Samantha L; Conway, Elizabeth; Heightman, Tom D; Johnson, Christopher N; Lapsley, Kate; Macdonald, Gregor J; MacPherson, David T; Mitchell, Darren J; Myatt, James W; Seal, Jon T; Stanway, Steven J; Stemp, Geoffrey; Thompson, Mervyn; Celestini, Paolo; Colombo, Andrea; Consonni, Alessandra; Gagliardi, Stefania; Riccaboni, Mauro; Ronzoni, Silvano; Briggs, Michael A; Matthews, Kim L; Stevens, Alexander J; Bolton, Victoria J; Boyfield, Izzy; Jarvie, Emma M; Stratton, Sharon C; Sanger, Gareth J

    2008-12-15

    Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.

  10. Improvement in psoriasis after treatment with the glucagon-like peptide-1 receptor agonist liraglutide

    DEFF Research Database (Denmark)

    Faurschou, A; Knop, F K; Thyssen, J P

    2011-01-01

    A 59-year old man with moderate and stable psoriasis through 15 years was admitted to our Department with inadequately controlled type 2 diabetes. Treatment was initiated with the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide. The patient experienced marked improvement in his...... improvement in comorbidities such as overweight. Randomized clinical trials are needed to reveal whether GLP-1R agonists represent a new therapeutic option for psoriasis....

  11. Terguride, a dopamine D(2) partial agonist, as a discriminative stimulus in rats.

    Science.gov (United States)

    Yamaguchi, M.; Kimura-Iwasaki, K.; Akai, T.; Nakada, Y.; Nakagawa, H.

    1991-06-01

    Drug discrimination training with terguride, a 9, 10-transdihydrogenated derivative of lisuride, was carried out using a two-lever food-reinforced procedure (FR 10) in rats, to investigate its influence on central dopaminergic (DA) and serotonergic (5-HT) functions. The terguride (0.05mg/kg, i.p.) discrimination was established within 64 +/- 5 training sessions (mean +/- S.E.) and was stably maintained thereafter. Higher doses of terguride could not be used for discriminative training due to response disruption. In generalization tests with terguride, drug-appropriate responding increased dose-dependently and reached levels of 45 and 99% at 0.01 and 0.05mg/kg i.p. The D(2) agonist lisuride at low doses and the DA autoreceptor agonist (-)-3-PPP substituted for terguride. The DA agonist apomorphine and the 5-HT agonist 5-MeO-DMT produced dose-dependent but incomplete substitution. The D(1) agonist SKF38393, the DA antagonist haloperidol, the D(2) antagonist sulpiride, the D(1) antagonist SCH23390, the 5-HT(1A) agonist 8-OH-DPAT, the 5-HT(1B) agonist m-CPP and the 5-HT(2) agonist DOI were not generalized. In antagonism tests, sulpride completely blocked the terguride-appropriate response, but SCH23390 and the 5-HT antagonist methysergide did not. These results indicate that discriminative stimulus properties of terguride in rats are mediated primarily by activation of receptors with characteristics similar to those of presynaptic D(2) autoreceptors.

  12. Effect of ventilation pressure on alveolar fluid clearance and beta-agonist responses in mice.

    Science.gov (United States)

    Yu, Erin N Z; Traylor, Zachary P; Davis, Ian C

    2009-10-01

    High tidal volume ventilation is detrimental to alveolar fluid clearance (AFC), but effects of ventilation pressure (P) on AFC are unknown. In anesthetized BALB/c mice ventilated at constant tidal volume (8 ml/kg), mean AFC rate was 12.8% at 6 cmH(2)O P, but increased to 37.3% at 18 cmH(2)O P. AFC rate declined at 22 cmH(2)O P, which also induced lung damage. Increased AFC at 18 cmH(2)O P did not result from elevated plasma catecholamines, hypercapnia, or hypocapnia, but was due to augmented Na(+) and Cl(-) absorption. PKA agonists and beta-agonists stimulated AFC at 10 cmH(2)O P by upregulating amiloride-sensitive Na(+) transport. However, at 18 cmH(2)O P, PKA agonists and beta-agonists reduced AFC. At 15 cmH(2)O P, the AFC rate was intermediate (mean 26.6%), and forskolin and beta-agonists had no effect. Comparable P dependency of AFC and beta-agonist responsiveness was found in C57BL/6 mice. The effect on AFC of increasing P to 18 cmH(2)O was blocked by adenosine deaminase or an A(2b)-adenosine receptor antagonist, and could be mimicked by adenosine in mice ventilated at 10 cmH(2)O P. Modulation of adenosine signaling also resulted in altered responsiveness to beta-agonists. These findings indicate that, in the normal mouse lung, basal AFC rates and responses to beta-agonists are impacted by ventilation pressure in an adenosine-dependent manner.

  13. PPAR agonists stimulate adipogenesis at the expense of osteoblast differentiation while inhibiting osteoclast formation and activity.

    Science.gov (United States)

    Patel, Jessal J; Butters, Oliver R; Arnett, Timothy R

    2014-06-01

    Drugs used in the treatment of type 2 diabetes and cardiovascular disease, specifically peroxisome proliferator-activated receptor (PPAR) agonists, have been reported to affect bone cell function and fracture risk. In this study, we assessed the direct effects of PPAR-γ agonists (rosiglitazone and troglitazone), used in the treatment of diabetes, and a PPAR-α agonist (fenofibrate), used to treat hyperlipidaemia, on the function of primary osteoblasts and osteoclasts. Formation of 'trabecular' bone structures by rat calvarial osteoblasts was reduced by up to 85% in cultures treated with rosiglitazone and by 45% in troglitazone-treated or fenofibrate-treated cultures; at the same time, lipid droplet formation was increased by 40-70%. The expression of key osteogenic markers was similarly downregulated in cultures treated with PPAR agonists, whereas adipogenesis markers were upregulated. Formation of osteoclasts in cultures derived from mouse marrow diminished with fenofibrate treatment, whereas both glitazones reduced resorptive activity without affecting osteoclast number. Metformin, although not a PPAR agonist, is also commonly used in the treatment of type 2 diabetes. Here, metformin was found to have no effect on bone cell function. Taken together, these data suggest that PPAR-γ agonists may enhance bone loss via increased adipogenesis at the expense of osteoblast formation. In contrast, PPAR-α agonists may prevent bone loss. Given that the prevalence of diabetes and cardiovascular disease is expected to rise significantly, greater attention may need to be paid to the effects of PPAR agonists on bone homeostasis. Copyright © 2014 John Wiley & Sons, Ltd.

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

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    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.

  15. Hierarchical Phosphorylation of δ-Opioid Receptor Regulates Agonist-induced Receptor Desensitization and Internalization*

    OpenAIRE

    Maestri-El Kouhen, Odile; Wang, Guilin; Solberg, Jonathan; Erickson, Laurie J.; Law, Ping-Yee; Loh, Horace H.

    2000-01-01

    Treatment of HEK293 cells expressing the δ-opioid receptor with agonist [d-Pen2,5]enkephalin (DPDPE) resulted in the rapid phosphorylation of the receptor. We constructed several mutants of the potential phosphorylation sites (Ser/Thr) at the carboxyl tail of the receptor in order to delineate the receptor phosphorylation sites and the agonist-induced desensitization and internalization. The Ser and Thr were substituted to alanine, and the corresponding mutants were transiently and stably exp...

  16. Discovery of Azetidinone Acids as Conformationally-Constrained Dual PPARalpha/gamma Agonists

    Energy Technology Data Exchange (ETDEWEB)

    Wang, W.; Devasthale, P; Farrelly, D; Gu, L; Harrity, T; Cap, M; Chu, C; Kunselman, L; Morgan, N; et. al.

    2008-01-01

    A novel class of azetidinone acid-derived dual PPAR{alpha}/{gamma} agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARa and PPAR? receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

  17. Evaluation of the Tolerability of Switching Patients on Chronic Full ?-Opioid Agonist Therapy to Buccal Buprenorphine

    OpenAIRE

    Webster, Lynn; Gruener, Daniel; Kirby, Todd; Xiang, Qinfang; Tzanis, Evan; Finn, Andrew

    2016-01-01

    Objective?Assess whether patients with chronic pain receiving 80 to 220?mg oral morphine sulfate equivalent of a full ?-opioid agonist could be transitioned to buccal buprenorphine at approximately 50% of their full dose without inducing opioid withdrawal or sacrificing analgesic efficacy. Methods.?A randomized, double-blind, double-dummy, active-controlled, two-period crossover study in adult patients receiving around-the-clock full opioid agonist therapy and confirmed to be opioid dependent...

  18. TRPA1 agonist activity of probenecid desensitizes channel responses: consequences for screening.

    Science.gov (United States)

    McClenaghan, Conor; Zeng, Fanning; Verkuyl, Jan Martin

    2012-12-01

    The transient receptor potential channel subtype A member 1 (TRPA1) is a nonselective cation channel widely viewed as having therapeutic potential, particularly for pain-related indications. Realization of this potential will require potent, selective modulators; however, currently the pharmacology of TRPA1 is poorly defined. As TRPA1 is calcium permeable, calcium indicators offer a simple assay format for high-throughput screening. In this report, we show that probenecid, a uricosuric agent used experimentally in screening to increase loading of calcium-sensitive dyes, activates TRPA1. Prolonged probenecid incubation during the dye-loading process reduces agonist potency upon subsequent challenge. When Chinese Hamster Ovary (CHO)-hTRPA1 or STC-1 cells, which endogenously express TRPA1, were dye loaded in the presence of 2 mM probenecid TRPA1, agonists appeared less potent; EC(50) for allyl isothiocyante agonists in CHO-hTRPA1 was increased from 1.5±0.19 to 7.32±1.20 μM (P<0.01). No significant effect on antagonist potency was observed when using the agonist EC(80) concentration determined under the appropriate dye-loading conditions. We suggest an alternative protocol for calcium imaging using another blocker of anion transport, sulfinpyrazone. This blocker significantly augments indicator dye loading and the screening window, but is not a TRPA1 agonist and has no effect on agonist potency.

  19. In vitro effects of Beta-2 agonists on skeletal muscle differentiation, hypertrophy, and atrophy.

    Science.gov (United States)

    Wannenes, Francesca; Magni, Loretta; Bonini, Matteo; Dimauro, Ivan; Caporossi, Daniela; Moretti, Costanzo; Bonini, Sergio

    2012-06-01

    : Beta-2 agonists are widely used in the treatment of asthma and chronic obstructive pulmonary disease for their effect on airway smooth muscle relaxation. They also act on skeletal muscle, although their reported ergogenic effect is controversial. : To evaluate the in vitro effects of short-acting and long-acting beta-2 agonists on adrenergic receptor (ADR) expression, hypertrophy, and atrophy markers, in a skeletal muscle cell line. : The C2C12 cell line was used as a model of skeletal muscle differentiation. ADR messenger RNA expression was evaluated in proliferating myoblasts, committed cells, and differentiated myotubes, in basal conditions and after treatment with 10 M clenbuterol, salbutamol, salmeterol, and formoterol. Effect of beta-2 agonists on gene and protein expression of hypertrophy and atrophy markers was assessed in differentiated myotubes. : Our study shows that beta-2 ADR messenger RNA was expressed and progressively increased during cell differentiation. Beta-2 agonist treatment did not affect its expression. Skeletal muscle hypertrophy markers (fast and slow myosin, myogenin) were not modulated by any of the beta-2 agonists evaluated. However, clenbuterol induced a significant, dose-dependent downregulation of skeletal muscle atrophy genes (atrogin-1, MuRF-1, and cathepsin L). : The reported ergogenic effect of beta-2 agonists, if any, should be considered as drug-specific and not class-specific and that of clenbuterol is mediated by the inhibition of the atrophic pathway.

  20. Effects of cannabinoid and vanilloid receptor agonists and their interaction on learning and memory in rats.

    Science.gov (United States)

    Shiri, Mariam; Komaki, Alireza; Oryan, Shahrbanoo; Taheri, Masoumeh; Komaki, Hamidreza; Etaee, Farshid

    2017-04-01

    Despite previous findings on the effects of cannabinoid and vanilloid systems on learning and memory, the effects of the combined stimulation of these 2 systems on learning and memory have not been studied. Therefore, in this study, we tested the interactive effects of cannabinoid and vanilloid systems on learning and memory in rats by using passive avoidance learning (PAL) tests. Forty male Wistar rats were divided into the following 4 groups: (1) control (DMSO+saline), (2) WIN55,212-2, (3) capsaicin, and (4) WIN55,212-2 + capsaicin. On test day, capsaicin, a vanilloid receptor type 1 (TRPV1) agonist, or WIN55,212-2, a cannabinoid receptor (CB 1 /CB 2 ) agonist, or both substances were injected intraperitoneally. Compared to the control group, the group treated with capsaicin (TRPV1 agonist) had better scores in the PAL acquisition and retention test, whereas treatment with WIN55,212-2 (CB 1 /CB 2 agonist) decreased the test scores. Capsaicin partly reduced the effects of WIN55,212-2 on PAL and memory. We conclude that the acute administration of a TRPV1 agonist improves the rats' cognitive performance in PAL tasks and that a vanilloid-related mechanism may underlie the agonistic effect of WIN55,212-2 on learning and memory.

  1. The good, the bad, and the ugly: agonistic behaviour in juvenile crocodilians.

    Directory of Open Access Journals (Sweden)

    Matthew L Brien

    Full Text Available We examined agonistic behaviour in seven species of hatchling and juvenile crocodilians held in small groups (N = 4 under similar laboratory conditions. Agonistic interactions occurred in all seven species, typically involved two individuals, were short in duration (5-15 seconds, and occurred between 1600-2200 h in open water. The nature and extent of agonistic interactions, the behaviours displayed, and the level of conspecific tolerance varied among species. Discrete postures, non-contact and contact movements are described. Three of these were species-specific: push downs by C. johnstoni; inflated tail sweeping by C. novaeguineae; and, side head striking combined with tail wagging by C. porosus. The two long-snouted species (C. johnstoni and G. gangeticus avoided contact involving the head and often raised the head up out of the way during agonistic interactions. Several behaviours not associated with aggression are also described, including snout rubbing, raising the head up high while at rest, and the use of vocalizations. The two most aggressive species (C. porosus, C. novaeguineae appeared to form dominance hierarchies, whereas the less aggressive species did not. Interspecific differences in agonistic behaviour may reflect evolutionary divergence associated with morphology, ecology, general life history and responses to interspecific conflict in areas where multiple species have co-existed. Understanding species-specific traits in agonistic behaviour and social tolerance has implications for the controlled raising of different species of hatchlings for conservation, management or production purposes.

  2. Reconstitution of high affinity α2 adrenergic agonist binding by fusion with a pertussis toxin substrate

    International Nuclear Information System (INIS)

    Kim, M.H.; Neubig, R.R.

    1986-01-01

    High affinity α 2 adrenergic agonist binding is thought to occur via a coupling of the α 2 receptor with N/sub i/, the inhibitory guanyl nucleotide binding protein. Human platelet membranes pretreated at pH 11.5 exhibit a selective inactivation of agonist binding and N/sub i/. To further study the mechanism of agonist binding, alkali treated membranes (ATM) were mixed with membranes pretreated with 10 μM phenoxybenzamine to block α 2 receptors (POB-M). The combined membrane pellet was incubated in 50% polyethylene glycol (PEG) to promote membrane-membrane fusion and assayed for binding to the α 2 agonist [ 3 H]UK 14,304 (UK) and the antagonist [ 3 H] yohimbine. PEG treatment resulted in a 2-4 fold enhancement of UK binding whereas yohimbine binding was unchanged. No enhancement of UK binding was observed in the absence of PEG treatment. The reconstitution was dependent on the addition of POB-M. They found that a 1:1 ratio of POB-M:ATM was optimal. Reconstituted binding was inhibited by GppNHp. Fusion of rat C6 glioma cell membranes, which do not contain α 2 receptors, also enhanced agonist binding to ATM. Fusion of C6 membranes from cells treated with pertussis toxin did not enhance [ 3 H] UK binding. These data show that a pertussis toxin sensitive membrane component, possibly N/sub i/, can reconstitute high affinity α 2 agonist binding

  3. Dopa-testotoxicosis: disruptive hypersexuality in hypogonadal men with prolactinomas treated with dopamine agonists.

    Science.gov (United States)

    De Sousa, Sunita M C; Chapman, Ian M; Falhammar, Henrik; Torpy, David J

    2017-02-01

    Dopamine agonists are the first line of therapy for prolactinomas, with high rates of biochemical control and tumour shrinkage. Toxicity is considered to be low and manageable by switching of agents and dose reduction. Dopamine agonist-induced impulse control disorders are well described in the neurology setting, but further data are required regarding this toxicity in prolactinoma patients. We performed a multicenter retrospective cohort study of eight men with prolactinomas and associated central hypogonadism. The eight men had no prior history of psychiatric disease, but each developed disruptive hypersexuality whilst on dopamine agonist therapy at various doses. Cabergoline, bromocriptine and quinagolide were all implicated. Hypersexuality had manifold consequences, including relationship discord, financial loss, reduced work performance, and illicit activity. We hypothesise that this phenomenon is due to synergy between reward pathway stimulation by dopamine agonists, together with rapid restoration of the eugonadal state after prolonged hypogonadism. We refer here to this distinct drug toxicity as 'dopa-testotoxicosis'. Given the profound impact in these patients and their families, cessation of dopamine agonists should be considered in men who develop hypersexuality, and pituitary surgery may be required to facilitate this. Awareness of this distinct impulse control disorder should enable further research into the prevalence, natural history and management of dopa-testotoxicosis. The condition is likely under-reported due to the highly personal nature of the symptoms and we suggest a simple written questionnaire to screen for hypersexuality and other behavioural symptoms within the first six months of dopamine agonist treatment.

  4. Radiolabelled D2 agonists as prolactinoma imaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Otto, C.A.

    1989-08-01

    During the past year, further studies on mAChR were conducted. These studies included verification of the difference in pituitary distribution based on ligand charge. The pituitary localization of TRB. A neutral mAChR ligand, was verified. The lack of QNB blockade of TRB uptake was tested by blockage with scopolamine, another mAChR antagonist and by testing the effect in a different strain of rat. Neither scopolamine or change of rat strain had any effect. We concluded that TRB uptake in pituitary is not a receptor-mediated process. Further studies were conducted with an additional quaternized mAChR ligand: MQNB. Pituitary localization of MQNB, like MTRB, could be blocked by pretreatment with QNB. We have tentatively concluded that permanent charge on a mAChR antagonist changes the mechanism of uptake in the pituitary. Time course studies and the effects of DES on myocardial uptake are reported. A brief report on preliminary results of evaluation of quaternized mAChR ligands in the heart is included. In a limited series of such ligands, we have observed a single binding site and a difference in B{sub max} values: QNB competition studies yield larger B{sub max} values than studies with {sup 3}H-NMS. Progress in the synthesis of D{sub 2} agonists includes solving a synthetic problem and preparation of the cold'' analogue of N-0437 using procedures applicable to eventual synthesis with {sup 11}C-CH{sub 3}I. 2 refs., 5 figs., 1 tab.

  5. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists.

    Science.gov (United States)

    Stahn, Cindy; Löwenberg, Mark; Hommes, Daniel W; Buttgereit, Frank

    2007-09-15

    Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused by the cytosolic glucocorticoid receptor (cGCR); secondary non-genomic effects which are also initiated by the cGCR; membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects; non-specific, non-genomic effects caused by interactions with cellular membranes. The classical, genomic mechanism of GC-action can be divided into two processes: "transrepression", which is responsible for a large number of desirable anti-inflammatory and immunomodulating effects, and "transactivation" which is associated with frequently occurring side effects as well as with some immunosuppressive activities [Ehrchen, J., Steinmuller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Sorg, C., Sunderkotter, C., Roth, J., 2007. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood 109, 1265-1274]. Great efforts have been made to diminish glucocorticoid-induced adverse effects, but the improvement of conventional glucocorticoids has almost reached its limits. As a consequence, new variations of the conventional "good old drugs" are being tested and nitro-steroids and long circulating liposomal glucocorticoids indeed show promising results. Nevertheless, crux of the matter should be the design of qualitatively new drugs, such as selective glucocorticoid receptor agonists (SEGRAs). These innovative steroidal or non-steroidal molecules induce transrepression, while transactivation processes are less affected. First reports on two different GCR ligands, A276575 and ZK216348, show promising results. Here, we review the above-mentioned mechanisms of glucocorticoid action and give particular attention

  6. Efficacy and safety of dopamine agonists in restless legs syndrome.

    Science.gov (United States)

    Hornyak, Magdolna; Trenkwalder, Claudia; Kohnen, Ralf; Scholz, Hanna

    2012-03-01

    Restless legs syndrome (RLS) is a common neurological disorder causing considerable impairment to daily living. This article is an overview of a comprehensive Cochrane meta-analysis on the efficacy and safety of dopamine agonists (DAs), the first-line treatment of RLS. CENTRAL, MEDLINE, EMBASE, PsycINFO, and CINAHL databases were searched for double-blind randomized controlled trials (RCTs) of DAs vs placebo. Thirty-five placebo-controlled RCTs (total number of patients=6954) were eligible. The likelihood of bias was considered to be low. The mean treatment duration of the RCTs was 10.3 (standard deviation 7.3) weeks, with treatment durations up to seven months. Overall, DAs showed a moderate improvement in the International RLS Severity Scale score (mean difference -5.7 points [95% confidence interval, CI, -6.7 to -4.7; PImpression-Improvement response (risk ratio 1.44 [95% CI 1.34-1.54; P<0.00001]) compared with placebo. Periodic limb movements decreased by -22.38/h (95% CI -27.8 to -16.9; P<0.00001) for DAs compared with placebo. Sleep quality and disease-specific quality of life increased slightly to moderately. Safety data confirmed the established safety characteristics of DAs. Augmentation, a specific side-effect of dopaminergic treatment of RLS, was not assessed adequately. This meta-analysis showed that DAs have moderate efficacy in the treatment of RLS. Actively controlled and long-term studies are still lacking. Large-scale comparative studies are needed to identify the most efficient treatments for this chronic disorder. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Transcriptome analysis of endometrial tissues following GnRH agonist treatment in a mouse adenomyosis model

    Directory of Open Access Journals (Sweden)

    Guo S

    2017-03-01

    Full Text Available Song Guo,1,* Xiaowei Lu,1,* Ruihuan Gu,2 Di Zhang,3 Yijuan Sun,2 Yun Feng1 1Department of Obstetrics and Gynecology, Reproductive Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Gynecology, Shanghai Ji Ai Genetics & In Vitro Fertilization Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Gynecology and Obstetrics, Jinan Military General Hospital, Jinan, People’s Republic of China *These authors contributed equally to this work Purpose: Adenomyosis is a common, benign gynecological condition of the female reproductive tract characterized by heavy menstrual bleeding and dysmenorrhea. Gonadotropin-releasing hormone (GnRH agonists are one of the medications used in adenomyosis treatment; however, their underlying mechanisms are poorly understood. Moreover, it is difficult to obtain endometrial samples from women undergoing such treatment. To overcome this, we generated an adenomyosis mouse model, which we treated with an GnRH agonist to determine its effect on pregnancy outcomes. We also analyzed endometrial gene expression following GnRH agonist treatment to determine the mechanisms that may affect pregnancy outcome in individuals with adenomyosis.Methods: Neonatal female mice were divided into a control group, an untreated adenomyosis group, and an adenomyosis group treated with a GnRH agonist (n=6 each. The pregnancy outcome was observed and compared among the groups. Then, three randomly chosen transcriptomes from endometrial tissues from day 4 of pregnancy were analyzed between the adenomyosis group and the GnRH agonist treatment group by RNA sequencing and quantitative reverse transcription polymerase chain reaction (PCR.Results: The litter size was significantly smaller in the adenomyosis group than in the control group (7±0.28 vs 11±0.26; P<0.05. However, the average live litter

  8. Heart rate variability after BRL37344, a beta-3 agonist, in experimental bladder outlet obstruction

    Directory of Open Access Journals (Sweden)

    Łukasz Dobrek

    2013-08-01

    Full Text Available Introduction: Bladder overactivity symptoms accompany benign prostatic hyperplasia (BPH syndrome. The autonomic nervous system (ANS disturbances may be involved in bladder dysfunction. An ameliorating effect on bladder overactivity is being assigned to the currently investigated β-3 adrenoreceptor agonists. However, little is known about the influence of β-3 agonists on ANS activity. The aim of our study was to estimate ANS activity using heart rate variability (HRV in experimental model of bladder outlet obstruction (BOO, reflecting human BPH.Material/Methods: 30 female rats, divided into control, non-treated BOO (LLBOO, and β-3 agonist (BRL37344 BOO treated (LLBOO β3 agonist were studied. BOO was evoked by 5-week long partial proximal urethra ligation. Next, 20-minute resting HRV recordings were performed in each of the studied groups following i.p. administration of the vehicle (LLBOO or BRL37344 (LLBOO β3 agonist.Results: LLBOO rats were characterized by diminished NN range, SDNN, and rMSSD in time-domain analysis. Similarly, TP and non-normalized spectral HRV parameters were also decreased. Contrary to these findings, normalized spectral parameters were lower (nLF and higher (nHF. The animals treated with BRL37344 demonstrated no significant differences in time--domain HRV parameters. In spectral analysis, a decrease in LF and HF, together with a fall in TP, was found. Moreover, both nLF and nHF reached almost the same values in control and β-3 agonist treated rats.Disscussion: Our data indicates that BRL37344 is an agent abolishing the autonomic imbalance in experimental BOO, which may contribute to relieving the symptoms of bladder overactivity in β-3 agonists treated participants.

  9. Detecting associations between behavioral addictions and dopamine agonists in the Food & Drug Administration's Adverse Event database.

    Science.gov (United States)

    Gendreau, Katherine E; Potenza, Marc N

    2014-03-01

    Studies have reported higher prevalences of four behavioral addictions (binge eating, compulsive shopping, hypersexuality, and pathological gambling) in dopamine agonist-treated Parkinson's disease relative to non-dopamine agonist-treated Parkinson's. However, recent case-control and epidemiological studies suggest that prevalences of behavioral addictions in dopamine agonist-treated Parkinson's may be similar to background population rates. This study tests that hypothesis by examining the FDA Adverse Event Reporting System (FAERS) for evidence of these associations, taking into account the potential impact of publicity on reporting rates. FAERS reports in 2004 (pre-publicity for all but pathological gambling) and 2007 (post-publicity for all four behaviors) were analyzed. A threshold consisting of ≥3 cases, proportional reporting ratio ≥2, and χ (2) with Yates' correction ≥4 was used to detect signals (drug-associated adverse reactions) involving any of five dopamine agonists and any of four behavioral addictions. No reports containing compulsive shopping and no signal for binge eating and dopamine agonists were found in either year. A weak signal was found for hypersexuality in 2004, with a stronger signal in 2007. A robust signal was found for pathological gambling in 2004, with a more robust signal in 2007. These results suggest that publicity may increase reporting rates in the FAERS. Findings for binge eating, compulsive shopping, and hypersexuality suggest that prevalences of these behaviors among those treated with dopamine agonists may be similar to background population rates and thus may not reflect an adverse safety signal. Further investigation of the relationship between dopamine agonists and behavioral addictions is warranted.

  10. Modulation of oral movements by intranigral 5-hydroxytryptamine receptor agonists in the rat.

    Science.gov (United States)

    Liminga, U; Johnson, A E; Andrén, P E; Gunne, L M

    1993-10-01

    Bilateral infusion of 5-hydroxytryptamine (5-HT) agonists into the substantia nigra pars reticulata (SNr) of awake rats was shown to influence oral behavior. The 5-HT1A agonist (R)-8-hydroxy-2-(di-propylamino)- tetralin (8-OH-DPAT) (1.3-13 nmol on each side) produced a dose-dependent depression of vacuous chewing movements (VCMs) that lasted about 20 min. The (R)-8-OH-DPAT-induced depression of VCMs was blocked by the simultaneous intranigral infusion of a specific 5-HT1A antagonist [(-)-(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin HCl (UH-301)], which had no effect when given alone. Another 5-HT1A agonist [(5-methoxy-N,N-dimethyltryptamine hydrogen oxalate (5-MeO-DMT)] also reduced VCM frequencies. Intranigral infusion of the nonspecific 5-HT-agonists 1-(3-triflouro-methylphenyl) piperazine (TFMPP) and 1(m-chlorophenyl)-piperazine (mCPP) and a 5-HT3 agonist [2-methyl-5-hydroxytryptamine (2-Me-5-HT)] increased VCM after 5- to 10-nmol doses. Another 5-HT3 agonist (1-phenylbiguanide) and a 5-HT2 agonist [1-(4-bromophenyl-2,5-dimethoxy)-2-aminopropane (DOB)] had no significant effect. As most 5-HT receptors in the SNr are of the 5-HT1B subtype, these results suggest that the increased VCM frequency was mediated via nigral 5-HT1B receptors. The importance of 5-HTergic mechanisms in the development of drug-induced dyskinesias is discussed.

  11. Glucagon-like peptide-1 receptor agonists suppress water intake independent of effects on food intake

    Science.gov (United States)

    McKay, Naomi J.; Kanoski, Scott E.; Hayes, Matthew R.

    2011-01-01

    Glucagon-like peptide-1 (GLP-1) is produced by and released from the small intestine following ingestion of nutrients. GLP-1 receptor (GLP-1R) agonists applied peripherally or centrally decrease food intake and increase glucose-stimulated insulin secretion. These effects make the GLP-1 system an attractive target for the treatment of type 2 diabetes mellitus and obesity. In addition to these more frequently studied effects of GLP-1R stimulation, previous reports indicate that GLP-1R agonists suppress water intake. The present experiments were designed to provide greater temporal resolution and site specificity for the effect of GLP-1 and the long-acting GLP-1R agonists, exendin-4 and liraglutide, on unstimulated water intake when food was and was not available. All three GLP-1R ligands suppressed water intake after peripheral intraperitoneal administration, both in the presence of and the absence of food; however, the magnitude and time frame of water intake suppression varied by drug. GLP-1 had an immediate, but transient, hypodipsic effect when administered peripherally, whereas the water intake suppression by IP exendin-4 and liraglutide was much more persistent. Additionally, intracerebroventricular administration of GLP-1R agonists suppressed water intake when food was absent, but the suppression of intake showed modest differences depending on whether the drug was administered to the lateral or fourth ventricle. To the best of our knowledge, this is the first demonstration of GLP-1 receptor agonists affecting unstimulated, overnight intake in the absence of food, the first test for antidipsogenic effects of hindbrain application of GLP-1 receptor agonists, and the first test of a central effect (forebrain or hindbrain) of liraglutide on water intake. Overall, these results show that GLP-1R agonists have a hypodipsic effect that is independent of GLP-1R-mediated effects on food intake, and this occurs, in part, through central nervous system GLP-1R activation

  12. Monoterpenoids induce agonist-specific desensitization of transient receptor potential vanilloid-3 (TRPV3) ion channels.

    Science.gov (United States)

    Sherkheli, Muhammad Azhar; Benecke, Heike; Doerner, Julia Franca; Kletke, Olaf; Vogt-Eisele, A K; Gisselmann, Guenter; Hatt, Hanns

    2009-01-01

    Transient receptor potential vanilloid-3 (TRPV3) is a thermo-sensitive ion channel expressed in skin keratinocytes and in a variety of neural cells. It is activated by warmth as well as monoterpenoids including camphor, menthol, dihydrocarveol and 1,8-cineol. TRPV3 is described as a putative nociceptor and previous studies revealed sensitization of the channel during repeated short-term stimulation with different agonists. In the present investigation TRPV3 was transiently expressed in either Xenopus oocytes or HEK293 cells. Whole-cell voltage-clamp techniques were used to characterize the behavior of TRPV3 when challenged with different agonists. Similarly, a human keratinocyte-derived cell line (HaCaT cells) was used to monitor the behavior of native TRPV3 when challenged with different agonists. We report here that prolonged exposure (5-15 minutes) of monoterpenoids results in agonist-specific desensitization of TRPV3. Long-term exposure to camphor and 1,8-cineol elicits desensitizing currents in TRPV3 expressing oocytes, whereas the non-terpenoid agonist 2-APB induces sustained currents. Agonist-specific desensitization of endogenous TRPV3 was also found in HaCaT cells, which may be taken as a representative for the native system. Terpenoids have a long history of use in therapeutics, pharmaceuticals and cosmetics but knowledge about underpinning molecular mechanisms is incomplete. Our finding on agonist-induced desensitization of TRPV3 by some monoterpenoids displays a novel mechanism through which TRP channels could be functionally modulated. Desensitization of TRPV3 channels might be the molecular basis of action for some of the medicinal properties of camphor and 1,8-cineol.

  13. The Effect of Coasting on Intracytoplasmic Sperm Injection Outcome in Antagonist and Agonist Cycle

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    İltemir Duvan Z.Candan,

    2017-01-01

    Full Text Available Background Coasting can reduce the ovarian hyperstimulation syndrome (OHSS risk in ovulation induction cycles before intracytoplasmic sperm injection (ICSI. This study aimed to investigate the effect of gonadotropin-releasing hormone (GnRH agonist and GnRH antagonist protocols to controlled ovarian hyperstimulation (COH cycles with coasting on the parameters of ICSI cycles and the outcome. Materials and Methods In a retrospective cohort study, 117 ICSI cycles were per- formed and coasting was applied due to hyperresponse, between 2006 and 2011. The ICSI outcomes after coasting were then compared between the GnRH agonist group (n=91 and the GnRH antagonist group (n=26. Results The duration of induction and the total consumption of gonadotropins were found to be similar. Estradiol (E2 levels on human chorionic gonadotropin (hCG day were found higher in the agonist group. Coasting days were similar when the two groups were compared. The number of mature oocytes and the fertilization rates were similar in both groups; however, the number of grade 1 (G1 embryos and the number of transferred embryos were higher in the agonist group. Implantation rates were significantly higher in the antagonist group compared to the agonist group. Pregnancy rates/embryo transfer rates were higher in the antagonist group; however, this difference was not statistically significant (32.8% for agonist group vs. 39.1% for antagonist group, P>0.05. Conclusion The present study showed that applying GnRH-agonist and GnRH-antago- nist protocols to coasted cycles did not result in any differences in cycle parameters and clinical pregnancy rates.

  14. Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism

    Science.gov (United States)

    di Leva, Francesco Saverio; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Novellino, Ettore; Fiorucci, Stefano; Zampella, Angela; Limongelli, Vittorio

    2015-11-01

    Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

  15. Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors.

    Science.gov (United States)

    Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi

    2016-05-03

    Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations.

  16. Agonist-induced desensitization of adenylyl cyclase in Y1 adrenocortical tumor cells

    International Nuclear Information System (INIS)

    Olson, M.F.; Tsao, J.; Pon, D.J.; Schimmer, B.P.

    1991-01-01

    Y1 adrenocortical tumor cells (Y1DS) and Y1 mutants resistant to ACTH-induced desensitization of adenylyl cyclase (Y1DR) were transfected with a gene encoding the mouse beta 2-adrenergic receptor (beta 2-AR). Transfectants expressed beta 2-ARs that were able to stimulate adenylyl cyclase activity and steroid biosynthesis. These transfectants were used to explore the basis for the DR mutation in Y1 cells. The authors demonstrate that beta-adrenergic agonists desensitize the adenylyl cyclase system in transfected Y1DS cells whereas transfected Y1DR cells are resistant to desensitization by beta-adrenergic agonists. The fate of the beta 2-ARs during desensitization was evaluated by photoaffinity labelling with [125I]iodocyanopindolol diazerine. Desensitization of Y1DS transfectants was accompanied by a modest loss in receptor density that was insufficient to account for the complete loss of responsiveness to beta-adrenergic agonists. The extent of receptor loss induced by beta-adrenergic agonists in Y1DR transfectants exceeded that in the Y1DS transfectants indicating that the mutation which protects Y1DR cells from agonist-induced desensitization is prior to receptor down-regulation in the desensitization pathway. From these results we infer that ACTH and isoproterenol desensitize adenylyl cyclase by a common pathway and that receptor loss is not a major component of the desensitization process in these cells

  17. Early investigational β3 adreno-receptor agonists for the management of the overactive bladder syndrome.

    Science.gov (United States)

    Thiagamoorthy, Ganesh; Giarenis, Ilias; Cardozo, Linda

    2015-01-01

    Antimuscarinic drugs form the mainstay of medical treatment for Overactive bladder Syndrome (OAB). With a proven efficacy but poor tolerability, other treatment modalities have been sought. Recent concerns regarding cumulative anticholinergic load and risk of dementia have provided further impetus to find novel OAB treatments. β3-adrenoceptor (β3-AR) agonists improve OAB symptoms by relaxing bladder tissue. As such, the search is underway to develop β3-AR agonist drugs for the treatment of OAB. The authors discuss studies on the only approved β3-AR agonist, mirabegron, followed by reports on β3-AR agonists in development, namely ritobegron and solabegron. The authors also discuss the early investigations of novel and putative β3-AR agonist drugs which are being assessed for management of OAB, including aryloxypropanolamine, TRK-380, AJ-9677, BRL37344 and CL 316,243. These investigations have also highlighted alternative unexpected modes of β3-AR action. There are a number of β3-ARs in the pipeline but it is uncertain which, if any, will come to market and aid in the management of OAB. A picture of a β3-AR dual action which was unknown previously is emerging. Overall, the authors believe that it is an exciting time for the pharmacological management of OAB with new drugs on the horizon which could potentially improve the patient's quality of life.

  18. Reconstitution of high-affinity opioid agonist binding in brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Remmers, A.E.; Medzihradsky, F. (Univ. of Michigan Medical School, Ann Arbor (United States))

    1991-03-15

    In synaptosomal membranes from rat brain cortex, the {mu} selective agonist ({sup 3}H)dihydromorphine in the absence of sodium, and the nonselective antagonist ({sup 3}H)naltrexone in the presence of sodium, bound to two populations of opioid receptor sites with K{sub d} values of 0.69 and 8.7 nM for dihydromorphine, and 0.34 and 5.5 nM for naltrexone. The addition of 5 {mu}M guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)) strongly reduced high-affinity agonist but not antagonist binding. Exposure of the membranes to high pH reduced the number of GTP({gamma}-{sup 35}S) binding sites by 90% and low K{sub m}, opioid-sensitive GTPase activity by 95%. In these membranes, high-affinity agonist binding was abolished and modulation of residual binding by GTP({gamma}S) was diminished. Alkali treatment of the glioma cell membranes prior to fusion inhibited most of the low K{sub m} GTPase activity and prevented the reconstitution of agonist binding. The results show that high-affinity opioid agonist binding reflects the ligand-occupied receptor - guanine nucleotide binding protein complex.

  19. Combined ovulation triggering with GnRH agonist and hCG in IVF patients.

    Science.gov (United States)

    Kasum, Miro; Kurdija, Kristijan; Orešković, Slavko; Čehić, Ermin; Pavičić-Baldani, Dinka; Škrgatić, Lana

    2016-11-01

    The aim of the review is to analyse the combination of a gonadotrophin releasing hormone (GnRH) agonist with a human chorionic gonadotrophin (hCG) trigger, for final oocyte maturation in in vitro fertilisation (IVF) cycles. The concept being a ''dual trigger'' combines a single dose of the GnRH agonist with a reduced or standard dosage of hCG at the time of triggering. The use of a GnRH agonist with a reduced dose of hCG in high responders demonstrated luteal phase support with improved pregnancy rates, similar to those after conventional hCG and a low risk of ovarian hyperstimulation syndrome (OHSS). The administration of a GnRH agonist and a standard hCG in normal responders, demonstrated significantly improved live-birth rates and a higher number of embryos of excellent quality, or cryopreserved embryos. The concept of the ''double trigger" represents a combination of a GnRH agonist and a standard hCG, when used 40 and 34 h prior to ovum pick-up, respectively. The use of the ''double trigger" has been successfully offered in the treatment of empty follicle syndrome and in patients with a history of immature oocytes retrieved or with low/poor oocytes yield. Further prospective studies are required to confirm the aforementioned observations prior to clinical implementation.

  20. GLP-1 Receptor Agonists: Nonglycemic Clinical Effects in Weight Loss and Beyond

    Science.gov (United States)

    Ryan, Donna; Acosta, Andres

    2015-01-01

    Obective Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for treatment of type 2 diabetes since they mimic the actions of native GLP-1 on pancreatic islet cells, stimulating insulin release, while inhibiting glucagon release, in a glucose-dependent manner. The observation of weight loss has led to exploration of their potential as antiobesity agents, with liraglutide 3.0 mg day−1 approved for weight management in the US on December 23, 2014, and in the EU on March 23, 2015. This review examines the potential nonglycemic effects of GLP-1 receptor agonists. Methods A literature search was conducted to identify preclinical and clinical evidence on nonglycemic effects of GLP-1 receptor agonists. Results GLP-1 receptors are distributed widely in a number of tissues in humans, and their effects are not limited to the well-recognized effects on glycemia. Nonglycemic effects include weight loss, which is perhaps the most widely recognized nonglycemic effect. In addition, effects on the cardiovascular, neurologic, and renal systems and on taste perception may occur independently of weight loss. Conclusions GLP-1 receptor agonists may provide other nonglycemic clinical effects besides weight loss. Understanding these effects is important for prescribers in using GLP-1 receptor agonists for diabetic patients, but also if approved for chronic weight management. PMID:25959380

  1. Evidence for air movement signals in the agonistic behaviour of a nocturnal arachnid (order Amblypygi).

    Science.gov (United States)

    Santer, Roger D; Hebets, Eileen A

    2011-01-01

    Many arthropods possess filiform hair sensilla (termed trichobothria in arachnids), which are extremely sensitive detectors of medium particle displacement. Electrophysiological evidence in some taxa suggests that these sensilla can detect air particle displacements resulting from intraspecific communication signals. However, it has not yet been shown for any species that the air particle displacements detected by the filiform hairs are themselves perceived as a 'signal' (i.e. that individuals make behavioural decisions based upon the responses of these organs to the displays of conspecifics). We investigate the agonistic behaviour of the whip spider Phrynus marginemaculatus and the role of its trichobothria in receiving agonistic signals. Whip spiders have extremely elongated 'antenniform' first legs, which they vibrate close to their opponents during agonistic interactions, inducing air movements that excite their opponents' trichobothria. We find that ablation of the trichobothria causes significant increases in: (I) contest duration, and (II) the probability of contest escalation past aggressive displays to physical fighting. Therefore, in the absence of air movement-sensitive sensilla, contest assessment is impaired. This suggests that whip spiders exploit true air movement signals during agonistic interactions, and that these are received by the trichobothria. Furthermore, these results indicate that, in whip spiders, such signals help mitigate the cost of agonistic interaction.

  2. Evidence for air movement signals in the agonistic behaviour of a nocturnal arachnid (order Amblypygi.

    Directory of Open Access Journals (Sweden)

    Roger D Santer

    Full Text Available Many arthropods possess filiform hair sensilla (termed trichobothria in arachnids, which are extremely sensitive detectors of medium particle displacement. Electrophysiological evidence in some taxa suggests that these sensilla can detect air particle displacements resulting from intraspecific communication signals. However, it has not yet been shown for any species that the air particle displacements detected by the filiform hairs are themselves perceived as a 'signal' (i.e. that individuals make behavioural decisions based upon the responses of these organs to the displays of conspecifics. We investigate the agonistic behaviour of the whip spider Phrynus marginemaculatus and the role of its trichobothria in receiving agonistic signals. Whip spiders have extremely elongated 'antenniform' first legs, which they vibrate close to their opponents during agonistic interactions, inducing air movements that excite their opponents' trichobothria. We find that ablation of the trichobothria causes significant increases in: (I contest duration, and (II the probability of contest escalation past aggressive displays to physical fighting. Therefore, in the absence of air movement-sensitive sensilla, contest assessment is impaired. This suggests that whip spiders exploit true air movement signals during agonistic interactions, and that these are received by the trichobothria. Furthermore, these results indicate that, in whip spiders, such signals help mitigate the cost of agonistic interaction.

  3. Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program.

    Science.gov (United States)

    Klimas, Jan; Muench, John; Wiest, Katharina; Croff, Raina; Rieckman, Traci; McCarty, Dennis

    2015-01-01

    Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention, and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n = 208) and in an opioid treatment program (n = 204) over a two-year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. In the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counselors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested that organizational, structural, provider, patient, and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow.

  4. Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor.

    Science.gov (United States)

    Schrage, R; Seemann, W K; Klöckner, J; Dallanoce, C; Racké, K; Kostenis, E; De Amici, M; Holzgrabe, U; Mohr, K

    2013-05-01

    Artificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such 'superagonism' has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a 'superagonist'. Signalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label-free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G-protein activation, evaluation of cell surface agonist binding and computation of operational efficacies. In CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi /Gs signalling competence. In the orthosteric loss-of-function mutant M2 -Y104(3.33) A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. 'Superagonism' is preserved in the physiological cellular context of MRC-5 human lung fibroblasts. Structure-signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that 'superagonism' of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points. Supraphysiological agonist efficacy at muscarinic M2 ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR 'superagonism' is provided. We suggest that iperoxo-like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

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

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    Yiyi Sun

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

  6. Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists

    Directory of Open Access Journals (Sweden)

    Martin B. Oleksiewicz

    2008-01-01

    Full Text Available Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology. Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

  7. At-risk for pathological gambling: imaging neural reward processing under chronic dopamine agonists.

    Science.gov (United States)

    Abler, Birgit; Hahlbrock, Roman; Unrath, Alexander; Grön, Georg; Kassubek, Jan

    2009-09-01

    Treatment with dopamine receptor agonists has been associated with impulse control disorders and pathological gambling (PG) secondary to medication in previously unaffected patients with Parkinson's disease or restless legs syndrome (RLS). In a within-subjects design, we investigated the underlying neurobiology in RLS patients using functional magnetic resonance imaging. We scanned 12 female RLS patients without a history of PG. All patients were scanned twice: once whilst taking their regular medication with low dose dopamine receptor agonists and once after a washout phase interval. They performed an established gambling game task involving expectation and receipt or omission of monetary rewards at different levels of probabilities. Upon expectation of rewards, reliable ventral striatal activation was detected only when patients were on, but not when patients were off medication. Upon receipt or omission of rewards, the observed ventral striatal signal under medication differed markedly from its predicted pattern which by contrast was apparent when patients were off medication. Orbitofrontal activation was not affected by medication. Chronic dopamine receptor agonist medication changed the neural signalling of reward expectation predisposing the dopaminergic reward system to mediate an increased appetitive drive. Even without manifest PG, chronic medication with dopamine receptor agonists led to markedly changed neural processing of negative consequences probably mediating dysfunctional learning of contingencies. Intact orbitofrontal functioning, potentially moderating impulse control, may explain why none of the patients actually developed PG. Our results support the notion of a general medication effect in patients under dopamine receptor agonists in terms of a sensitization towards impulse control disorders.

  8. Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists

    Science.gov (United States)

    Pertwee, R.G.

    2010-01-01

    It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Δ9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor agonists and CB1/CB2 antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB1 and CB2 receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB1, non-CB2 G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB1 and/or CB2 receptors. PMID:20166927

  9. Detection of glucocorticoid receptor agonists in effluents from sewage treatment plants in Japan.

    Science.gov (United States)

    Suzuki, Go; Sato, Kentaro; Isobe, Tomohiko; Takigami, Hidetaka; Brouwer, Abraham; Nakayama, Kei

    2015-09-15

    Glucocorticoids (GCs) are widely used as anti-inflammatory drugs. Our previous study demonstrated that several GCs such as cortisol and dexamethasone (Dex) were frequently detected in effluents collected from Japanese sewage treatment plants (STPs) in 2012. In this study, we used the GC-Responsive Chemical-Activated LUciferase gene eXpression (GR-CALUX) assay to elucidate GC receptor (GR) agonistic activities of ten pure synthetic GCs and selected STP effluents in Japan for assessment of the risks associated with the presence of GR agonists. The tested GCs demonstrated dose-dependent agonistic effects in the GR-CALUX assay and their EC50 values were calculated for estimation of relative potencies (REPs) compared to Dex. The GR agonistic potency was in the rank of: clobetasol propionate > clobetasone butyrate > betamethasone 17-valerate > difluprednate > betamethasone 17,21-dipropionate > Dex > betamethasone > 6α-methylprednisolone > prednisolone > cortisol. The GR agonistic activity in STP effluents as measured in Dex-equivalent (Dex-EQ) activities ranged from effluents in Japan. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Clinical significance of suboptimal hormonal levels in men with prostate cancer treated with LHRH agonists.

    Science.gov (United States)

    Kawakami, Jun; Morales, Alvaro

    2013-01-01

    We examined the serum levels of testosterone (T) (total and bioavailable) dehydroepiandrosterone (DHEA), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prostate-specific antigen (PSA) in men receiving treatment with luteinizing hormone releasing-hormone (LHRH) agonists for metastatic prostate cancer. In doing this, we want to determine the efficacy of these agents in lowering T levels and whether a possible relationship exists between PSA values, as a surrogate measure of tumour activity, and hormone levels. This was a single centre prospective study of patients on LHRH agonists. Of all the 100 eligible patients, 31 did not qualify (10 were receiving their first injection, 13 were on intermittent hormonal therapy, 7 refused to enter the trial and 1 patient's blood sample was lost). Therefore in total, 69 patients were included in the final analysis. Each patient had their blood sample drawn immediately before the administration of a LHRH agonist. The new proposed criteria of values are more commonly found in patients with suboptimal levels of testosterone receiving LHRH analogs, but the clinical importance of this finding has not been established. There is no significant difference with respect to hormonal levels reached among patients on a variety of LHRH agonists. Total testosterone determinations should be considered in patients on LHRH agonist therapy, particularly when the PSA values begin to rise since it may lead to further beneficial hormonal manipulation.

  11. Antinociceptive action of NOP and opioid receptor agonists in the mouse orofacial formalin test.

    Science.gov (United States)

    Rizzi, A; Ruzza, C; Bianco, S; Trapella, C; Calo', G

    2017-08-01

    Nociceptin/orphanin FQ (N/OFQ) modulates several biological functions, including pain transmission via selective activation of a specific receptor named NOP. The aim of this study was the investigation of the antinociceptive properties of NOP agonists and their interaction with opioids in the trigeminal territory. The orofacial formalin (OFF) test in mice was used to investigate the antinociceptive potential associated to the activation of NOP and opioid receptors. Mice subjected to OFF test displayed the typical biphasic nociceptive response and sensitivity to opioid and NSAID drugs. Mice knockout for the NOP gene displayed a robust pronociceptive phenotype. The NOP selective agonist Ro 65-6570 (0.1-1mgkg -1 ) and morphine (0.1-10mgkg -1 ) elicited dose dependent antinociceptive effects in the OFF with the alkaloid showing larger effects; the isobologram analysis of their actions demonstrated an additive type of interaction. The mixed NOP/opioid receptor agonist cebranopadol elicited potent (0.01-0.1mgkg -1 ) and robust antinociceptive effects. In the investigated dose range, all drugs did not modify the motor performance of the mice in the rotarod test. Collectively the results of this study demonstrated that selective NOP agonists and particularly mixed NOP/opioid agonists are worthy of development as innovative drugs to treat painful conditions of the trigeminal territory. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Isoprenylated flavonoids from Morus nigra and their PPAR γ agonistic activities.

    Science.gov (United States)

    Xu, Liang-Jin; Yu, Mei-Hua; Huang, Chun-Yue; Niu, Li-Xin; Wang, Yi-Fan; Wu, Chun-Zhen; Yang, Pei-Ming; Hu, Xiao

    2018-02-08

    A novel dihydroflavonol unprecedentedly with a prenyl group at C-2, nigragenon A (1), four new sanggenon-type flavonones, nigragenons B-E (2-5), along with six known isoprenylated flavonoids (6-11) were isolated from the twigs of Morus nigra. Their structures were elucidated through extensive analysis of spectroscopic data. Interestingly, compound 1 was the first reported biogenetic precursor of sanggenon-type flavanones and the biogenetic pathway from 1 to sanggenol F was proposed. The PPAR γ agonistic activity was investigated in HEK293 cells using dual luciferase reporter assay. Compounds 2, 4, 7, and 9 showed obvious agonistic activities on PPAR γ, and compound 2 was a potential PPAR γ partial agonist. Moreover, the preliminary structure-activity relationships for the tested compounds were discussed. Copyright © 2018. Published by Elsevier B.V.

  13. Quantitative Measure of Receptor Agonist and Modulator Equi-Response and Equi-Occupancy Selectivity

    Science.gov (United States)

    Zhang, Rumin; Kavana, Michael

    2016-01-01

    G protein-coupled receptors (GPCRs) are an important class of drug targets. Quantitative analysis by global curve fitting of properly designed dose-dependent GPCR agonism and allosterism data permits the determination of all affinity and efficacy parameters based on a general operational model. We report here a quantitative and panoramic measure of receptor agonist and modulator equi-response and equi-occupancy selectivity calculated from these parameters. The selectivity values help to differentiate not only one agonist or modulator from another, but on-target from off-target receptor or functional pathway as well. Furthermore, in conjunction with target site free drug concentrations and endogenous agonist tones, the allosterism parameters and selectivity values may be used to predict in vivo efficacy and safety margins. PMID:27116909

  14. The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives

    DEFF Research Database (Denmark)

    Humaidan, Peter; Papanikolaou, E G; Kyrou, D

    2012-01-01

    is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal......-phase insufficiency seen after GnRHa triggering and the various trials that have been performed to assess the most optimal luteal support in relation to GnRHa triggering. Although more research is needed, GnRHa triggering is now an alternative to HCG triggering, combining a significant reduction in OHSS with high...... with a GnRH agonist instead of human chorionic gonadotrophin (HCG). The first studies applying this concept, however, showed a very poor pregnancy rate, despite standard luteal-phase support with progesterone. This review discusses the reason for the poor results and the newest studies, using GnRH agonist...

  15. Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors

    DEFF Research Database (Denmark)

    Rohde, Line Aagot Hede; Ahring, Philip Kiær; Jensen, Marianne Lerbech

    2012-01-01

    The a4ß2 subtype of the nicotinic acetylcholine receptor (nAChR) has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of a4ß2 agonists is lacking....... Using binding experiments, electrophysiology and X-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at a4ß2 and the acetylcholine binding protein from...... Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for a4ß2 receptors. Crystal structures of five agonists with efficacies at a4ß2 from 21-76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead...

  16. Oxidation of nutrients in bull calves treated with beta-adrenergic agonists

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    , with CO2 reduced for CO2 from fermentation processes, and nitrogen excretion in urine. The beta-agonist had no effect on the level of rumen fermentation as indicated by the same methane production for control and treated animals. Heat Production (HE, RQx) increased by the treatment of beta......Oxidation of protein (OXP), carbohydrate (OXCHO) and fat (OXF) was investigated with 12 growing bulls treated with beta-agonist (L-644, 969) during two 6 weeks trials (Section A and B) at a mean live weight of 195 and 335 kg. Heat production and nutrient oxidation was calculated from gas exchange......-agonist corresponding to the increment in the protein retention. OXP/HE,RQx was reduced to about 10% in treated animals, indicating that in order to supply amino acids for an increased protein deposition oxidation of protein is decreased. OXF/HE,RQx were markedly higher in treated animals, but as indicated by the same...

  17. Cyclic AMP agonist inhibition increases at low levels of histamine release from human basophils

    Energy Technology Data Exchange (ETDEWEB)

    Tung, R.S.; Lichtenstein, L.M.

    1981-09-01

    The relationship between the intensity of the signal for antigen-induced immunoglobulin E-mediated histamine release from human basophils and the concentration of agonist needed to inhibit release has been determined. The agonists, prostaglandin E1, dimaprit, fenoterol, isobutylmethylxanthine and dibutyryl cyclic AMP, all act by increasing the cyclic AMP level. Each agonist was 10- to 1000-fold more potent (relative ID50) at low levels of histamine release (5-10% of total histamine) than at high levels (50-80%). Thus, the inhibitory potential of a drug is a function of the concentration of antigen used to initiate the response. Our results are now more in accord with the inhibitory profile of these drugs in human lung tissue. It is suggested that in vivo release is likely to be low and that this is the level at which to evaluate drugs in vitro.

  18. A novel nicotinic agonist facilitates induction of long-term potentiation in the rat hippocampus.

    Science.gov (United States)

    Hunter, B E; de Fiebre, C M; Papke, R L; Kem, W R; Meyer, E M

    1994-02-28

    Long-term potentiation (LTP) can be modulated by a number of neurotransmitter receptors including muscarinic and GABAergic receptor types. We have found that a novel nicotinic agonist, 2,4-dimethoxybenzylidene anabaseine (DMXB), facilitated the induction of LTP in the hippocampus in a dose-dependent and mecamylamine-sensitive manner. DMXB displaced high affinity nicotinic [125I]alpha-bungarotoxin and [3H]acetylcholine binding in rat brain. Xenopus oocyte studies demonstrated that DMXB has agonist activity at alpha 7 but not alpha 4/beta 2 nicotinic receptor subtypes. These results indicated that DMXB is a novel nicotinic agonist with apparent specificity for the alpha 7/alpha-bungarotoxin nicotinic receptor subtype and indicate that nicotinic receptor activation is capable of modulating the induction of long-term potentiation.

  19. Protective effects of the angiotensin II ATreceptor agonist compound 21 in ischemic stroke

    DEFF Research Database (Denmark)

    Bennion, Douglas M; Jones, Chad H; Dang, Alex N

    2018-01-01

    ) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver......-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective...... in certain human central nervous system diseases, the N2B application of AT2receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients....

  20. Design, synthesis and evaluation of bicyclic benzamides as novel 5-HT1F receptor agonists.

    Science.gov (United States)

    Zhang, Deyi; Kohlman, Dan; Krushinski, Joseph; Liang, Sidney; Ying, Bai-Ping; Reilly, John E; Dinn, Sean R; Wainscott, David B; Nutter, Suzanne; Gough, Wendy; Nelson, David L G; Schaus, John M; Xu, Yao-Chang

    2004-12-20

    Several fused bicyclic systems have been investigated to serve as the core structure of potent and selective 5-HT1F receptor agonists. Replacement of the indole nucleus in 2 with indazole and 'inverted' indazole provided more potent and selective 5-HT1F receptor ligands. Indoline and 1,2-benzisoxazole systems also provided potent 5-HT1F receptor agonists, and the 5-HT1A receptor selectivity of the indoline- and 1,2-benzisoxazole-based 5-HT1F receptor agonists could be improved with modification of the benzoyl moiety of the benzamides. Through these studies, we found that the inherent geometries of the templates, not the nature of hybridization of the linking atom, were important for the 5-HT1F receptor recognition.

  1. [Development of chronic myelogenous leukemia during treatment with TPO receptor agonist for ITP].

    Science.gov (United States)

    Hattori, Hideki; Kuwayama, Maki; Takamori, Hiroyuki; Nishiura, Nobuko; Karasuno, Takahiro

    2014-12-01

    We report a 77-year-old Japanese man with idiopathic thrombocytopenic purpura (ITP) which developed into chronic myelogenous leukemia (CML) during treatment with eltrombopag, a thrombopoetin (TPO) receptor agonist, because the disease was refractory to prednisolone. Eltrombopag can induce a good reaction in terms of the platelet count. However, CML in the chronic phase developed in about 19 months in our present case. Dasatinib was administered because he had diabetes. However, a blastic crisis immediately occurred. He died despite switching to Nilotinib. Recently, the occurrence of myelofibrosis and hematological malignancies due to long-term use of TPO receptor agonists has become a concern. This is the first report of a TPO receptor agonist possibly contributing to CML onset and crisis.

  2. Quantitative phosphoproteomics dissection of seven-transmembrane receptor signaling using full and biased agonists

    DEFF Research Database (Denmark)

    Christensen, Gitte L; Kelstrup, Christian D; Lyngsø, Christina

    2010-01-01

    and an important drug target in cardiovascular diseases. "Biased agonists" with intrinsic "functional selectivity" that simultaneously blocks Galpha(q) protein activity and activates G protein-independent pathways of the AT(1)R confer important perspectives in treatment of cardiovascular diseases. In this study......, we performed a global quantitative phosphoproteomics analysis of the AT(1)R signaling network. We analyzed ligand-stimulated SILAC (stable isotope labeling by amino acids in cell culture) cells by high resolution (LTQ-Orbitrap) MS and compared the phosphoproteomes of the AT(1)R agonist angiotensin II...... and the biased agonist [Sar(1),Ile(4),Ile(8)]angiotensin II (SII angiotensin II), which only activates the Galpha(q) protein-independent signaling. We quantified more than 10,000 phosphorylation sites of which 1183 were regulated by angiotensin II or its analogue SII angiotensin II. 36% of the AT(1)R...

  3. Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3

    DEFF Research Database (Denmark)

    Milanos, Lampros; Brox, Regine; Frank, Theresa

    2016-01-01

    In this work we report a design, synthesis, and detailed functional characterization of unique strongly biased allosteric agonists of CXCR3 that contain tetrahydroisoquinoline carboxamide cores. Compound 11 (FAUC1036) is the first strongly biased allosteric agonist of CXCR3 that selectively induces...... weak chemotaxis and leads to receptor internalization and the β-arrestin 2 recruitment with potency comparable to that of the chemokine CXCL11 without any activation of G proteins. A subtle structural change (addition of a methoxy group, 14 (FAUC1104)) led to a contrasting biased allosteric partial...... agonist that activated solely G proteins, induced chemotaxis, but failed to induce receptor internalization or β-arrestin 2 recruitment. Concomitant structure-activity relationship studies indicated very steep structure-activity relationships, which steer the ligand bias between the β-arrestin 2 and G...

  4. Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.

    Science.gov (United States)

    Weichert, Dietmar; Stanek, Markus; Hübner, Harald; Gmeiner, Peter

    2016-06-15

    Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Discovery of benzamide analogues as a novel class of 5-HT3 receptor agonists

    DEFF Research Database (Denmark)

    Jørgensen, Charlotte Grube; Frølund, Bente Flensborg; Kehler, Jan

    2011-01-01

    A 5-HT(3) receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT(3) A receptor...... yielded substantial information concerning the analogues as 5-HT(3) receptor agonists. However, the potencies of the derived analogues were not significantly improved over that of the initial hit. The benzamide scaffold constitutes a novel type of 5-HT(3) receptor agonist, as it does not possess...... a positively charged functionality, which is essential for the binding of all orthosteric ligands to the receptor. Preliminary investigations suggest that the compounds may exert their effects on 5-HT(3) receptors by binding to an allosteric site in the receptor complex....

  6. Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor.

    Science.gov (United States)

    Lin, Wenwei; Yang, Lei; Chai, Sergio C; Lu, Yan; Chen, Taosheng

    2016-01-27

    Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer cells to chemotherapeutic drugs. We recently reported a novel CAR inhibitor/inverse agonist CINPA1 (11). Here, we have obtained or designed 54 analogs of CINPA1 and used a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to evaluate their CAR inhibition potency. Many of the 54 analogs showed CAR inverse agonistic activities higher than those of CINPA1, which has an IC50 value of 687 nM. Among them, 72 has an IC50 value of 11.7 nM, which is about 59-fold more potent than CINPA1 and over 10-fold more potent than clotrimazole (an IC50 value of 126.9 nM), the most potent CAR inverse agonist in a biochemical assay previously reported by others. Docking studies provide a molecular explanation of the structure-activity relationship (SAR) observed experimentally. To our knowledge, this effort is the first chemistry endeavor in designing and identifying potent CAR inverse agonists based on a novel chemical scaffold, leading to 72 as the most potent CAR inverse agonist so far. The 54 chemicals presented are novel and unique tools for characterizing CAR's function, and the SAR information gained from these 54 analogs could guide future efforts to develop improved CAR inverse agonists. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  7. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    International Nuclear Information System (INIS)

    Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice; Erchegyi, Judit; Rivier, Jean E.

    2010-01-01

    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst 1 -sst 5 ) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst 2 and sst 3 internalization in vitro in HEK293 cells stably expressing the human sst 2 or sst 3 receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst 2 internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst 3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst 3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  8. Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

    DEFF Research Database (Denmark)

    Sasmal, Pradip K; Krishna, C Vamsee; Sudheerkumar Adabala, S

    2015-01-01

    Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR...... and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR...

  9. Regulation of p53 stability and apoptosis by a ROR agonist.

    Directory of Open Access Journals (Sweden)

    Yongjun Wang

    Full Text Available Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORα. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer.

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

    Directory of Open Access Journals (Sweden)

    Jordi Riba

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

  11. 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...

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

    Directory of Open Access Journals (Sweden)

    Liu L

    2013-04-01

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

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

    Science.gov (United States)

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

    2013-01-01

    Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (PTarnopolsky, M. A., Thurberg, B. L., Bali, D., Koeberl, D. D. Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease. PMID:22993195

  14. 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 J

    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...... of the anticipated effects of lixisenatide on glycemic measures and weight; favorable results would place lixisenatide for consideration among other GLP-1R agonists in the treatment armamentarium for T2DM....

  15. 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 AMPA receptor subtypes. Compound 5 was shown to be a subtype-discriminating agonist at AMPA receptors with higher binding affinity and functional potency at GluA1/2 compared to GluA3/4, unlike the isomeric analogue (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA, 4...

  16. Non-nucleotide Agonists Triggering P2X7 Receptor Activation and Pore Formation

    OpenAIRE

    Francesco Di Virgilio; Anna L. Giuliani; Valentina Vultaggio-Poma; Simonetta Falzoni; Alba C. Sarti

    2018-01-01

    The P2X7 receptor (P2X7R) is a ligand-gated plasma membrane ion channel belonging to the P2X receptor subfamily activated by extracellular nucleotides. General consensus holds that the physiological (and maybe the only) agonist is ATP. However, scattered evidence generated over the last several years suggests that ATP might not be the only agonist, especially at inflammatory sites. Solid data show that NAD+ covalently modifies the P2X7R of mouse T lymphocytes, thus lowering the ATP threshold ...

  17. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs.

    Science.gov (United States)

    Moore, Thomas J; Glenmullen, Joseph; Mattison, Donald R

    2014-12-01

    Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia. To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs. We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System. Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs. We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001). Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present

  18. Antagonist-agonist combinations as therapies for heroin addiction: back to the future?

    Science.gov (United States)

    Nutt, David J

    2010-02-01

    Psychopharmacology is a powerful approach to the treatment of many psychiatric disorders. In this article I discuss the conceptual and practical issues in relation to the use of mu opioid receptor agonist, antagonist and partial agonist drugs in the treatment of opioid addiction, as this is one therapeutic area where all three types of agents are currently available. The choice of pharmacological agent is largely determined by patient profile, existence of ongoing drug misuse, and the kinetics of the drugs available. These principles, however, can be applied to other disorders as and when other pharmacological approaches become refined in these areas.

  19. Monocyte targeting and activation by cationic liposomes formulated with a TLR7 agonist

    DEFF Research Database (Denmark)

    Johansen, Pia Thermann; Zucker, Daniel; Parhamifar, Ladan

    2015-01-01

    adaptive immune responses has drawn attention to modulate monocyte responses therapeutically within cancer, inflammation and infectious diseases. We present a technology for targeting of nnonocytes and delivery of a toll-like receptor (TLR) agonist in fresh blood using liposomes with a positively charged...... induction of IL-6 and IL-12p40, and differentiation into CD14+ and DC-SIGN+ DCs.Conclusion: Our present liposomes selectively target monocytes in fresh blood, enabling delivery of TLR7 agonists to the intracellular TLR7 receptor, with subsequent monocyte activation and boost in secretion of proinflammatory...

  20. Acute and Chronic Effects of ß2-Adrenoceptor Agonists in Relation to Exercise Performance and Doping with Emphasis on Terbutaline

    DEFF Research Database (Denmark)

    Hostrup, Morten

    This thesis addresses the performance enhancing effects of β2-agonists (asthma medication) with emphasis on terbutaline in the context of doping. Given the high prevalence of asthma in the athletic population, β2-agonists are among the most used drugs in competitive sport. While there is consensu...

  1. Selective structure-based virtual screening for full and partial agonists of the beta2 adrenergic receptor

    NARCIS (Netherlands)

    de Graaf, C.; Rognan, Didier

    2008-01-01

    The recently solved high-resolution X-ray structure of the beta2 adrenergic receptor has been challenged for its ability to discriminate inverse agonists/antagonists from partial/full agonists. Whereas the X-ray structure of the ground state receptor was unsuitable to distinguish true ligands with

  2. A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

    DEFF Research Database (Denmark)

    Botfield, Hannah F; Uldall, Maria S; Westgate, Connar S J

    2017-01-01

    , in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R-mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful...

  3. ß2-adrenoceptor agonist-induced upregulation of tachykinin NK2 receptor expression and function in airway smooth muscle

    NARCIS (Netherlands)

    Katsunuma, T; Roffel, A.F; Elzinga, C.R S; Zaagsma, Hans; Barnes, P.J; Mak, J.CW

    Neurokinin A (NKA) induces bronchoconstriction mediated by tachykinin NK2 receptors in animals and humans, and may be increased in asthma. Because beta(2)-adrenoceptor agonists are the most widely used bronchodilators in asthma, we investigated the effects of the beta(2)-adrenoceptor agonist

  4. Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel γ-aminobutyric acidA receptor agonists

    DEFF Research Database (Denmark)

    Petersen, Jette Gellert; Sørensen, Troels Ersted; Damgaard, Maria

    2014-01-01

    interaction field calculations and docking studies in a α1β2γ2 GABAA receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABAAR agonists reported to date is challenged by our findings. New openings for agonist...

  5. The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist

    Energy Technology Data Exchange (ETDEWEB)

    Madauss, Kevin P.; Bledsoe, Randy K.; Mclay, Iain; Stewart, Eugene L.; Uings, Iain J.; Weingarten, Gordon; Williams, Shawn P. (GSKNC); (GSK)

    2009-07-23

    The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).

  6. Correlating the Metabolic Stability of Psychedelic 5-HT2A Agonists with Anecdotal Reports of Human Oral Bioavailability

    DEFF Research Database (Denmark)

    Leth-Petersen, Sebastian; Bundgaard, Christoffer; Hansen, Martin

    2014-01-01

    2,5-Dimethoxyphenethylamines and their N-benzylated derivatives are potent 5-HT2A agonists with psychedelic effects in humans. The N-benzylated derivatives are among the most selective 5-HT2A agonists currently available and their usage as biochemical and brain imaging tools is increasing, yet ve...

  7. Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139

    DEFF Research Database (Denmark)

    Shehata, Mohamed A; Jensen, Anne Cathrine Nøhr; Lissa, Delphine

    2016-01-01

    and Parkinson's disease. The two aromatic amino acids L-Trp and L-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from...

  8. Acute and Chronic Effects of ß2-Adrenoceptor Agonists in Relation to Exercise Performance and Doping with Emphasis on Terbutaline

    DEFF Research Database (Denmark)

    Hostrup, Morten

    This thesis addresses the performance enhancing effects of β2-agonists (asthma medication) with emphasis on terbutaline in the context of doping. Given the high prevalence of asthma in the athletic population, β2-agonists are among the most used drugs in competitive sport. While there is consensus...

  9. Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.; Rose, M. Franklin (Technical Monitor)

    2000-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

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

    DEFF Research Database (Denmark)

    Fredsted, Anne; Gissel, Hanne; Ortenblad, Niels

    2012-01-01

    )-agonists affect force and ion homeostasis in anoxic muscles. In the present study isolated rat extensor digitorum longus (EDL) muscles exposed to anoxia showed a considerable loss of force, which was markedly reduced by the β(2)-agonists salbutamol (10(-6) M) and terbutaline (10(-6) M). Intermittent...

  11. Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability

    DEFF Research Database (Denmark)

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

    2013-01-01

    reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral...

  12. In vivo effects of the IKr agonist NS3623 on cardiac electrophysiology of the guinea pig

    DEFF Research Database (Denmark)

    Hansen, Rie Schultz; Olesen, Søren-Peter; Rønn, Lars Christian B

    2008-01-01

    ERG channel antagonist (0.15 mg/kg E-4031) could be reverted by injection of NS3623 (50 mg/kg) in conscious guinea pigs. In conclusion, the present in vivo study demonstrates that injection of the hERG channel agonist NS3623 results in shortening of the QTc interval as well as reversal of a pharmacologically...

  13. The cortico-medial amygdala in the central nervous system organization of agonistic behavior

    NARCIS (Netherlands)

    Luiten, P G; Koolhaas, J M; de Boer, Sietse; Koopmans, S.J.

    1985-01-01

    Previous studies suggested that the corticomedial amygdala is involved in agonistic behavior by affecting social learning processes. The present study shows that deficits in the avoidance of a dominant male rat conditioned by defeat were only observed after bilateral lesions restricted to the medial

  14. Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus

    Science.gov (United States)

    Segev, Amir; Akirav, Irit

    2011-01-01

    We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 [mu]g/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval.…

  15. Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo.

    Science.gov (United States)

    Kataria, Hardeep; Lutz, David; Chaudhary, Harshita; Schachner, Melitta; Loers, Gabriele

    2016-09-01

    Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery after injury, leading to severe disabilities in motor functions and pain. Peripheral nerve injury impairs motor, sensory, and autonomic functions, particularly in cases where nerve gaps are large and chronic nerve injury ensues. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration after acute injury. We screened libraries of known drugs for small molecule agonists of L1 and evaluated the effect of hit compounds in cell-based assays in vitro and in mice after femoral nerve and spinal cord injuries in vivo. We identified eight small molecule L1 agonists and showed in cell-based assays that they stimulate neuronal survival, neuronal migration, and neurite outgrowth and enhance Schwann cell proliferation and migration and myelination of neurons in an L1-dependent manner. In a femoral nerve injury mouse model, enhanced functional regeneration and remyelination after application of the L1 agonists were observed. In a spinal cord injury mouse model, L1 agonists improved recovery of motor functions, being paralleled by enhanced remyelination, neuronal survival, and monoaminergic innervation, reduced astrogliosis, and activation of microglia. Together, these findings suggest that application of small organic compounds that bind to L1 and stimulate the beneficial homophilic L1 functions may prove to be a valuable addition to treatments of nervous system injuries.

  16. Small-molecule agonists for the glucagon-like peptide 1 receptor

    DEFF Research Database (Denmark)

    Knudsen, Lotte Bjerre; Kiel, Dan; Teng, Min

    2007-01-01

    The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been...

  17. Evaluation of potential agonist radioligands for imaging dopamine D2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, J.P.

    2015-01-01

    Imaging dopamine receptors with PET and SPECT can shed light on the nature of neuropsychiatric disorders which are characterized by disturbances in dopamine D2/3 receptor functioning. Agonist radioligands are considered superior to antagonists because they are more sensitive to detect dopamine

  18. NICOTINE EFFECTS ON THE ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.

    Science.gov (United States)

    Considerable research has shown long-lasting effects of early exposure in experimental animals to nicotine. Anatoxin-a is produced by cyanobacteria and has been shown to be a potent nicotinic agonist. This experiment evaluated the motor activity of adult mice, and their respons...

  19. Quantitative phosphoproteomics dissection of 7TM receptor signaling using full and biased agonists

    DEFF Research Database (Denmark)

    Christensen, Gitte Lund; Kelstrup, Christian; Lyngsø, Christina

    2010-01-01

    pathways. We foresee that the amount and diversity of G protein independent signaling may be more pronounced than previously recognized for other 7TMRs as well. Quantitative mass spectrometry is a promising tool for evaluation of the signaling properties of biased agonists to other receptors in the future....

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

    Directory of Open Access Journals (Sweden)

    Antonietta Bernardo

    2008-01-01

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

  1. 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...

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

    Directory of Open Access Journals (Sweden)

    Karlie R. Jones

    2015-01-01

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

  3. Molecular determinants of selective agonist and antagonist binding to the histamine H₄ receptor

    NARCIS (Netherlands)

    Istyastono, Enade P; de Graaf, Chris; de Esch, Iwan J P; Leurs, Rob

    2011-01-01

    The deorphanization of the histamine H₄ receptor (H₄R) has led to a significant number of scientific publications and patent applications. Whereas some histamine H₁, H₂ and H₃ receptor ligands were found to have significant affinity for H₄R, several agonists and antagonists with high affinity for

  4. Quantitative protein and fat metabolism in bull calves treated with beta-adrenergic agonist

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    Protein and energy utilization and quantitative retention of protein, fat and energy was investigated with 12 Red Danish bulls during two subsequent 6 weeks trials (Sections A and B) at a mean live weight of 195 and 335 kg respectively. Treatments were control (Group 1) and beta-agonist (L-644,96...

  5. Novel non-indolic melatonin receptor agonists differentially entrain endogenous melatonin rhythm and increase its amplitude

    NARCIS (Netherlands)

    Drijfhout, W.J; de Vries, J.B; Homan, E.J; Brons, H.F; Copinga, S; Gruppen, G; Beresford, I.J M; Hagan, R.M; Grol, Cor; Westerink, B.H.C.

    1999-01-01

    In this study we have examined the ability of melatonin and four synthetic melatonin receptor agonists to entrain endogenous melatonin secretion in rats, free running in constant darkness. The circadian melatonin profile was measured by trans-pineal microdialysis, which not only reveals the time of

  6. β2 Agonists Enhance the Efficacy of Simultaneous Enzyme Replacement Therapy in Murine Pompe Disease

    Science.gov (United States)

    Koeberl, Dwight D.; Li, Songtao; Dai, Jian; Thurberg, Beth L.; Bali, Deeksha; Kishnani, Priya S.

    2011-01-01

    Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes. PMID:22154081

  7. Ingestion of transient receptor potential channel agonists attenuates exercise-induced muscle cramps.

    Science.gov (United States)

    Craighead, Daniel H; Shank, Sean W; Gottschall, Jinger S; Passe, Dennis H; Murray, Bob; Alexander, Lacy M; Kenney, W Larry

    2017-09-01

    Exercise-associated muscle cramping (EAMC) is a poorly understood problem that is neuromuscular in origin. Ingestion of transient receptor potential (TRP) channel agonists has been efficacious in attenuating electrically induced muscle cramps. This study examines the effect of TRP agonist ingestion on voluntarily induced EAMC and motor function. Study 1: Thirty-nine participants completed 2 trials after ingesting TRP agonist-containing active treatment (A), or vehicle (V) control. Cramping in the triceps surae muscle was induced via voluntary isometric contraction. Study 2: After ingesting A or V, 31 participants performed kinematic and psychomotor tests of manual dexterity. A increased precramp contraction duration (A, 36.9 ± 4.1 s; V, 27.8 ± 3.1 s), decreased cramp EMG area under the curve (A, 37.3 ± 7.7 %EMG max ·s; V, 77.2 ± 17.7 %EMG max ·s), increased contraction force to produce the cramp (A, 13.8 ± 1.8 kg; V, 9.9 ± 1.6 kg), and decreased postcramp soreness (A, 4.1 ± 0.3 arbitrary units (a.u.); V, 4.7 ± 0.3 a.u.). Kinematic and psychomotor tests were not affected. TRP agonist ingestion attenuated EAMC characteristics without affecting motor function. Muscle Nerve 56: 379-385, 2017. © 2017 Wiley Periodicals, Inc.

  8. GnRH-agonist versus GnRH-antagonist IVF cycles

    DEFF Research Database (Denmark)

    Papanikolaou, E G; Pados, G; Grimbizis, G

    2012-01-01

    In view of the current debate concerning possible differences in efficacy between the two GnRH analogues used in IVF stimulated cycles, the current study aimed to explore whether progesterone control in the late follicular phase differs when GnRH antagonist is used as compared with GnRH agonist, ...

  9. Serotonin syndrome after challenge with the 5-HT agonist meta-chlorophenylpiperazine

    NARCIS (Netherlands)

    Klaassen, T; Pian, KLH; Westenberg, HGM; den Boer, JA; van Praag, HM

    1998-01-01

    meta-Chlorophenylpiperazine (mCPP) is a non-selective 5-HT-receptor agonist/antagonist that is used extensively in psychiatry to assess central serotonergic function. We report on three patients who developed symptoms of the serotonin syndrome when they participated in an mCPP (0.5 mg/kg body weight

  10. The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis

    Directory of Open Access Journals (Sweden)

    Kristine Griffett

    2015-04-01

    Conclusions: Here, we demonstrate that an LXR inverse agonist, SR9238, is effective in reduction of hepatic steatosis, inflammation and fibrosis in an animal model of NASH. These results have important implications for the development of therapeutics for treatment NASH in humans.

  11. Structure-Guided Design of Selective Epac1 and Epac2 Agonists

    NARCIS (Netherlands)

    Schwede, Frank; Bertinetti, Daniela; Langerijs, Carianne N.; Hadders, Michael A.|info:eu-repo/dai/nl/304837393; Wienk, Hans; Ellenbroek, Johanne H.; de Koning, Eelco J P|info:eu-repo/dai/nl/126426562; Bos, Johannes L.|info:eu-repo/dai/nl/067853323; Herberg, Friedrich W.; Genieser, Hans Gottfried; Janssen, Richard A J; Rehmann, Holger|info:eu-repo/dai/nl/25564566X

    2015-01-01

    The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and

  12. Structure-guided design of selective Epac1 and Epac2 agonists

    NARCIS (Netherlands)

    Schwede, Frank; Bertinetti, Daniela; Langerijs, Carianne N; Hadders, Michael A; Wienk, Hans; Ellenbroek, Johanne H; de Koning, Eelco J P; Bos, Johannes L; Herberg, Friedrich W; Genieser, Hans-Gottfried; Janssen, Richard A J; Rehmann, Holger

    The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and

  13. Structure-guided design of selective epac1 and epac2 agonists

    NARCIS (Netherlands)

    Schwede, Frank; Bertinetti, Daniela; Langerijs, Carianne N; Hadders, Michael A; Wienk, Hans; Ellenbroek, Johanne H; de Koning, Eelco J P; Bos, Johannes L; Herberg, Friedrich W; Genieser, Hans-Gottfried; Janssen, Richard A J; Rehmann, Holger

    The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and

  14. Conformational variability of the glycine receptor M2 domain in response to activation by different agonists

    DEFF Research Database (Denmark)

    Pless, Stephan Alexander; Dibas, Mohammed I; Lester, Henry A

    2007-01-01

    change. Although taurine and beta-alanine were weak partial agonists at the alpha1R19'C glycine receptor, they induced large fluorescence changes. Propofol, which drastically enhanced these currents, did not induce a glycine-like blue shift in the spectral emission peak. The inhibitors strychnine...

  15. Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function

    DEFF Research Database (Denmark)

    Jørgensen, Peter G; Jensen, Magnus T; Mensberg, Pernille

    2017-01-01

    In patients with type 2 diabetes, both supervised exercise and treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) liraglutide may improve cardiac function. We evaluated cardiac function before and after 16 weeks of treatment with the GLP-1RA liraglutide or placebo...

  16. Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

    Science.gov (United States)

    Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of ...

  17. [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.

  18. THE MORPHOLOGICAL BASIS FOR OLFACTORY PERCEPTION OF STEROIDS DUING AGONISTIC BEHAVIOR IN LOBSTER: PRELIMINARY EXPERIMENTS

    Science.gov (United States)

    The morphological basis for olfactory perception of steroids during agonistic behavior in lobsters: preliminary experiments. Borsay Horowitz, DJ1, Kass-Simon, G2, Coglianese, D2, Martin, L2, Boseman, M2, Cromarty, S3, Randall, K3, Fini, A.3 1US EPA, NHEERL, ORD, Atlantic Ecology...

  19. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Analysis of Agonist and Antagonist Effects on Thyroid Hormone Receptor Conformation by Hydrogen/Deuterium Exchange

    NARCIS (Netherlands)

    Figueira, A C M; Saidemberg, D M; Telles de Souza, Paulo; Martínez, L; Scanlan, T S; Baxter, J D; Skaf, M S; Palma, M S; Webb, P M; Polikarpov, I

    Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains

  1. Desirable properties of β(3)-adrenoceptor agonists: Implications for the selection of drug development candidates

    NARCIS (Netherlands)

    Michel, Martin C.; Cernecka, Hana; Ochodnicky, Peter

    2011-01-01

    β(3)-adrenoceptor agonists are currently in clinical development for the treatment of overactive bladder and considered for several other indications. This Perspective discusses desirable properties of such drugs mainly based on the example of overactive bladder, but at least partly they should also

  2. Desirable properties of β3-adrenoceptor agonists : implications for the selection of drug development candidates

    NARCIS (Netherlands)

    Michel, Martin C; Cernecka, Hana; Ochodnicky, Peter

    2011-01-01

    β3-adrenoceptor agonists are currently in clinical development for the treatment of overactive bladder and considered for several other indications. This Perspective discusses desirable properties of such drugs mainly based on the example of overactive bladder, but at least partly they should also

  3. Enantiomers of bronchodilating beta2-adrenoceptor agonists: is there a cause for concern?

    Science.gov (United States)

    Waldeck, B

    1999-05-01

    All bronchodilating beta2-adrenoceptor agonists in current clinical use are derivatives of adrenaline and are available as racemates. Whereas the vast majority of the pharmacologic and clinical documentation has been made with the racemates, there are a few studies with the individual enantiomers. It thus appears that all established pharmacologic effects of racemic beta2-agonists reside in the (R)-enantiomer, with the (S)-enantiomer being virtually inactive. In recent years the suspicion has been raised that the (S)-enantiomer of the beta2-agonists is responsible for induction of airway hyperreactivity. This suspicion is based primarily on results obtained in guinea pigs exposed to (S)-enantiomers of beta2-agonists. A number of experiments in vitro have been undertaken to find a mechanism of action for these observations in vivo. Most of the results obtained are equivocal. However, the observation that (S)-salbutamol may cause mobilization of intracellular Ca2+, apparently by means of a cholinergic mechanism, deserves further investigation. The clinical studies are focused on the enantiomers of salbutamol. They confirm the preclinical findings that the pulmonary, as well as the extrapulmonary, effects of salbutamol reside in the (R)-enantiomer. The studies available so far do not convincingly show clinically significant airway hyperreactivity after exposure to the (S)-enantiomer. Further studies are needed to settle this issue.

  4. In utero Exposure to beta-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders

    DEFF Research Database (Denmark)

    Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor

    2016-01-01

    OBJECTIVES: The purpose of this study was to investigate associations between use of β-2-adrenergic receptor (B2AR) agonist drugs during pregnancy and risk for autism spectrum disorders (ASD). METHODS: A case-control study was conducted by using Denmark’s health and population registers. Among...

  5. 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

  6. Peroxisome Proliferator-Activated Receptor Agonists Modulate Neuropathic Pain: a Link to Chemokines?

    Directory of Open Access Journals (Sweden)

    Caroline eFreitag

    2014-08-01

    Full Text Available Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1α, fractalkine, SDF-1 among others have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between PPAR agonists' pain ameliorating effects and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide, shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain.

  7. Extremely high-frequency electromagnetic radiation enhances neutrophil response to particulate agonists.

    Science.gov (United States)

    Vlasova, Irina I; Mikhalchik, Elena V; Gusev, Alexandr A; Balabushevich, Nadezhda G; Gusev, Sergey A; Kazarinov, Konstantin D

    2018-02-01

    The growing use of extremely high-frequency electromagnetic radiation (EHF EMR) in information and communication technology and in biomedical applications has raised concerns regarding the potential biological impact of millimeter waves (MMWs). Here, we elucidated the effects of MMW radiation on neutrophil activation induced by opsonized zymosan or E. coli in whole blood ex vivo. After agonist addition to blood, two samples were prepared. A control sample was incubated at ambient conditions without any treatment, and a test sample was exposed to EHF EMR (32.9-39.6 GHz, 100 W/m 2 ). We used methods that allowed us to assess the functional status of neutrophils immediately after exposure: oxidant production levels were measured by luminol-dependent chemiluminescence, and morphofunctional changes to neutrophils were observed in blood smears. Results revealed that the response of neutrophils to both agonists was intensified if blood was exposed to MMW radiation for 15 min. Neutrophils were intact in both the control and irradiated samples if no agonist was added to blood before incubation. Similarly, exposing suspensions of isolated neutrophils in plasma to MMW radiation enhanced cell response to both zymosan and E. coli. Heating blood samples was shown to be the primary mechanism underlying enhanced EHF EMR-induced oxidant production by neutrophils in response to particulate agonists. Bioelectromagnetics. 39:144-155, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  8. 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

    BACKGROUND: Drug-induced hypothermia reduces brain damage in animal stroke models and is an undiscovered potential in human stroke treatment. We studied hypothermia induced by the serotonergic agonists S14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine) and ipsapirone in a rat...

  9. The GABAA receptor agonist THIP is neuroprotective in organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Kristensen, Bjarne Winther; Noraberg, Jens; Zimmer, Jens

    2003-01-01

    The potential neuroprotective effects of the GABA(A) receptor agonists THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and muscimol, and the selective GluR5 kainate receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid), which activates GABAergic interneu......The potential neuroprotective effects of the GABA(A) receptor agonists THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and muscimol, and the selective GluR5 kainate receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid), which activates GABAergic...... interneurons, were examined in hippocampal slice cultures exposed to N-methyl-D-aspartate (NMDA). The NMDA-induced excitotoxicity was quantified by densitometric measurements of propidium iodide (PI) uptake. THIP (100-1000 microM) was neuroprotective in slice cultures co-exposed to NMDA (10 microM) for 48 h......, while muscimol (100-1000 microM) and ATPA (1-3 microM) were without effect. The results demonstrate that direct GABA(A) agonism can mediate neuroprotection in the hippocampus in vitro as previously suggested in vivo....

  10. Dopamine receptor agonists modulate voluntary alcohol intake independently of individual levels of alcohol intake in rats

    NARCIS (Netherlands)

    Spoelder, M.; Baars, A.M.; Rotte, M.D.; Vanderschuren, L.J.; Lesscher, H.M.

    2016-01-01

    RATIONALE: Individual susceptibility to alcohol use disorder has been related to functional changes in dopaminergic neurotransmission. OBJECTIVES: The aim of the current work was to assess the effects of selective dopamine D1 and D2 receptor agonists and antagonists on alcohol consumption in rats

  11. Detection and identification of "new" beta-agonists in black-market preparations

    NARCIS (Netherlands)

    van Ginkel LA; Stephany RW; van Rossum HJ; Visser T; den Engelsman T; de Jong APJM; Jacquemijns M; Zomer G

    1992-01-01

    In several "black-market" used for growth promotion preparations new compounds were found belonging to the group of N-phenylethanolamines with structures very similar to compounds known to be used for veal calf and cattle production, the so called beta-agonists. The two most important

  12. Excitotoxic effects of non-NMDA receptor agonists in organotypic corticostriatal slice cultures

    DEFF Research Database (Denmark)

    Kristensen, B W; Noraberg, J; Jakobsen, B

    1999-01-01

    The excitotoxic effects of the glutamate receptor agonists kainic acid (KA) and 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and the corresponding neuroprotective effects of the AMPA/KA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) were examined in c...

  13. Prostaglandin E receptor subtype EP4 agonist serves better to protect cochlea than prostaglandin E1.

    Science.gov (United States)

    Hori, Ryusuke; Nakagawa, Takayuki; Yamamoto, Norio; Hamaguchi, Kiyomi; Ito, Juichi

    2013-12-01

    The present study aimed to examine whether an E-prostanoid receptor 4 (EP4) agonist has superior protective effects to those of prostaglandin E1 (PGE1) in a guinea pig model of noise trauma. Drugs were locally applied on the round window membrane of guinea pig cochleae, followed by exposure of the test animals to intense noise. Protective effects mediated by an EP4 agonist were compared with those mediated by PGE1. Auditory function was monitored by measurements of the auditory brainstem response (ABR), and histological damage was assessed by immunohistochemical analysis of cochlear specimens. Animals treated with an EP4 agonist exhibited significantly better hearing recovery than those pretreated with PGE1. Histologically, the numbers of remaining outer hair cells in cochleae treated with the EP4 agonist were significantly higher than in those treated with PGE1. The selective activation of EP4 has a stronger protective effect on cochleae against noise trauma than does the broad activation of EPs by PGE1. Copyright © 2013. Published by Elsevier Ireland Ltd.

  14. Contradictory effects of GABA-B receptor agonists on cortical epileptic afterdischarges in immature rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel; Tabashidze, Nana

    2008-01-01

    Roč. 75, č. 1 (2008), s. 173-178 ISSN 0361-9230 R&D Projects: GA ČR(CZ) GA305/05/2581 Institutional research plan: CEZ:AV0Z50110509 Keywords : GABA -B receptor agonists * epileptic afterdischarges * cortex Subject RIV: FH - Neurology Impact factor: 2.281, year: 2008

  15. Effects of glucagon-like peptide-1 (GLP-1) receptor agonists on cardiovascular risk factors

    DEFF Research Database (Denmark)

    Dalsgaard, Niels B; Vilsbøll, Tina; Knop, Filip K

    2018-01-01

    trials for diabetes therapies. To determine if different glucagon-like peptide-1 receptor agonists (GLP-1RAs) had varying effects on these CV risk factors, we reviewed 16 head-to-head trials directly comparing GLP-1RAs that included at least one of the five factors. Few trials reported statistical...

  16. Agonistic behavior and environmental enrichment of cats communally housed in a shelter.

    Science.gov (United States)

    Dantas, Leticia M S; Crowell-Davis, Sharon L; Alford, Kelly; Genaro, Gelson; D'Almeida, Jose Mario; Paixao, Rita L

    2011-09-15

    To evaluate the presence of a dominance rank in a group of cats and the relation between agonistic behavior and the use of resources, including environmental enrichment, in these cats. Observational analytic study. 27 neutered cats in a shelter in Sao Paulo, Brazil. The cats were video recorded for 4 consecutive days to obtain baseline data. Subsequently, a puzzle feeder was added as an enrichment device every other day over 8 days, for a total of 4 days with enrichment. Cats were also video recorded on these days. All pretreatment and posttreatment agonistic behaviors and interactions with the puzzle feeder were recorded by reviewing the videotapes. 143 agonistic encounters were recorded, of which 44 were related to resources and 99 were not. There were insufficient agonistic interactions to determine a dominance rank. Presence or absence of the puzzle feeder did not affect the rate of aggression. There was no significant effect of weight, sex, or coat color on the rate of aggression, and aggressive behavior did not correlate with time spent with the puzzle feeder. Twenty-three of the 27 cats interacted with the puzzle feeder. In a stable group of communally housed cats, environmental enrichment did not cause increased aggression as a result of competition for the source of enrichment. Because environmental enrichment increases the opportunity to perform exploratory behaviors, it may improve the welfare of groups of cats maintained long-term in shelters, sanctuaries, or multicat households.

  17. Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

    Directory of Open Access Journals (Sweden)

    Mette Trauelsen

    2017-12-01

    Conclusions: These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy.

  18. Gonadotropin-Releasing Hormone Agonist Treatment in Postmenopausal Women with Hyperandrogenism of Ovarian Origin

    NARCIS (Netherlands)

    Vollaard, Esther S.; van Beek, Andre P.; Verburg, Frederik A. J.; Roos, Annemieke; Land, Jolande A.

    Context: The most frequent cause of virilization in postmenopausal women is excessive androgen production of ovarian origin. Bilateral oophorectomy is usually performed, even in cases of benign tumors or hyperthecosis. This is the first report of a case series of long-term GnRH-agonist treatment of

  19. B1 but not B2 bradykinin receptor agonists promote DU145 prostate ...

    African Journals Online (AJOL)

    Background: The kallikrein-kinin system (KKS) is an endogenous pathway involved in angiogenesis and tumourigenesis, both vital for cancer growth and progression. Objectives: To investigate the effect of two bradykinin receptor (B1R and B2R) agonists on growth and motility of prostate tumour (DU145) and ...

  20. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action

    DEFF Research Database (Denmark)

    Lucas, Guillaume; Rymar, Vladimir V; Du, Jenny

    2007-01-01

    Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain...

  1. Agonistic Recognition in Education: On Arendt's Qualification of Political and Moral Meaning

    Science.gov (United States)

    Ljunggren, Carsten

    2010-01-01

    Agonistic recognition in education has three interlinked modes of aesthetic experience and self-presentation where one is related to actions in the public realm; one is related to plurality in the way in which it comes into existence in confrontation with others; and one is related to the subject-self, disclosed by "thinking. Arendt"s conception…

  2. Rapid analysis of ß-agonists in urine by thermospray tandem mass spectrometry

    NARCIS (Netherlands)

    Rhijn, van J.A.; O'Keeffe, M.; Heskamp, H.H.; Collins, S.

    1995-01-01

    A method is described for the analysis of -agonists in urine of cattle. The method uses solid-phase extraction (SPE), followed by analysis of the resulting extract by flow injection thermospray tandem mass spectrometry (TSP-MS-MS). Sample preparation is performed using a mixed-bed SPE procedure

  3. GnRH agonist for triggering of final oocyte maturation: time for a change of practice?

    DEFF Research Database (Denmark)

    Humaidan, P; Kol, Stefan; Papanikolaou, E G

    2011-01-01

    GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase...

  4. Relaxing action of adrenergic β2-agonists on guinea-pig skinned tracheal muscle

    Directory of Open Access Journals (Sweden)

    Kayo Nemoto

    1999-01-01

    Full Text Available Although adrenergic β2-agonist-induced smooth muscle relaxation has been attributed to increased intracellular cyclic AMP (cAMP, a relaxation response has been observed at low β2-agonist concentrations that do not cause increased cAMP To elucidate the mechanism of tracheal muscle relaxation induced by low concentrations of β2-agonists, we used a guinea-pig skinned tracheal smooth muscle preparation to examine the effects on the contractile protein system. The isotonic contraction of β-escin-treated skinned tracheal muscle from guinea-pig was measured. When the intracellular Ca2+ concentration was maintained at 1 μmol/L in the presence of guanosine 5′-triphosphate (GTP; 100 μmol/L, neither isoproterenol (10nmol/L nor salbutamol (60 nmol/L affected Ca2+ sensitivity, but a significant decrease in Ca2+ sensitivity was observed in the presence of okadaic acid (1 μmol/L. The decrease in Ca2+ sensitivity was a slow response and was blocked by pretreatment with propranolol (1 μmol/L. Forskolin (1 μmol/L did not affect Ca2+ sensitivity. These results suggest that adrenergic b 2-agonists may activate protein phosphatase through an unknown pathway involving the β2-receptor, which enhances dephosphorylation of the myosin light chain and/or thin filament proteins, resulting in relaxation of the tracheal smooth muscle.

  5. Development of a radioreceptor assay for {beta}{sub 2} adrenergic agonists

    Energy Technology Data Exchange (ETDEWEB)

    Helbo, V. [Lab. d`analyse des denrees alimentaires d`origine animale, Faculte de Medecine Veterinaire de l`Universite, Liege (Belgium); Vandenbroeck, M. [Lab. d`analyse des denrees alimentaires d`origine animale, Faculte de Medecine Veterinaire de l`Universite, Liege (Belgium); Maghuin-Rogister, G. [Lab. d`analyse des denrees alimentaires d`origine animale, Faculte de Medecine Veterinaire de l`Universite, Liege (Belgium)

    1994-05-01

    Several {beta}{sub 2} adrenergic agonists are illegally used as growth promoters in meat production. We have developed and evaluated a radioreceptor assay for the multianalyte detection of these compounds. The method is based on a competition for binding with receptors (plasma membranes prepared from bovine teat muscles) between a radioactive tracer ({sup 3}H-dihydroalprenolol) and {beta}{sub 2} agonist residues present in the samples. The method has been validated for three {beta}{sub 2} agonists (clenbuterol, mabuterol and cimaterol) in bovine urine samples. The detection limit (mean of ``blank`` values + 3 SEM) in urine was 2.4 ppb clenbuterol. Using this procedure, samples containing at least 5 ppb of clenbuterol, mabuterol or cimaterol could be identified as positive for the presence of {beta}{sub 2} agonists. (orig.) [Deutsch] Mehrere {beta}{sub 2} adrenerge Agonisten werden illegal als Wachstumsfoerderer in der Fleischproduktion eingesetzt. Wir entwickelten und testeten einen RRA (``Radioreceptor Assay``) zur Mehrfachrueckstandsanalyse dieser Zusammensetzungen. Die Methode basiert auf einer Kompetition eines radioaktiven Markers ({sup 3}H-dihydroalpenolol) mit den Rueckstaenden der {beta}{sub 2} Agonisten der Proben um Bindungsstellen der Rezeptoren (Plasmamembranen, welche aus Muskelzellen von Rinderzitzen gewonnen wurden). Die Methode wurde fuer 3 {beta}{sub 2} Agonisten (Clenbuterol, Mabuterol und Cimaterol) in Harnproben anerkannt. Die Nachweisgrenze (Durchschnitt der Leerwerte + 3 Standardabweichungen) bei Harnproben liegt bei 2,4 ppb fuer Clenbuterol. Diese Methode ermoeglicht, Konzentrationen von mindestens 5 ppb an Clenbuterol, Mabuterol und Cimaterol im Probenmaterial nachzuweisen. (orig.)

  6. Do agonistic interactions underlie the segregation and relative abundances between two Loxosceles species (Araneae: Sicariidae)?

    Science.gov (United States)

    Fischer, Marta L; Diniz, Suzana; Vasconcellos-Neto, João

    2014-05-01

    The medically important spiders Loxosceles intermedia Mello-Leitão and Loxosceles laeta (Nicolet) are segregated in Curitiba, southern Brazil, where L. intermedia is more abundant and widespread than L. laeta. Because they share similar microhabitat preferences and wander in search of web sites, agonistic encounters are likely to occur. The purposes of this study were to describe agonistic interactions and interpret their consequences for the relative abundances and spatial segregation of L. intermedia and L. laeta. Experimental contests were performed between residents and intruders. Asymmetries between contestants included sex, age, species, weight, and residence status. Nine behavioral categories were defined. Through discriminant analyses, it was possible to differentiate spider sex, species, and residence based on their agonistic behaviors. Intruders, juveniles, and L. intermedia individuals were better characterized by exploratory behaviors, whereas L. laeta females were differentiated by aggressiveness. By performing a multiple logistic regression, with winning or defeat as a dependent variable of sex, age, species, size, weight, and residence, it was possible to say that residents and L. intermedia individuals had the highest winning odds in contests, whereas juveniles had lower winning odds than adults. Advantages of the prior residence may help to explain the predominance of L. laeta in old colonization sites, whereas the higher winning odds of L. intermedia and less aggressive behavior toward conspecifics may lead to a successful establishment of dense populations in new sites. A better understanding of agonistic interactions as a mechanism of spacing, segregation, and species replacement among spiders may be helpful for control purposes.

  7. Characterization of structurally novel G protein biased CB1 agonists: Implications for drug development.

    Science.gov (United States)

    Ford, Benjamin M; Franks, Lirit N; Tai, Sherrica; Fantegrossi, William E; Stahl, Edward L; Berquist, Michael D; Cabanlong, Christian V; Wilson, Catheryn D; Penthala, Narsimha R; Crooks, Peter A; Prather, Paul L

    2017-11-01

    The human cannabinoid subtype 1 receptor (hCB 1 R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB 1 R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCB 1 Rs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to β-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB 1 Rs might be improved by development of G-protein biased hCB 1 R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB 1 receptors. Our studies found that a novel IQD-derived hCB 1 receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non-biased hCB 1 R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no β-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to β-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced β-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB 1

  8. Heterologous Expression in Remodeled C. elegans: A Platform for Monoaminergic Agonist Identification and Anthelmintic Screening.

    Directory of Open Access Journals (Sweden)

    Wenjing Law

    2015-04-01

    Full Text Available Monoamines, such as 5-HT and tyramine (TA, paralyze both free-living and parasitic nematodes when applied exogenously and serotonergic agonists have been used to clear Haemonchus contortus infections in vivo. Since nematode cell lines are not available and animal screening options are limited, we have developed a screening platform to identify monoamine receptor agonists. Key receptors were expressed heterologously in chimeric, genetically-engineered Caenorhabditis elegans, at sites likely to yield robust phenotypes upon agonist stimulation. This approach potentially preserves the unique pharmacologies of the receptors, while including nematode-specific accessory proteins and the nematode cuticle. Importantly, the sensitivity of monoamine-dependent paralysis could be increased dramatically by hypotonic incubation or the use of bus mutants with increased cuticular permeabilities. We have demonstrated that the monoamine-dependent inhibition of key interneurons, cholinergic motor neurons or body wall muscle inhibited locomotion and caused paralysis. Specifically, 5-HT paralyzed C. elegans 5-HT receptor null animals expressing either nematode, insect or human orthologues of a key Gαo-coupled 5-HT1-like receptor in the cholinergic motor neurons. Importantly, 8-OH-DPAT and PAPP, 5-HT receptor agonists, differentially paralyzed the transgenic animals, with 8-OH-DPAT paralyzing mutant animals expressing the human receptor at concentrations well below those affecting its C. elegans or insect orthologues. Similarly, 5-HT and TA paralyzed C. elegans 5-HT or TA receptor null animals, respectively, expressing either C. elegans or H. contortus 5-HT or TA-gated Cl- channels in either C. elegans cholinergic motor neurons or body wall muscles. Together, these data suggest that this heterologous, ectopic expression screening approach will be useful for the identification of agonists for key monoamine receptors from parasites and could have broad application for

  9. An Accessory Agonist Binding Site Promotes Activation of α4β2* Nicotinic Acetylcholine Receptors.

    Science.gov (United States)

    Wang, Jingyi; Kuryatov, Alexander; Sriram, Aarati; Jin, Zhuang; Kamenecka, Theodore M; Kenny, Paul J; Lindstrom, Jon

    2015-05-29

    Neuronal nicotinic acetylcholine receptors containing α4, β2, and sometimes other subunits (α4β2* nAChRs) regulate addictive and other behavioral effects of nicotine. These nAChRs exist in several stoichiometries, typically with two high affinity acetylcholine (ACh) binding sites at the interface of α4 and β2 subunits and a fifth accessory subunit. A third low affinity ACh binding site is formed when this accessory subunit is α4 but not if it is β2. Agonists selective for the accessory ACh site, such as 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283), cannot alone activate a nAChR but can facilitate more efficient activation in combination with agonists at the canonical α4β2 sites. We therefore suggest categorizing agonists according to their site selectivity. NS9283 binds to the accessory ACh binding site; thus it is termed an accessory site-selective agonist. We expressed (α4β2)2 concatamers in Xenopus oocytes with free accessory subunits to obtain defined nAChR stoichiometries and α4/accessory subunit interfaces. We show that α2, α3, α4, and α6 accessory subunits can form binding sites for ACh and NS9283 at interfaces with α4 subunits, but β2 and β4 accessory subunits cannot. To permit selective blockage of the accessory site, α4 threonine 126 located on the minus side of α4 that contributes to the accessory site, but not the α4β2 sites, was mutated to cysteine. Alkylation of this cysteine with a thioreactive reagent blocked activity of ACh and NS9283 at the accessory site. Accessory agonist binding sites are promising drug targets. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review.

    Science.gov (United States)

    Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M; Heiss, Elke H; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M; Atanasov, Atanas G

    2014-11-01

    Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Estrogen Receptor β Agonists Differentially Affect the Growth of Human Melanoma Cell Lines.

    Directory of Open Access Journals (Sweden)

    Monica Marzagalli

    Full Text Available Cutaneous melanoma is an aggressive malignancy; its incidence is increasing worldwide and its prognosis remains poor. Clinical observations indicate that estrogen receptor β (ERβ is expressed in melanoma tissues and its expression decreases with tumor progression, suggesting its tumor suppressive function. These experiments were performed to investigate the effects of ERβ activation on melanoma cell growth.Protein expression was analyzed by Western blot and immunofluorescence assays. Cell proliferation was assessed by counting the cells by hemocytometer. ERβ transcriptional activity was evaluated by gene reporter assay. Global DNA methylation was analyzed by restriction enzyme assay and ERβ isoforms were identified by qRT-PCR. We demonstrated that ERβ is expressed in a panel of human melanoma cell lines (BLM, WM115, A375, WM1552. In BLM (NRAS-mutant cells, ERβ agonists significantly and specifically inhibited cell proliferation. ERβ activation triggered its cytoplasmic-to-nuclear translocation and transcriptional activity. Moreover, the antiproliferative activity of ERβ agonists was associated with an altered expression of G1-S transition-related proteins. In these cells, global DNA was found to be hypomethylated when compared to normal melanocytes; this DNA hypomethylation status was reverted by ERβ activation. ERβ agonists also decreased the proliferation of WM115 (BRAF V600D-mutant cells, while they failed to reduce the growth of A375 and WM1552 (BRAF V600E-mutant cells. Finally, we could observe that ERβ isoforms are expressed at different levels in the various cell lines. Specific oncogenic mutations or differential expression of receptor isoforms might be responsible for the different responses of cell lines to ERβ agonists.Our results demonstrate that ERβ is expressed in melanoma cell lines and that ERβ agonists differentially regulate the proliferation of these cells. These data confirm the notion that melanoma is a

  12. Prediction of response to GLP-1 receptor agonist therapy in Japanese patients with type 2 diabetes.

    Science.gov (United States)

    Imai, Kenjiro; Tsujimoto, Tetsuro; Goto, Atsushi; Goto, Maki; Kishimoto, Miyako; Yamamoto-Honda, Ritsuko; Noto, Hiroshi; Kajio, Hiroshi; Noda, Mitsuhiko

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists can maintain good glycemic control in some diabetic. Here we compared the clinical characteristics and parameters reflecting glucose metabolism at the time of the initiation of GLP-1 receptor agonist therapy between patients who responded well to therapy and those who did not. The records of 43 patients with type 2 diabetes who started receiving GLP-1 receptor agonist therapy during hospitalization were retrospectively reviewed. Glucagon stimulation tests were performed, and patients were started on liraglutide or exenatide therapy. Preprandial blood glucose levels were measured on days 2 and 3 of GLP-1 receptor agonist therapy. We used the Cox proportional hazard model to compare clinical parameters between responders (HbA1c level ratio [HR] for non-response was 5.3 (95% confidence interval [CI]: 1.16-24.6, P = 0.03) for insulin therapy and 5.0 (95% CI: 1.13-22.16, P = 0.03) for sulfonylurea therapy. Compared with the lowest tertile, the HRs for non-response in the highest tertile were 3.1 (95% CI: 1.04-8.97, P = 0.04) for the mean preprandial blood glucose level on days 2 and 3 and 3.4 (95% CI: 1.05-11.01, P = 0.04) for the body mass index. The response was not significantly associated with the duration of diabetes or the glucagon stimulation test results. A receiver operating curve analysis showed that the mean preprandial blood glucose level had the highest area under the curve value (=0.72) for the prediction of non-responders. In patients with poorly controlled diabetes, the response to GLP-1 receptor agonist therapy was significantly associated with the treatment used before the initiation of therapy, the body mass index, and the mean preprandial blood glucose level during the 2 days after the initiation of therapy.

  13. Behavioral effects of the novel potent cannabinoid CB1 agonist AM 4054.

    Science.gov (United States)

    McLaughlin, Peter J; Thakur, Ganesh A; Vemuri, V Kiran; McClure, Evan D; Brown, Cara M; Winston, Keisha M; Wood, Jodianne T; Makriyannis, Alexandros; Salamone, John D

    2013-08-01

    Due to the ubiquity of the CB1 cannabinoid receptor throughout the nervous system, as well as the many potential therapeutic uses of CB1 agonist-based interventions, it is desirable to synthesize novel probes of the CB1 receptor. Here, the acute behavioral effects of systemic (i.p.) administration of the putative novel CB1 full agonist AM 4054 were tested in rats. In Experiment 1, a dose range (0.15625-1.25 mg/kg) of AM 4054 produced effects consistent with CB1 agonism in the cannabinoid tetrad of tasks in rats, including induction of analgesia, catalepsy, hypothermia, and locomotor suppression. These effects were reversed with the CB1-selective inverse agonist AM 251 in Experiment 2, indicating that AM 4054 produced CB1 receptor-mediated effects. Analysis of open-field activity indicated that the reduction in locomotion is more consistent with general motor slowing than anxiogenesis. AM 4054 (0.0625-0.5 mg/kg) also dose-dependently reduced fixed-ratio 5 (FR5) operant responding for food in Experiment 3, and microanalysis of the timing and rate of lever pressing indicated a pattern of suppression similar to other CB1 agonists. Minimum doses of AM 4054 (0.125-0.3125 mg/kg) required to produce significant effects in these behavioral assays were lower than those of many CB1 agonists. It is likely that AM 4054 is a potent pharmacological tool for assessment of cannabinoid receptor function. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Interactions of dopaminergic agonists and antagonists with dopaminergic D3 binding sites in rat striatum. Evidence that [3H]dopamine can label a high affinity agonist-binding state of the D1 dopamine receptor

    International Nuclear Information System (INIS)

    Leff, S.E.; Creese, I.

    1985-01-01

    The interactions of dopaminergic agonists and antagonists with 3 H-agonist labeled D3 dopaminergic binding sites of rat striatum have been characterized by radioligand-binding techniques. When the binding of [ 3 H]dopamine and [ 3 H]apomorphine to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone, these ligands appear to label selectively the previously termed D3 binding site. Antagonist/[ 3 H]dopamine competition curves are of uniformly steep slope (nH . 1.0), suggesting the presence of a single D3 binding site. The relative potencies of antagonists to inhibit D3 specific [ 3 H]dopamine binding are significantly correlated with their potencies to block D1 dopamine receptors as measured by the inhibition of both dopamine-stimulated adenylate cyclase and [ 3 H]flupentixol-binding activities. The affinities of agonists to inhibit D3 specific [ 3 H]dopamine binding are also correlated with estimates of these agonists affinities for the high affinity binding component of agonist/[ 3 H]flupentixol competition curves. Both D3 specific [ 3 H] dopamine binding and the high affinity agonist-binding component of dopamine/[ 3 H]flupentixol competition curves show a similar sensitivity to guanine nucleotides. Taken together, these data strongly suggest that the D3 binding site is related to a high affinity agonist-binding state of the D1 dopamine receptor

  15. Multiresidue analysis of beta(2)-agonists in human and calf urine using multimodal solid-phase extraction and high-performance liquid chromatography with electrochemical detection

    NARCIS (Netherlands)

    Koole, A; Bosman, J; Franke, JP; de Zeeuw, RA

    1999-01-01

    Various beta(2)-agonists are used as illegal growth promoters in man and in animals. We developed a multiresidue procedure for the analysis of four beta-agonists in human and calf urine. The sample was pre-extracted with an Extrelut column at alkaline pH. The beta-agonists were eluted with a mixture

  16. Identification of Buctopamine and Mebuctopamine, a β2Receptor Agonist and Its Metabolite, in Swine Hair and Feed Additives.

    Science.gov (United States)

    Chen, Ying-Heng; Yang, Chia-Ying; Cheng, Chih Wen; Lin, Yi-Ying; Kuo, Su Lien; Hsin, Ling-Wei

    2017-05-17

    4-[2-(t-Butylamino)-1-hydroxyethyl]phenol (buctopamine, 4), a new β 2 receptor agonist (β 2 -agonist), was found to be an adulterant in feed additives for swine in Taiwan, where using β 2 -agonists in food-production animals is prohibited. Buctopamine and its metabolite, 4-[2-(t-butylamino)-1-hydroxyethyl]-2-methoxyphenol (mebuctopamine, 2), were detected in swine hair specimens. Authentic compounds 2 and 4 were synthesized with 98.6% and 97.7% purity, respectively, as reference standards for analysis, and both compounds were more hydrophilic than ractopamine and clenbuterol. In a preliminary pharmacological evaluation, compounds 2 and 4 exhibited moderate human β 2 receptor binding affinity and did not show significant affinities for the human α 1 , α 2 , β 1 , and β 3 receptors. After addition of compounds 2-4 into the β 2 -agonist library, a multiresidue analysis of 26 β 2 -agonists by using triple quadrupole LC/MS/MS for routine screening conducted by regulatory authorities was established, in which the common limits of quantification for the 26 β 2 -agonists in swine feed and hair are 10 and 25 ng/g, respectively. In addition, the illegal use of buctopamine (4) has been effectively prevented. The results of this study are also useful for controlling the illegal use of new β 2 -agonists in food-production animals.

  17. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.

    2003-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

  18. Peroxisome proliferator-activated receptor-gamma agonists suppress tissue factor overexpression in rat balloon injury model with paclitaxel infusion.

    Directory of Open Access Journals (Sweden)

    Jun-Bean Park

    Full Text Available The role and underlying mechanisms of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ agonist, on myocardial infarction are poorly understood. We investigated the effects of this PPAR-γ agonist on the expression of tissue factor (TF, a primary molecule for thrombosis, and elucidated its underlying mechanisms. The PPAR-γ agonist inhibited TF expression in response to TNF-α in human umbilical vein endothelial cells, human monocytic leukemia cell line, and human umbilical arterial smooth muscle cells. The overexpression of TF was mediated by increased phosphorylation of mitogen-activated protein kinase (MAPK, which was blocked by the PPAR-γ agonist. The effective MAPK differed depending on each cell type. Luciferase and ChIP assays showed that transcription factor, activator protein-1 (AP-1, was a pivotal target of the PPAR-γ agonist to lower TF transcription. Intriguingly, two main drugs for drug-eluting stent, paclitaxel or rapamycin, significantly exaggerated thrombin-induced TF expression, which was also effectively blocked by the PPAR-γ agonist in all cell types. This PPAR-γ agonist did not impair TF pathway inhibitor (TFPI in three cell types. In rat balloon injury model (Sprague-Dawley rats, n = 10/group with continuous paclitaxel infusion, the PPAR-γ agonist attenuated TF expression by 70±5% (n = 4; P<0.0001 in injured vasculature. Taken together, rosiglitazone reduced TF expression in three critical cell types involved in vascular thrombus formation via MAPK and AP-1 inhibitions. Also, this PPAR-γ agonist reversed the paclitaxel-induced aggravation of TF expression, which suggests a possibility that the benefits might outweigh its risks in a group of patients with paclitaxel-eluting stent implanted.

  19. Interaction between Mu and Delta Opioid Receptor Agonists in an Assay of Capsaicin-Induced Thermal Allodynia in Rhesus Monkeys

    Directory of Open Access Journals (Sweden)

    S. Stevens Negus

    2012-01-01

    Full Text Available Delta opioid agonists enhance antinociceptive effects of mu-opioid agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+-4-[(αR-α-((2S,5R-4-allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine. Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg. SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception.

  20. Agonist action of adenosine triphosphates at the human P2Y1 receptor.

    Science.gov (United States)

    Palmer, R K; Boyer, J L; Schachter, J B; Nicholas, R A; Harden, T K

    1998-12-01

    The agonist selectivity for adenosine di- and triphosphates was determined for the human P2Y1 receptor stably expressed in human 1321N1 astrocytoma cells and was studied under conditions in which nucleotide metabolism was both minimized and assessed. Cells were grown at low density on glass coverslips, encased in a flow-through chamber, and continuously superfused with medium, and Ca2+ responses to nucleotides were quantified. Superfusion with high performance liquid chromatographically purified ADP, ATP, 2-methylthio-ADP, and 2-methylthio-ATP resulted in rapid Ca2+ responses, with EC50 values of 10 +/- 5, 304 +/- 51, 2 +/- 1, and 116 +/- 50 nM, respectively. Similar peak responses were observed with maximal concentrations of these four agonists and with the hydrolysis-resistant adenine nucleoside triphosphate adenosine-5'-O-(3-thiotriphosphate). No conversion of [3H]ATP to [3H]ADP occurred under these conditions. Similar full agonist activities of ATP, 2-methylthio-ATP, and ADP were observed in human embryonic kidney 293 cells, which natively express the P2Y1 receptor. In contrast to these results, Leon et al. [FEBS Lett 403:26-30 (1997)] and Hechler et al. [Mol Pharmacol 53:727-733 (1998)] recently reported that, whereas ADP and 2-methylthio-ADP were agonists, ATP and 2-methylthio-ATP were weak antagonists in studies of the human P2Y1 receptor expressed in human Jurkat cells. To assess whether differences in the degree of receptor reserve might explain this discrepancy of results, P2Y1 receptor-expressing 1321N1 cells were incubated for 24 hr with adenosine-5'-O-(2-thiodiphosphate), with the goal of down-regulating the level of functional receptors. Pretreatment with adenosine-5'-O-(2-thiodiphosphate) resulted in a 10-fold rightward shift in the concentration-effect curve for ADP; in contrast, the agonist activity of ATP was completely abolished. Taken together, our results indicate that adenosine di- and triphosphates are agonists at the human P2Y1 receptor

  1. An overview of once-weekly glucagon-like peptide-1 receptor agonists--available efficacy and safety data and perspectives for the future

    DEFF Research Database (Denmark)

    Madsbad, S; Kielgast, U; Asmar, M

    2011-01-01

    to the currently available agonists, exenatide BID and liraglutide QD. A greater reduction in haemoglobin A1c (HbA1c) and fasting plasma glucose was found with the once-weekly GLP-1 receptor agonists compared with exenatide BID, while the effect on postprandial hyperglycaemia was modest with the once-weekly GLP-1...... receptor agonist. The reduction in HbA1c was in most studies greater compared to oral antidiabetic drugs and insulin glargine. The reduction in weight did not differ between the short- and long-acting agonists. The gastrointestinal side effects were less with the once-weekly agonists compared...

  2. Therapeutic Effects of Melatonin Receptor Agonists on Sleep and Comorbid Disorders

    Directory of Open Access Journals (Sweden)

    Moshe Laudon

    2014-09-01

    Full Text Available Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, agomelatine and tasimelteon have recently become available for the treatment of insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy and safety profiles of these compounds in the treatment of the indicated disorders are reviewed. Accumulating evidence indicates that sleep-wake disorders and co-existing medical conditions are mutually exacerbating. This understanding has now been incorporated into the new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5. Therefore, when evaluating the risk/benefit ratio of sleep drugs, it is pertinent to also evaluate their effects on wake and comorbid condition. Beneficial effects of melatonin receptor agonists on comorbid neurological, psychiatric, cardiovascular and metabolic symptomatology beyond sleep regulation are also described. The review underlines the beneficial value of enhancing physiological sleep in comorbid conditions.

  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. Allosteric agonists of the calcium receptor (CaR): fluorine and SF5 analogues of cinacalcet.

    Science.gov (United States)

    Chia, Poh Wai; Brennan, Sarah C; Slawin, Alexandra M Z; Riccardi, Daniela; O'Hagan, David

    2012-10-21

    Three selectively fluorinated cinacalcet analogues are prepared and their activity as calcium-sensing receptor (CaR) agonists is assessed. Individual (2R,1'R)-2 and (2S,1'R)-3 fluorocinacalcet diastereoisomers were prepared using the MacMillan asymmetric fluorination reaction. Assays with the recombinant human CaR revealed that both diastereoisomers have a similar potency to each other although slightly lower (75-80%) than that of cinacalcet 1. The SF(5)-cinacalcet analogue 4 was prepared from meta-pentafluorosulfanyl benzyl alcohol and has ~75% agonist activity relative to cinacalcet 1 indicating that the SF(5) group can replace the CF(3) group and retain significant bioactivity.

  5. Liver X Receptor Agonists Inhibit the Phospholipid Regulatory Gene CTP: Phosphoethanolamine Cytidylyltransferase-Pcyt2

    Directory of Open Access Journals (Sweden)

    Lin Zhu

    2008-01-01

    Full Text Available Metabolic pulse-chase experiments demonstrated that 25-hydroxycholesterol (25-OH, the endogenous activator of the liver X receptor (LXR, significantly reduced the biosynthesis of phosphatidylethanolamine via CDP-ethanolamine (Kennedy pathway at the step catalyzed by CTP: phosphoethanolamine cytidylyltransferase (Pcyt2. In the mouse embryonic fibroblasts C3H10T1/2, the LXR synthetic agonist TO901317 lowered Pcyt2 promoter-luciferase activity in a concentration-dependent manner. Furthermore, 25-OH and TO901317 reduced mouse Pcyt2 mRNA and protein levels by 35–60%. The inhibitory effects of oxysterols and TO901317 on the Pcyt2 promoter function, mRNA and protein expression were conserved in the human breast cancer cells MCF-7. These studies identify the Pcyt2 gene as a novel target whereby LXR agonists may indirectly modulate inflammatory responses and atherosclerosis.

  6. Transcriptomic and phenotypic profiling in developing zebrafish exposed to thyroid hormone receptor agonists

    Energy Technology Data Exchange (ETDEWEB)

    Haggard, Derik E.; Noyes, Pamela D.; Waters, Katrina M.; Tanguay, Robert L.

    2018-04-01

    There is a need to develop novel, high-throughput screening and prioritization methods to identify chemicals with adverse estrogen, androgen, and thyroid activity to protect human health and the environment and is of interest to the Endocrine Disruptor Screening Program. The current aim is to explore the utility of zebrafish as a testing paradigm to classify endocrine activity using phenotypically anchored transcriptome profiling. Transcriptome analysis was conducted on embryos exposed to 25 estrogen-, androgen-, or thyroid-active chemicals at a concentration that elicited adverse malformations or mortality at 120 hours post-fertilization in 80% of the animals exposed. Analysis of the top 1000 significant differentially expressed transcripts across all treatments identified a unique transcriptional and phenotypic profile for thyroid hormone receptor agonists, which can be used as a biomarker screen for potential thyroid hormone agonists.

  7. Structure-guided design of selective Epac1 and Epac2 agonists.

    Directory of Open Access Journals (Sweden)

    Frank Schwede

    2015-01-01

    Full Text Available The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and in vivo. These analogues activate Epac2 about two orders of magnitude more potently than cAMP. The high potency arises from increased affinity as well as increased maximal activation. Crystallographic studies demonstrate that this is due to unique interactions. At least one of the Epac2-specific agonists, Sp-8-BnT-cAMPS (S-220, enhances glucose-induced insulin secretion in human pancreatic cells. Selective targeting of Epac2 is thus proven possible and may be an option in diabetes treatment.

  8. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes

    DEFF Research Database (Denmark)

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

    2014-01-01

    , slowing of gastric emptying and suppression of appetite. In circulation, GLP-1 has a half-life of approximately 2min due to rapid degradation by the enzyme dipeptidyl peptidase 4 (DPP-4). Because of this short half-life GLP-1 receptor (GLP-1R) agonists, resistant to degradation by DPP-4 have been...... effects. This review gives an overview of the clinical data on GLP-1R agonists that have been compared in head-to-head studies and focuses on relevant differences between the compounds. Highlighting these similarities and differences could be beneficial for physicians in choosing the best treatment......Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, secreted in response to ingestion of nutrients, and has important effects on several of the pathophysiological features of type 2 diabetes (T2D). The effects include potentiation of insulin secretion, suppression of glucagon secretion...

  9. Once-weekly GLP-1 agonists: How do they differ from exenatide and liraglutide?

    DEFF Research Database (Denmark)

    Christensen, Mikkel; Knop, Filip Krag

    2010-01-01

    Incretin mimetics offer a new modality in diabetes treatment. This modality is based on the effects of the naturally occurring glucoregulatory gut hormone glucagon-like peptide-1 (GLP-1), which counteracts several pathophysiologic traits in type 2 diabetes. GLP-1 receptor agonists with extended...... the presently published data (with emphasis on clinical pharmacokinetics, efficacy, and safety) on GLP-1 agonists, which currently are in development and intended for once-weekly dosing: albiglutide/albugon, CJC-1131, CJC-1134-PC, exenatide once weekly, and taspoglutide....... half-lives entailing fewer injections and presumably an improved throughout-the-day glycemic control are in clinical development. This article summarizes the physiologic effects of GLP-1; the effects of the already marketed GLP-1 analogues for daily dosing, exenatide and liraglutide; and reviews...

  10. Inhibition of glucagon secretion by GLP-1 agonists and DPP4 inhibitors

    DEFF Research Database (Denmark)

    Hansen, Morten; Juul Hare, Kristine; Holst, Jens Juul

    2011-01-01

    with emphasis on their glucagon-lowering effects. Finally, we review available glucagon data from current clinical studies on incretin-based treatment modalities (dipeptidyl peptidase 4 [DPP4] inhibitors and GLP-1 receptor agonists). Most of these studies suggest that both DPP4 inhibitors and GLP-1 receptor......*both known to contribute significantly to the hyperglycemic state of patients with T2DM. This article outlines the role of hyperglucagonemia in type 2 diabetic pathophysiology, summarizes the physiologic effects of glucagon-like peptide-1 (GLP-1), and gives an introduction to incretin-based treatments...... agonists lower fasting and postprandial plasma glucagon, and recent data suggest that these effects contribute importantly to the glucose-lowering effect of these treatments....

  11. 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.

  12. Excitotoxic effects of non-NMDA receptor agonists in organotypic corticostriatal slice cultures

    DEFF Research Database (Denmark)

    Kristensen, B W; Noraberg, J; Jakobsen, B

    1999-01-01

    of the cytosolic enzyme lactate dehydrogenase (LDH) into the culture medium and loss of glutamic acid decarboxylase (GAD) activity in the tissue. Histological sections were also stained by the fluorescent dye Fluoro-Jade (FJ), for degenerating neurons and by immunocytochemical staining for gamma-aminobutyric acid......The excitotoxic effects of the glutamate receptor agonists kainic acid (KA) and 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and the corresponding neuroprotective effects of the AMPA/KA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) were examined...... with an established set of markers for neuronal cell damage appears to be a feasible model for studies of the neurotoxic and neuroprotective effects of glutamate receptor agonists and antagonists....

  13. The Effect of Glutamate Receptor Agonists on Mouse Retinal Astrocyte [Ca2+]i

    Directory of Open Access Journals (Sweden)

    Stephanie N. Blandford

    2016-01-01

    Full Text Available Calcium-imaging techniques were used to determine if mouse retinal astrocytes in situ respond to agonists of ionotropic (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA; N-methyl-D-aspartate, NMDA and metabotropic (S-3,5-dihydroxyphenylglycine, DHPG; trans-1-amino-1,3-cyclopentanedicarboxylic acid, ACPD glutamate receptors. In most cases we found no evidence that retinal astrocyte intracellular calcium ion concentration (Ca2+i increased in response to these glutamate agonists. The one exception was AMPA that increased Ca2+i in some, but not all, mouse retinal astrocytes in situ. However, AMPA did not increase Ca2+i in mouse retinal astrocytes in vitro, suggesting that the effect of AMPA in situ may be indirect.

  14. The Effect of Glutamate Receptor Agonists on Mouse Retinal Astrocyte [Ca(2+)]i.

    Science.gov (United States)

    Blandford, Stephanie N; Baldridge, William H

    2016-01-01

    Calcium-imaging techniques were used to determine if mouse retinal astrocytes in situ respond to agonists of ionotropic (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA; N-methyl-D-aspartate, NMDA) and metabotropic (S-3,5-dihydroxyphenylglycine, DHPG; trans-1-amino-1,3-cyclopentanedicarboxylic acid, ACPD) glutamate receptors. In most cases we found no evidence that retinal astrocyte intracellular calcium ion concentration ([Ca(2+)]i) increased in response to these glutamate agonists. The one exception was AMPA that increased [Ca(2+)]i in some, but not all, mouse retinal astrocytes in situ. However, AMPA did not increase [Ca(2+)]i in mouse retinal astrocytes in vitro, suggesting that the effect of AMPA in situ may be indirect.

  15. Guanine nucleotide regulation of dopamine receptor agonist affinity states in rat estradiol-induced pituitary tumors

    Energy Technology Data Exchange (ETDEWEB)

    Di Paolo, T.; Falardeau, P.

    1987-08-31

    The authors have investigated dopamine (DA) receptor agonist high- and low-affinity states in female rate estradiol-induced prolactin (PRL)-secreting pituitary tumors and intact pituitary tissue. Estradiol treatment increased the anterior pituitary weight 9-fold and plasma prolactin levels 74-fold and these measures are correlated (R = 0.745, n = 73, p < 0.001). Competition for (/sup 3/H)-spiperone binding to the DA receptor by apomorphine was compared in normal and adenomatous pituitary tissue. The inhibition constants (Ki) and the proportions of the two apomorphine sites are unchanged in tumors compared to intact pituitary tissue. Guanosine 5'-(..beta..-..gamma..-imino)triphosphate (Gpp(NH)p) causes complete conversion of the high into low affinity dopaminergic agonist site in normal pituitary and in tumors. These results suggest that rats with primary estradiol-induced pituitary tumors have normal and functional DA receptors. 9 references, 2 tables.

  16. Guanine nucleotide regulation of dopamine receptor agonist affinity states in rat estradiol-induced pituitary tumors

    International Nuclear Information System (INIS)

    Di Paolo, T.; Falardeau, P.

    1987-01-01

    The authors have investigated dopamine (DA) receptor agonist high- and low-affinity states in female rate estradiol-induced prolactin (PRL)-secreting pituitary tumors and intact pituitary tissue. Estradiol treatment increased the anterior pituitary weight 9-fold and plasma prolactin levels 74-fold and these measures are correlated (R = 0.745, n = 73, p 3 H]-spiperone binding to the DA receptor by apomorphine was compared in normal and adenomatous pituitary tissue. The inhibition constants (Ki) and the proportions of the two apomorphine sites are unchanged in tumors compared to intact pituitary tissue. Guanosine 5'-[β-γ-imino]triphosphate (Gpp(NH)p) causes complete conversion of the high into low affinity dopaminergic agonist site in normal pituitary and in tumors. These results suggest that rats with primary estradiol-induced pituitary tumors have normal and functional DA receptors. 9 references, 2 tables

  17. Sphingosine-1-Phosphate Receptor-1 Selective Agonist Enhances Collateral Growth and Protects against Subsequent Stroke.

    Directory of Open Access Journals (Sweden)

    Masahiko Ichijo

    Full Text Available Collateral growth after acute occlusion of an intracranial artery is triggered by increasing shear stress in preexisting collateral pathways. Recently, sphingosine-1-phosphate receptor-1 (S1PR1 on endothelial cells was reported to be essential in sensing fluid shear stress. Here, we evaluated the expression of S1PR1 in the hypoperfused mouse brain and investigated the effect of a selective S1PR1 agonist on leptomeningeal collateral growth and subsequent ischemic damage after focal ischemia.In C57Bl/6 mice (n = 133 subjected to unilateral common carotid occlusion (CCAO and sham surgery. The first series examined the time course of collateral growth, cell proliferation, and S1PR1 expression in the leptomeningeal arteries after CCAO. The second series examined the relationship between pharmacological regulation of S1PR1 and collateral growth of leptomeningeal anastomoses. Animals were randomly assigned to one of the following groups: LtCCAO and daily intraperitoneal (i.p. injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day; sham surgery and daily i.p. injection for 7 days of SEW2871 after surgery; LtCCAO and daily i.p. injection for 7 days of SEW2871 and an S1PR1 inverse agonist (VPC23019, 0.5 mg/kg; LtCCAO and daily i.p. injection of DMSO for 7 days after surgery; and sham surgery and daily i.p. injection of DMSO for 7 days. Leptomeningeal anastomoses were visualized 14 days after LtCCAO by latex perfusion method, and a set of animals underwent subsequent permanent middle cerebral artery occlusion (pMCAO 7 days after the treatment termination. Neurological functions 1 hour, 1, 4, and 7 days and infarction volume 7 days after pMCAO were evaluated.In parallel with the increase in S1PR1 mRNA levels, S1PR1 expression colocalized with endothelial cell markers in the leptomeningeal arteries, increased markedly on the side of the CCAO, and peaked 7 days after CCAO. Mitotic cell numbers in the leptomeningeal arteries increased after

  18. Therapeutic Effects of Melatonin Receptor Agonists on Sleep and Comorbid Disorders

    Science.gov (United States)

    Laudon, Moshe; Frydman-Marom, Anat

    2014-01-01

    Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, agomelatine and tasimelteon) have recently become available for the treatment of insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy and safety profiles of these compounds in the treatment of the indicated disorders are reviewed. Accumulating evidence indicates that sleep-wake disorders and co-existing medical conditions are mutually exacerbating. This understanding has now been incorporated into the new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Therefore, when evaluating the risk/benefit ratio of sleep drugs, it is pertinent to also evaluate their effects on wake and comorbid condition. Beneficial effects of melatonin receptor agonists on comorbid neurological, psychiatric, cardiovascular and metabolic symptomatology beyond sleep regulation are also described. The review underlines the beneficial value of enhancing physiological sleep in comorbid conditions. PMID:25207602

  19. Investigation of pyrazolo-sulfonamides as putative small molecule oxytocin receptor agonists.

    Science.gov (United States)

    Katte, Timothy A; Reekie, Tristan A; Werry, Eryn L; Jorgensen, William T; Boyd, Rochelle; Wong, Erick C N; Gulliver, Damien W; Connor, Mark; Kassiou, Michael

    2017-08-18

    The neuropeptide oxytocin has been implicated in multiple central nervous system functions in mammalian species. Increased levels have been reported to improve trust, alleviate symptoms related to autism and social phobias, and reduce social anxiety. Hoffman-La Roche published a patent claiming to have found potent small molecule oxytocin receptor agonists, smaller than the first non-peptide oxytocin agonist reported, WAY 267,464. We selected two of the more potent compounds from the patent and, in addition, created WAY 267,464 hybrid structures and determined their oxytocin and vasopressin receptor activity. Human embryonic kidney and Chinese hamster ovary cells were used for the expression of oxytocin or vasopressin 1a receptors and activity assessed via IP1 accumulation assays and calcium FLIPR assays. The results concluded that the reported compounds in the patent and the hybrid structures have no activity at the oxytocin or vasopressin 1a receptors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  20. High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist

    DEFF Research Database (Denmark)

    Holst, Birgitte; Cygankiewicz, Adam; Jensen, Tine Halkjaer

    2003-01-01

    Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake. By measuring inositol phosphate turnover or by using a reporter assay for transcriptional activity controlled by cAMP-responsive elements, the ghrelin receptor showed strong, ligand......-independent signaling in transfected COS-7 or human embryonic kidney 293 cells. Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further. In contrast, the low potency ghrelin antagonist, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P was surprisingly...... found to be a high potency (EC50 = 5.2 nm) full inverse agonist as it decreased the constitutive signaling of the ghrelin receptor down to that observed in untransfected cells. The homologous motilin receptor functioned as a negative control as it did not display any sign of constitutive activity...

  1. 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.

  2. Quantitative protein and fat metabolism in bull calves treated with beta-adrenergic agonist

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    Protein and energy utilization and quantitative retention of protein, fat and energy was investigated with 12 Red Danish bulls during two subsequent 6 weeks trials (Sections A and B) at a mean live weight of 195 and 335 kg respectively. Treatments were control (Group 1) and beta-agonist (L-644...... was strongly influenced by treatment, with the highest values for Group 2 in both sections. The protein retention increased with 25% in Group 2, with the highest increment of 113 g/d in Section B. The fat retention decreased in treated animals, most pronounced in Group 3, where the reduction was about 50......% with a mean decrease of 145 g/d in Section B. The total energy retention was not different between control animals and Group 2 in both sections, but there was a shift in energy retention from fat to protein. The higher levels of beta-agonist used in Group 3 generated the same increase in protein retention...

  3. Ghrelin Agonist JMV 1843 Increases Food Intake, Body Weight and Expression of Orexigenic Neuropeptides in Mice

    Czech Academy of Sciences Publication Activity Database

    Holubová, Martina; Špolcová, Andrea; Demianova, Zuzana; Sýkora, D.; Fehrentz, J. A.; Martinez, J.; Štofková, A.; Jurčovičová, J.; Drápalová, J.; Lacinová, Z.; Haluzík, M.; Železná, Blanka; Maletínská, Lenka

    2013-01-01

    Roč. 62, č. 4 (2013), s. 435-444 ISSN 0862-8408 R&D Projects: GA ČR GA303/09/0744; GA ČR GAP303/10/1368 Institutional support: RVO:61388963 Keywords : GHS-R agonists * JMV 1843 * male C57BL/6 mice * food intake * NPY/AgRP Subject RIV: CE - Biochemistry Impact factor: 1.487, year: 2013

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

    Directory of Open Access Journals (Sweden)

    Fabio Cattaneo

    2013-04-01

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

  5. Working memory span capacity improved by a D2 but not D1 receptor family agonist.

    Science.gov (United States)

    Tarantino, Isadore S; Sharp, Richard F; Geyer, Mark A; Meves, Jessica M; Young, Jared W

    2011-06-01

    Patients with schizophrenia exhibit poor working memory (WM). Although several subcomponents of WM can be measured, evidence suggests the primary subcomponent affected in schizophrenia is span capacity (WMC). Indeed, the NIMH-funded MATRICS initiative recommended assaying the WMC when assessing the efficacy of a putative therapeutic for FDA approval. Although dopamine D1 receptor agonists improve delay-dependent memory in animals, evidence for improvements in WMC due to dopamine D1 receptor activation is limited. In contrast, the dopamine D2-family agonist bromocriptine improves WMC in humans. The radial arm maze (RAM) can be used to assess WMC, although complications due to ceiling effects or strategy confounds have limited its use. We describe a 12-arm RAM protocol designed to assess whether the dopamine D1-family agonist SKF 38393 (0, 1, 3, and 10 mg/kg) or bromocriptine (0, 1, 3, and 10 mg/kg) could improve WMC in C57BL/6N mice (n=12) in cross-over designs. WMC increased and strategy usage decreased with training. The dopamine D1 agonist SKF 38393 had no effect on WMC or long-term memory. Bromocriptine decreased WMC errors, without affecting long-term memory, consistent with human studies. These data confirm that WMC can be measured in mice and reveal drug effects that are consistent with reported effects in humans. Future research is warranted to identify the subtype of the D2-family of receptors responsible for the observed improvement in WMC. Finally, this RAM procedure may prove useful in developing animal models of deficient WMC to further assess putative treatments for the cognitive deficits in schizophrenia. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms

    Czech Academy of Sciences Publication Activity Database

    Randáková, Alena; Dolejší, Eva; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; El-Fakahany, E. E.; Jakubík, Jan

    2015-01-01

    Roč. 97, Jul 2015 (2015), s. 27-39 ISSN 1043-6618 R&D Projects: GA ČR(CZ) GA305/09/0681; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) EE2.3.30.0025 Institutional support: RVO:67985823 Keywords : muscarinic acetylcholine receptors * atypical agonists * xanomeline * activation mechanism Subject RIV: ED - Physiology Impact factor: 4.816, year: 2015

  7. Chronic exposure to dopamine agonists affects the integrity of striatal D2 receptors in Parkinson's patients

    Directory of Open Access Journals (Sweden)

    Marios Politis

    2017-01-01

    Full Text Available We aimed to investigate the integrity and clinical relevance of striatal dopamine receptor type-2 (D2R availability in Parkinson's disease (PD patients. We studied 68 PD patients, spanning from early to advanced disease stages, and 12 healthy controls. All participants received one [11C]raclopride PET scan in an OFF medication condition for quantification of striatal D2R availability in vivo. Parametric images of [11C]raclopride non-displaceable binding potential were generated from the dynamic [11C]raclopride scans using implementation of the simplified reference tissue model with cerebellum as the reference tissue. PET data were interrogated for correlations with clinical data related to disease burden and dopaminergic treatment. PD patients showed a mean 16.7% decrease in caudate D2R and a mean 3.5% increase in putaminal D2R availability compared to healthy controls. Lower caudate [11C]raclopride BPND correlated with longer PD duration. PD patients on dopamine agonist treatment had 9.2% reduced D2R availability in the caudate and 12.8% in the putamen compared to PD patients who never received treatment with dopamine agonists. Higher amounts of lifetime dopamine agonist therapy correlated with reduced D2Rs availability in both caudate and putamen. No associations between striatal D2R availability and levodopa treatment and dyskinesias were found. In advancing PD the caudate and putamen D2R availability are differentially affected. Chronic exposure to treatment with dopamine agonists, but no levodopa, suppresses striatal D2R availability, which may have relevance to output signaling to frontal lobes and the occurrence of executive deficits, but not dyskinesias.

  8. Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor

    OpenAIRE

    Lin, Wenwei; Yang, Lei; Chai, Sergio C.; Lu, Yan; Chen, Taosheng

    2015-01-01

    Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer cells to chemotherapeutic drugs. We recently reported a novel CAR inhibitor/inverse agonist CINPA1 (11). Here, we have obtained or designed 54 analogs of CINPA1 and used a ti...

  9. Oxidative Stress Markers in GnRH Agonist and Antagonist Protocols in IVF

    OpenAIRE

    Tuli?, Lidija; Vidakovi?, Sne?ana; Tuli?, Ivan; ?ur?i?, Marijana; Stojni?, Jelena; Jeremi?, Katarina

    2017-01-01

    Summary Background Our aim was to study the effect of GnRH agonist and antagonist protocols of ovarian stimulation on oxidative stress parameters in serum and the influence of oxidative stress parameters change on the outcome of IVF cycles. Methods This prospective study included 82 patients who underwent IVF procedures. We determined SOD, MDA and SH groups in serum. Serum samples were obtained between the second and fourth day of the cycle and on the day of HCG administration during ovarian ...

  10. In Vivo Protection against Strychnine Toxicity in Mice by the Glycine Receptor Agonist Ivermectin

    OpenAIRE

    Maher, Ahmed; Radwan, Rasha; Breitinger, Hans-Georg

    2014-01-01

    The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1 mg/kg ...

  11. Stereostructure-activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors

    DEFF Research Database (Denmark)

    Johansen, Tommy N; Greenwood, Jeremy R; Frydenvang, Karla Andrea

    2003-01-01

    (S)-Glutamic acid (Glu), the major excitatory neurotransmitter in the central nervous system, operates through ionotropic as well as metabotropic receptors and is considered to be involved in certain neurological disorders and degenerative brain diseases that are currently without any satisfactory...... design of ligands, especially for the AMPA and kainate subtypes of ionotropic Glu receptors. This mini-review will focus on structure-activity relationships on AMPA and kainate receptor agonists with special emphasis on stereochemical and three-dimensional aspects....

  12. GnRH agonist for triggering of final oocyte maturation: time for a change of practice?

    DEFF Research Database (Denmark)

    Humaidan, P; Kol, Stefan; Papanikolaou, E G

    2011-01-01

    GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase...... deficiency. Therefore, the challenge has been to rescue the luteal phase. Studies now report a luteal phase rescue, with a reproductive outcome comparable to that seen after hCG triggering....

  13. Psychopathological symptoms of patients with heroin addiction entering opioid agonist or therapeutic community treatment

    OpenAIRE

    Pani, Pier Paolo; Trogu, Emanuela; Vigna-Taglianti, Federica; Mathis, Federica; Diecidue, Roberto; Kirchmayer, Ursula; Amato, Laura; Davoli, Marina; Ghibaudi, Joli; Camposeragna, Antonella; Saponaro, Alessio; Faggiano, Fabrizio; Maremmani, Angelo Giovanni Icro; Maremmani, Icro

    2014-01-01

    Background The relationship between substance use disorders and psychiatric pathology is still an open question. The main aim of the present study was to verify whether the five psychopathological dimensions identified through the SCL-90 tool in a previous study carried out on patients with heroin addiction entering an outpatient opioid agonist treatment (OAT) were also observable in those entering a residential treatment community (TC). Further aims were to look at differences in the psychop...

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

    Science.gov (United States)

    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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. GPR119 Agonist AS1269574 Activates TRPA1 Cation Channels to Stimulate GLP-1 Secretion.

    Science.gov (United States)

    Chepurny, Oleg G; Holz, George G; Roe, Michael W; Leech, Colin A

    2016-06-01

    GPR119 is a G protein-coupled receptor expressed on intestinal L cells that synthesize and secrete the blood glucose-lowering hormone glucagon-like peptide-1 (GLP-1). GPR119 agonists stimulate the release of GLP-1 from L cells, and for this reason there is interest in their potential use as a new treatment for type 2 diabetes mellitus. AS1269574 is one such GPR119 agonist, and it is the prototype of a series of 2,4,6 trisubstituted pyrimidines that exert positive glucoregulatory actions in mice. Here we report the unexpected finding that AS1269574 stimulates GLP-1 release from the STC-1 intestinal cell line by directly promoting Ca(2+) influx through transient receptor potential ankyrin 1 (TRPA1) cation channels. These GPR119-independent actions of AS1269574 are inhibited by TRPA1 channel blockers (AP-18, A967079, HC030031) and are not secondary to intracellular Ca(2+) release or cAMP production. Patch clamp studies reveal that AS1269574 activates an outwardly rectifying membrane current with properties expected of TRPA1 channels. However, the TRPA1 channel-mediated action of AS1269574 to increase intracellular free calcium concentration is not replicated by GPR119 agonists (AR231453, oleoylethanolamide) unrelated in structure to AS1269574. Using human embryonic kidney-293 cells expressing recombinant rat TRPA1 channels but not GPR119, direct TRPA1 channel activating properties of AS1269574 are validated. Because we find that AS1269574 also acts in a conventional GPR119-mediated manner to stimulate proglucagon gene promoter activity in the GLUTag intestinal L cell line, new findings reported here reveal the surprising capacity of AS1269574 to act as a dual agonist at two molecular targets (GPR119/TRPA1) important to the control of L-cell function and type 2 diabetes mellitus drug discovery research.

  16. Airway mucosal thickening and bronchial hyperresponsiveness induced by inhaled beta 2-agonist in mice.

    Science.gov (United States)

    Tamaoki, Jun; Tagaya, Etsuko; Kawatani, Kiyomi; Nakata, Junko; Endo, Yumie; Nagai, Atsushi

    2004-07-01

    Patients with chronic persistent asthma require frequent use of inhaled beta(2)-agonist, which may result in aggravation of asthma symptoms. Our recent in vitro study has shown that beta(2)-agonist stimulates the growth of human airway epithelial cell lines. To determine whether beta(2)-agonist likewise affects airway epithelial cell proliferation in vivo and, if so, what the mechanism of action is, we examined the effect of salbutamol on the morphology of murine airways. Seventy-two BALB/c mice were administered aerosolized salbutamol using "flow-through" nose-only inhalation chambers at daily doses of 0.2 to 20 microg for up to 6 weeks. Morphology of tracheal mucosa, labeling of epithelial cells with 5-bromo-2'-deoxyuridine (BrdU), and bronchial responsiveness were assessed. Exposure to salbutamol increased the thickness of tracheal epithelial layer and the number of BrdU-positive epithelial cells in a dose- and time-dependent manner: the values in mice receiving 20 microg salbutamol for 6 weeks were 247% and 642%, respectively, of those in control animals receiving saline solution alone. These effects were inhibited by the mitogen-activated protein (MAP) kinase kinase inhibitors PD98059 and U0126. Salbutamol also caused a decrease in the provocative concentration of methacholine to achieve 400% of baseline enhanced pause. Combined treatment with inhaled budesonide attenuated salbutamol-induced airway morphologic changes and bronchial hyperresponsiveness. beta(2)-agonist stimulates proliferation of airway epithelial cells and produces airway wall thickening in vivo via MAP kinase-dependent pathway, and these effects are prevented by inhaled corticosteroid.

  17. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.

    Science.gov (United States)

    Oh, Da Young; Walenta, Evelyn; Akiyama, Taro E; Lagakos, William S; Lackey, Denise; Pessentheiner, Ariane R; Sasik, Roman; Hah, Nasun; Chi, Tyler J; Cox, Jason M; Powels, Mary Ann; Di Salvo, Jerry; Sinz, Christopher; Watkins, Steven M; Armando, Aaron M; Chung, Heekyung; Evans, Ronald M; Quehenberger, Oswald; McNelis, Joanne; Bogner-Strauss, Juliane G; Olefsky, Jerrold M

    2014-08-01

    It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.

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

    Science.gov (United States)

    Niu, Ai-Qin; Xie, Liang-Jun; Wang, Hui; Zhu, Bing; Wang, Sheng-Qi

    2016-01-01

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

  19. Treating the cognitive deficits of schizophrenia with alpha4beta2 neuronal nicotinic receptor agonists.

    Science.gov (United States)

    Radek, Richard J; Kohlhaas, Kathy L; Rueter, Lynne E; Mohler, Eric G

    2010-01-01

    Schizophrenic patients exhibit debilitating impairments of intellectual function. Typical and atypical antipsychotic medications are largely ineffective at treating the cognitive deficits of schizophrenia (CDS), and efforts to discover compounds that treat these symptoms are ongoing. Considerable tobacco use in schizophrenic patients, genetic linkage, and receptor binding studies suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in schizophrenia. Neuronal alpha4beta2 nAChRs are widely distributed in the mammalian brain, and are implicated in normal cognitive functioning in animal models. Ligands of various selectivity and potency have been used to study the role of the alpha4beta2 subtype in schizophrenia. For instance, studies in rodents show that alpha4beta2 agonists improve sensory gating, an information processing function that is deficient in schizophrenia. Pharmacological studies in animals also suggest that alpha4beta2 nAChRs are involved in other cognitive domains that are impaired in schizophrenia, including speed of processing, working memory, visual learning and memory, and social cognition. The non-selective nAChR agonist nicotine has been shown to improve CDS in several human clinical studies, and recent trials have been undertaken to evaluate the efficacy of more alpha4beta2 selective compounds. It remains to be determined whether alpha4beta2 agonists will provide greater efficacy than nicotine for CDS or reducing tobacco use in patients. Pre-clinical evidence to date suggests that agonists of the nicotinic alpha4beta2 subtype could be useful in improving cognitive function in schizophrenic patients.

  20. Discovery of the imidazole-derived GPR40 agonist AM-3189.

    Science.gov (United States)

    Ma, Zhihua; Lin, Daniel C-H; Sharma, Rajiv; Liu, Jinqian; Zhu, Liusheng; Li, An-Rong; Kohn, Todd; Wang, Yingcai; Liu, Jiwen Jim; Bartberger, Michael D; Medina, Julio C; Zhuang, Run; Li, Frank; Zhang, Jane; Luo, Jian; Wong, Simon; Tonn, George R; Houze, Jonathan B

    2016-01-01

    As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Role of prucalopride, a serotonin (5-HT4 receptor agonist, for the treatment of chronic constipation

    Directory of Open Access Journals (Sweden)

    Banny S Wong

    2010-05-01

    Full Text Available Banny S Wong, Noriaki Manabe, Michael CamilleriClinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R., Mayo Clinic, Rochester, Minnesota, USAAbstract: Constipation affects up to a quarter of the population in developed countries and is associated with poor quality of life and significant economic burden. Many patients with chronic constipation are dissatisfied with current therapy due to lack of long-term efficacy or side effects. Previous nonselective 5-hydroxytryptamine receptor 4 (5-HT4 agonists have been associated with significant interactions with other receptors (5-HT1B, 5-HT1D, and 5-HT2B for tegaserod; hERG for cisapride, leading to adverse cardiovascular events resulting in withdrawal of these drugs from the market. Prucalopride is a novel gastrointestinal prokinetic agent. It acts as a high affinity, highly-selective 5-HT4 agonist. Its efficacy in patients with chronic constipation has been demonstrated in several phase II and phase III clinical trials showing significant improvements in bowel transit, bowel function, gastrointestinal symptoms, and quality of life, with benefit maintained for up to 24 months in open label, multicenter, follow-up studies. Prucalopride’s high selectivity for the 5-HT4 receptor may explain its favorable safety and tolerability profiles, even in elderly subjects with stable cardiovascular disease. Prucalopride is a well tolerated and efficacious prokinetic medication that should enhance the treatment of chronic constipation unresponsive to first-line treatments.Keywords: prucalopride, 5-HT4 agonist, serotonin agonist, efficacy, prokinetic

  2. β2-agonists promote host defense against bacterial infection in primary human bronchial epithelial cells

    Directory of Open Access Journals (Sweden)

    Weinberger Andrew R

    2010-05-01

    Full Text Available Abstract Background Airway epithelial cells are critical in host defense against bacteria including Mycoplasma pneumoniae (Mp in chronic obstructive pulmonary disease (COPD and asthma. β2-agonists are mainstay of COPD and asthma therapy, but whether β2-agonists directly affect airway epithelial host defense functions is unclear. Methods Epithelial cells from bronchial brushings of normal (n = 8, asthma (n = 8 and COPD (n = 8 subjects were grown in air-liquid interface cultures, and treated with cigarette smoke extract (CSE and/or Th2 cytokine IL-13, followed by Mp infection and treatment with β2-agonists albuterol and formoterol for up to seven days. Mp and host defense proteins short palate, lung, and nasal epithelial clone 1 (SPLUNC1 and β-defensin-2 were quantified. Expression of β2-adrenergic receptors was also measured by real-time quantitative RT-PCR. Results (R- or racemic albuterol and (R,R- or racemic formoterol significantly decreased Mp levels in normal and asthma epithelial cells. Normal cells treated with Mp and (R- or racemic albuterol showed an increase in SPLUNC1, but not in β-defensin-2. COPD cells did not respond to drug treatment with a significant decrease in Mp or an increase in SPLUNC1. IL-13 attenuated drug effects on Mp, and markedly decreased SPLUNC1 and β2-adrenergic receptors. Conclusions These results for the first time show that β2-agonists enhance host defense functions of primary bronchial epithelial cells from normal and asthma subjects, which is attenuated by IL-13.

  3. Specific response of mouse tumor-feeding arterioles to stimulation by 5-HT1 agonists

    International Nuclear Information System (INIS)

    Stuecker, Olivier; Laemmel, Elisabeth; Teisseire, Bernard; Vicaut, Eric

    1997-01-01

    Using intravital microscopy, we compared the responses to 5-HT 1 receptor stimulation by the host-modified arterioles feeding a Meth-A tumor implanted in the flank of female Balb/c mice with the responses of tumor-independent arterioles (TIA) and those of control arterioles from mice without tumor. Topical administration of 5 x 10 -5 M serotonin in the presence of 10 -4 M ketanserin (5-HT 2 receptors inhibitor) induced arteriolar vasodilation in TIA (+13%) and in the control arterioles (+19%), but induced constriction (-14%) in the tumor-feeding arterioles (TFA). Topical administration of the general 5-HT 1 agonist 5-carboxamidotryptamine maleate (10 -6 to 10 -4 M) or the 5-HT 1A agonist buspirone (2 x 10 -6 to 2 x 10 -4 M) induced vasoconstriction that was dramatically higher in TFA than in TIA or control arterioles (p 1B agonist M-trifluoromethylphenylpiperazine (2 x 10 -6 to 2 x 10 -4 M) produced opposite responses, i.e., dose-dependent vasodilation in TIA and control arterioles, and dose-dependent constriction in TFA. Since we observed the same degree of vasodilation in response to 10 -4 M acetylcholine in all three groups of arterioles, the differences between the responses to 5-HT 1 receptor stimulation were not due to the absence of endothelial-dependent dilatory mechanisms in the tumor-feeding arterioles. We conclude that 5-HT 1 agonists are interesting pharmacologic tools for the modulation of tumoral blood flow, since they more dramatically constrict the microvasculature feeding the tumors than that feeding normal tissue

  4. 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

  5. LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone

    Energy Technology Data Exchange (ETDEWEB)

    Bian, Xuting; Zhong, Hongyu; Li, Fen; Cai, Yulong; Li, Xin; Wang, Lian; Fan, Xiaotang, E-mail: fanxiaotang2005@163.com

    2016-09-02

    Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects.

  6. Design and synthesis of small molecule agonists of EphA2 receptor.

    Science.gov (United States)

    Petty, Aaron; Idippily, Nethrie; Bobba, Viharika; Geldenhuys, Werner J; Zhong, Bo; Su, Bin; Wang, Bingcheng

    2018-01-01

    Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure-activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is very different to the parental compound. Compound 27 with a twelve-carbon linker of the dimer activated the kinase and induced receptor internalization and cell death with the best potency. Another dimer with a six-carbon linker has significantly reduced potency compared to the dimer with a longer linker, suggesting that the length of the linker is critical for the activity of the dimeric agonist. To explore the receptor binding characteristics of the new molecules, we applied a docking study to examine how the small molecule binds to the EphA2 receptor. The results reveal that compounds 24 and 27 form more hydrogen bonds to EphA2 than Doxazosin, suggesting that they may have higher binding affinity to the receptor. Published by Elsevier Masson SAS.

  7. α1 -AR agonist induced piloerection protects against the development of traction alopecia.

    Science.gov (United States)

    Goren, Andy; Shapiro, Jerry; Sinclair, Rodney; Kovacevic, Maja; McCoy, John

    2016-05-01

    Traction alopecia is hair loss that occurs after persistent pulling (e.g., during cosmetic procedures) on the roots of hair over time. Unlike plucking, which is painful, persistent pulling may go unnoticed until a patient presents with either bald spots or diffuse telogen shedding. Each hair follicle in the scalp contains an arrector pili muscle that, when contracted, erects the hair. The smooth muscle in the arrector pili expresses α1 adrenergic receptors (α1 -AR). As such, we hypothesized that contraction of the arrector pili muscle via an α1 -AR agonist would increase the threshold of force required to pluck hair during cosmetic procedures. Female subjects, ages 18-40, were recruited to study the effect of topically applied phenylephrine, a selective α1 -AR agonist, on epilation force and hair shedding during cosmetic procedures. In our blinded study, 80% of subjects demonstrated reduced shedding on days using phenylephrine compared to days using a placebo solution. The average reduction in hair loss was approximately 42%. In addition, the force threshold required for epilation increased by approximately 172% following topical phenylephrine application. To our knowledge this is the first study demonstrating the utility of α1 -AR agonists in the treatment of traction alopecia and hair shedding during cosmetic procedures. © 2015 Wiley Periodicals, Inc.

  8. Adenosine A(2A) receptor dynamics studied with the novel fluorescent agonist Alexa488-APEC.

    Science.gov (United States)

    Brand, Frank; Klutz, Athena M; Jacobson, Kenneth A; Fredholm, Bertil B; Schulte, Gunnar

    2008-08-20

    G protein-coupled receptors, such as the adenosine A(2A) receptor, are dynamic proteins, which undergo agonist-dependent redistribution from the cell surface to intracellular membranous compartments, such as endosomes. In order to study the kinetics of adenosine A(2A) receptor redistribution in living cells, we synthesized a novel fluorescent agonist, Alexa488-APEC. Alexa488-APEC binds to adenosine A(2A) (K(i)=149+/-27 nM) as well as A(3) receptors (K(i)=240+/-160 nM) but not to adenosine A(1) receptors. Further, we characterized the dose-dependent increase in Alexa488-APEC-induced cAMP production as well as cAMP response element binding (CREB) protein phosphorylation, verifying the ligand's functionality at adenosine A(2A) but not A(2B) receptors. In live-cell imaging studies, Alexa488-APEC-induced adenosine A(2A) receptor internalization, which was blocked by the competitive reversible antagonist ZM 241385 and hyperosmolaric sucrose. Further, internalized adenosine A(2A) receptors co-localized with clathrin and Rab5, indicating that agonist stimulation promotes adenosine A(2A) receptor uptake through a clathrin-dependent mechanism to Rab5-positive endosomes. The basic characterization of Alexa488-APEC described here showed that it provides a useful tool for tracing adenosine A(2A) receptors in vitro.

  9. Treating ADHD in Prison: Focus on Alpha-2 Agonists (Clonidine and Guanfacine).

    Science.gov (United States)

    Mattes, Jeffrey A

    2016-06-01

    Attention deficit/hyperactivity disorder (ADHD) is prevalent in prison populations, but optimal treatment recommendations in prison are uncertain. Stimulants are problematic because of the potential for abuse. This article is a review of medication options for ADHD, focusing on the α2 agonists clonidine and guanfacine, which, in their extended-release (ER) forms, are U.S. Food and Drug Administration (FDA) approved for the treatment of ADHD, although they are probably less efficacious, overall, than stimulants. Advantages of α2 agonists in prison include: they are not controlled substances and have no known abuse potential; they may be particularly helpful for ADHD with associated aggression and other features of conduct disorder; they may reduce anxiety and symptoms of posttraumatic stress disorder; and they are somewhat sedating. The pharmacology of these agents and the presumed mechanism of action are discussed, including the fact that guanfacine more specifically affects α2A receptors, which are postsynaptic in the frontal cortex. Other differences between clonidine and guanfacine and between the generic immediate-release (IR) forms and the ER forms are also discussed. The IR forms, while themselves not FDA approved for ADHD, may, with dosage adjustment, be reasonable alternatives (with considerable cost savings). Overall, given the FDA-accepted evidence of efficacy, the lack of abuse potential, and the favorable side effect profile, α agonists may be the treatment of choice for prison inmates with ADHD. © 2016 American Academy of Psychiatry and the Law.

  10. Kinetics of agonist-induced intrinsic fluorescence changes in the Torpedo acetylcholine receptor.

    Science.gov (United States)

    Kawai, Hideki; Raftery, Michael A

    2010-05-01

    The nicotinic acetylcholine receptor from Torpedo electric organs is a ligand-gated ion channel that undergoes conformational transitions for activation and/or desensitization. Earlier work suggested that intrinsic fluorescence changes of the receptor monitors kinetic transitions toward the high-affinity, desensitized state. Here, using highly purified membrane preparations to minimize contaminating fluorescence, we examined kinetic mechanisms of the receptor as monitored by its intrinsic fluorescence. Fluorescence changes were specific to the receptor as they were blocked by alpha-bungarotoxin and were induced by agonists, but not by the antagonist hexamethonium. Acetylcholine, carbamylcholine and suberyldicholine showed only one kinetic phase with relatively fast rates (t(1/2) = 0.2-1.2 s). Effective dissociation constants were at least an order of magnitude higher than the high affinity, equilibrium binding constants for these agonists. A semirigid agonist isoarecolone-methiodide, whose activation constant was approximately 3-fold lower than acetylcholine, induced an additional slow phase (t(1/2) = 4.5-9 s) with apparent rates that increased and then decreased in a concentration dependent manner, revealing a branched mechanism for conformational transitions. We propose that the intrinsic fluorescence changes of the receptor describe a process(es) toward a fast desensitization state prior to the formation of the high affinity state.

  11. Increased Carotid Artery Lesion Inflammation Upon Treatment With the CD137 Agonistic Antibody 2A.

    Science.gov (United States)

    Söderström, Leif Å; Jin, Hong; Caravaca, April S; Klement, Maria L; Li, Yuhuang; Gisterå, Anton; Hedin, Ulf; Maegdefessel, Lars; Hansson, Göran K; Olofsson, Peder S

    2017-11-24

    Increased inflammatory activity destabilizes the atherosclerotic lesion and may lead to atherothrombosis and symptomatic cardiovascular disease. Co-stimulatory molecules, such as CD137, are key regulators of inflammation, and CD137 activity regulates inflammation in experimental atherosclerosis. Here, we hypothesized that CD137 activation promotes carotid artery inflammation and atherothrombosis.Methods and Results:In a model of inducible atherothrombosis with surgical ligation of the right carotid artery and a subsequent placement of a polyethene cuff, elevated levels of CD137 and CD137 ligand mRNA in atherothrombotic vs. non-atherothrombotic murine carotid lesions was observed. Mice treated with the CD137 agonistic antibody 2A showed signs of increased inflammation in the aorta and a higher proportion of CD8 + T cells in spleen and blood. In carotid lesions of 2A-treated mice, significantly higher counts of CD8 + and major histocompatibility (MHC)-class II molecule I-A b+ cells were observed. Treatment with the CD137 agonistic antibody 2A did not significantly affect the atherothrombosis frequency in 16-week-old mice in this model. Levels of CD137 and CD137 ligand mRNA were higher in advanced atherosclerotic disease compared to control vessels, and treatment with the CD137 agonistic antibody 2A, in a murine model for inducible atherothrombosis promoted vascular inflammation, but had no significant effect on atherothrombosis frequency at this early disease stage.

  12. Identification of Natural Compound Carnosol as a Novel TRPA1 Receptor Agonist

    Directory of Open Access Journals (Sweden)

    Chenxi Zhai

    2014-11-01

    Full Text Available The transient receptor potential ankyrin 1 (TRPA1 cation channel is one of the well-known targets for pain therapy. Herbal medicine is a rich source for new drugs and potentially useful therapeutic agents. To discover novel natural TRPA1 agonists, compounds isolated from Chinese herbs were screened using a cell-based calcium mobilization assay. Out of the 158 natural compounds derived from traditional Chinese herbal medicines, carnosol was identified as a novel agonist of TRPA1 with an EC50 value of 12.46 µM. And the agonistic effect of carnosol on TRPA1 could be blocked by A-967079, a selective TRPA1 antagonist. Furthermore, the specificity of carnosol was verified as it showed no significant effects on two other typical targets of TRP family member: TRPM8 and TRPV3. Carnosol exhibited anti-inflammatory and anti-nociceptive properties; the activation of TRPA1 might be responsible for the modulation of inflammatory nociceptive transmission. Collectively, our findings indicate that carnosol is a new anti-nociceptive agent targeting TRPA1 that can be used to explore further biological role in pain therapy.

  13. Pharmacophore modeling, comprehensive 3D-QSAR, and binding mode analysis of TGR5 agonists.

    Science.gov (United States)

    Sindhu, Thangaraj; Srinivasan, Pappu

    2017-04-01

    Takeda G-protein-coupled receptor 5 (TGR5) is emerging as an important and promising target for the development of anti-diabetic drugs. Pharmacophore modeling and atom-based 3D-QSAR studies were carried out on a new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as highly potent agonists of TGR5. The generated best six featured pharmacophore model AAHHRR consists of two hydrogen bond acceptors (A): two hydrophobic groups (H) and two aromatic rings (R). The constructed 3D-QSAR model acquired excellent correlation coefficient value (R 2  =   0.9018), exhibited good predictive power (Q 2  =   0.8494) and high Fisher ratio (F = 61.2). The pharmacophore model was validated through Guner-Henry (GH) scoring method. The GH value of 0.5743 indicated that the AAHHRR model was statistically valuable and reliable in the identification of TGR5 agonists. Furthermore, the combined approach of molecular docking and binding free energy calculations were carried out for the 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides to explore the binding mode and interaction pattern. The generated contour maps revealed the important structural insights for the activity of the compounds. The results obtained from this study could be helpful in the development of novel and more potent agonists of TGR5.

  14. Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Harpsøe, Kasper; Ahring, Philip K; Christensen, Jeppe K

    2011-01-01

    The neuronal a4ß2 nicotinic acetylcholine receptors exist as two distinct subtypes, (a4)(2)(ß2)(3) and (a4)(3)(ß2)(2), and biphasic responses to acetylcholine and other agonists have been ascribed previously to coexistence of these two receptor subtypes. We offer a novel and radical explanation...... for the observation of two distinct agonist sensitivities. Using different expression ratios of mammalian a4 and ß2 subunits and concatenated constructs, we demonstrate that a biphasic response is an intrinsic functional property of the (a4)(3)(ß2)(2) receptor. In addition to two high-sensitivity sites at a4ß2...... interfaces, the (a4)(3)(ß2)(2) receptor contains a third low-sensitivity agonist binding site in the a4a4 interface. Occupation of this site is required for full activation and is responsible for the widened dynamic response range of this receptor subtype. By site-directed mutagenesis, we show that three...

  15. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond

    Directory of Open Access Journals (Sweden)

    Lalita Prasad-Reddy

    2015-07-01

    Full Text Available The prevalence of type 2 diabetes is increasing at an astounding rate. Many of the agents used to treat type 2 diabetes have undesirable adverse effects of hypoglycemia and weight gain. Glucagon-like peptide-1 (GLP-1 receptor agonists represent a unique approach to the treatment of diabetes, with benefits extending outside glucose control, including positive effects on weight, blood pressure, cholesterol levels, and beta-cell function. They mimic the effects of the incretin hormone GLP-1, which is released from the intestine in response to food intake. Their effects include increasing insulin secretion, decreasing glucagon release, increasing satiety, and slowing gastric emptying. There are currently four approved GLP-1 receptor agonists in the United States: exenatide, liraglutide, albiglutide, and dulaglutide. A fifth agent, lixisenatide, is available in Europe. There are important pharmacodynamic, pharmacokinetic, and clinical differences of each agent. The most common adverse effects seen with GLP-1 therapy include nausea, vomiting, and injection-site reactions. Other warnings and precautions include pancreatitis and thyroid cell carcinomas. GLP-1 receptor agonists are an innovative and effective option to improve blood glucose control, with other potential benefits of preserving beta-cell function, weight loss, and increasing insulin sensitivity. Once-weekly formulations may also improve patient adherence. Overall, these are effective agents for patients with type 2 diabetes, who are either uncontrolled on metformin or intolerant to metformin.

  16. Osteoprotegerin and β2-Agonists Mitigate Muscular Dystrophy in Slow- and Fast-Twitch Skeletal Muscles.

    Science.gov (United States)

    Dufresne, Sébastien S; Boulanger-Piette, Antoine; Frenette, Jérôme

    2017-03-01

    Our recent work showed that daily injections of osteoprotegerin (OPG)-immunoglobulin fragment complex (OPG-Fc) completely restore the function of fast-twitch extensor digitorum longus muscles in dystrophic mdx mice, a murine model of Duchenne muscular dystrophy. However, despite marked improvements, OPG-Fc was not as effective in preventing the loss of function of slow-twitch soleus and diaphragm muscles. Because β 2 -agonists enhance the function of slow- and fast-twitch dystrophic muscles and because their use is limited by their adverse effects on bone and cardiac tissues, we hypothesized that OPG-Fc, a bone and skeletal muscle protector, acts synergistically with β 2 -agonists and potentiates their positive effects on skeletal muscles. We observed that the content of β 2 -adrenergic receptors, which are mainly expressed in skeletal muscle, is significantly reduced in dystrophic muscles but is rescued by the injection of OPG-Fc. Most important, OPG-Fc combined with a low dose of formoterol, a member of a new generation of β 2 -agonists, histologically and functionally rescued slow-twitch dystrophic muscles. This combination of therapeutic agents, which have already been tested and approved for human use, may open up new therapeutic avenues for Duchenne muscular dystrophy and possibly other neuromuscular diseases. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. 2'-C-Methyl analogues of selective adenosine receptor agonists: synthesis and binding studies.

    Science.gov (United States)

    Franchetti, P; Cappellacci, L; Marchetti, S; Trincavelli, L; Martini, C; Mazzoni, M R; Lucacchini, A; Grifantini, M

    1998-05-07

    2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A1 and A2A receptors in bovine brain membranes and at A3 in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A2A and A3 receptors. When such modification was combined with N6-substitutions with groups which induce high potency and selectivity at A1 receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N6-cyclopentyladenosine (2'-Me-CCPA), which displayed a Ki value of 1.8 nM at A1 receptors, was selective for A1 vs A2A and A3 receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A1-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.

  18. Dopamine agonist 3-PPP fails to protect against MPTP-induced toxicity.

    Science.gov (United States)

    Muralikrishnan, Dhanasekaran; Ebadi, Manuchair; Brown-Borg, Holly M

    2004-02-01

    We investigated the neuroprotective effect of the dopamine agonist, 3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine] against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP (30 mg/kg, i.p., twice, 16 h apart) causes significant dopamine depletion in nucleus caudatus putamen (NCP) by 1 week. 3-PPP had no effect on the monoamine oxidase-B activity (MAO-B) activity in NCP. 3-PPP did not affect dopamine uptake, whereas mazindol significantly blocked the uptake of dopamine dose dependently. MPTP-induced behavioral changes in mice were not reduced by pretreatment with 3-PPP. This dopamine agonist did not prevent dopamine depletion caused by MPTP. MPP+ (20 microM) significantly inhibited the cell proliferation of SH-SY5Y dopaminergic neuronal cells. 3-PPP had no effect on the SH-SY5Y neuronal cell growth in culture and did not block the MPP(+)-induced cytotoxicity. This study shows that the dopamine agonist 3-PPP failed to protect against MPTP-induced dopaminergic neurotoxicity.

  19. Quantum chemical study of agonist-receptor vibrational interactions for activation of the glutamate receptor.

    Science.gov (United States)

    Kubo, M; Odai, K; Sugimoto, T; Ito, E

    2001-06-01

    To understand the mechanism of activation of a receptor by its agonist, the excitation and relaxation processes of the vibrational states of the receptor should be examined. As a first approach to this problem, we calculated the normal vibrational modes of agonists (glutamate and kainate) and an antagonist (6-cyano-7-nitroquinoxaline-2,3-dione: CNQX) of the glutamate receptor, and then investigated the vibrational interactions between kainate and the binding site of glutamate receptor subunit GluR2 by use of a semiempirical molecular orbital method (MOPAC2000-PM3). We found that two local vibrational modes of kainate, which were also observed in glutamate but not in CNQX, interacted through hydrogen bonds with the vibrational modes of GluR2: (i) the bending vibration of the amine group of kainate, interacting with the stretching vibration of the carboxyl group of Glu705 of GluR2, and (ii) the symmetric stretching vibration of the carboxyl group of kainate, interacting with the bending vibration of the guanidinium group of Arg485. We also found collective modes with low frequency at the binding site of GluR2 in the kainate-bound state. The vibrational energy supplied by an agonist may flow from the high-frequency local modes to the low-frequency collective modes in a receptor, resulting in receptor activation.

  20. Beta-Adrenergic Receptors and Mechanisms in Asthma: The New Long-Acting Beta-Agonists

    Directory of Open Access Journals (Sweden)

    Robert G Townley

    1996-01-01

    Full Text Available The objective is to review β-adrenergic receptors and mechanisms in the immediate and late bronchial reaction in asthma and the new long-acting β-agonist. This will be discussed in light of the controversy of the potential adverse effect of regular use of long-acting β-agonists. We studied the effect of formoterol on the late asthmatic response (LAR and airway inflammation in guinea-pigs. Formoterol suppressed the LAR, antigen-induced airway inflammation and hyperresponsiveness, although isoproterenol failed to inhibit these parameters. β-Adrenergic hyporesponsiveness, and cholinergic and a- adrenergic hyperresponsiveness have been implicated in the pathogenesis of asthma. A decrease in β-adrenoreceptor function can result either from exogenously administered β-agonist or from exposure to allergens resulting in a late bronchial reaction. There is increasing evidence that eosinophils, macrophages, and lymphocytes which are of primary importance in the late bronchial reaction are also modulated by β2- adrenoreceptors. In functional studies of guinea-pig or human isolated trachea and lung parenchyma, PAF and certain cytokines significantly reduced the potency of isoproterenol to reverse methacholine- or histamine-induced contraction. The effect of glucocorticoids on pulmonary β-adrenergic receptors and responses suggests an important role for glucocorticoids to increase β-adrenergic receptors and responsiveness.

  1. Molecular and Therapeutic Characterization of Anti-ectodysplasin A Receptor (EDAR) Agonist Monoclonal Antibodies*

    Science.gov (United States)

    Kowalczyk, Christine; Dunkel, Nathalie; Willen, Laure; Casal, Margret L.; Mauldin, Elizabeth A.; Gaide, Olivier; Tardivel, Aubry; Badic, Giovanna; Etter, Anne-Lise; Favre, Manuel; Jefferson, Douglas M.; Headon, Denis J.; Demotz, Stéphane; Schneider, Pascal

    2011-01-01

    The TNF family ligand ectodysplasin A (EDA) and its receptor EDAR are required for proper development of skin appendages such as hair, teeth, and eccrine sweat glands. Loss of function mutations in the Eda gene cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition that can be ameliorated in mice and dogs by timely administration of recombinant EDA. In this study, several agonist anti-EDAR monoclonal antibodies were generated that cross-react with the extracellular domains of human, dog, rat, mouse, and chicken EDAR. Their half-life in adult mice was about 11 days. They induced tail hair and sweat gland formation when administered to newborn EDA-deficient Tabby mice, with an EC50 of 0.1 to 0.7 mg/kg. Divalency was necessary and sufficient for this therapeutic activity. Only some antibodies were also agonists in an in vitro surrogate activity assay based on the activation of the apoptotic Fas pathway. Activity in this assay correlated with small dissociation constants. When administered in utero in mice or at birth in dogs, agonist antibodies reverted several ectodermal dysplasia features, including tooth morphology. These antibodies are therefore predicted to efficiently trigger EDAR signaling in many vertebrate species and will be particularly suited for long term treatments. PMID:21730053

  2. Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies.

    Science.gov (United States)

    Kowalczyk, Christine; Dunkel, Nathalie; Willen, Laure; Casal, Margret L; Mauldin, Elizabeth A; Gaide, Olivier; Tardivel, Aubry; Badic, Giovanna; Etter, Anne-Lise; Favre, Manuel; Jefferson, Douglas M; Headon, Denis J; Demotz, Stéphane; Schneider, Pascal

    2011-09-02

    The TNF family ligand ectodysplasin A (EDA) and its receptor EDAR are required for proper development of skin appendages such as hair, teeth, and eccrine sweat glands. Loss of function mutations in the Eda gene cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition that can be ameliorated in mice and dogs by timely administration of recombinant EDA. In this study, several agonist anti-EDAR monoclonal antibodies were generated that cross-react with the extracellular domains of human, dog, rat, mouse, and chicken EDAR. Their half-life in adult mice was about 11 days. They induced tail hair and sweat gland formation when administered to newborn EDA-deficient Tabby mice, with an EC(50) of 0.1 to 0.7 mg/kg. Divalency was necessary and sufficient for this therapeutic activity. Only some antibodies were also agonists in an in vitro surrogate activity assay based on the activation of the apoptotic Fas pathway. Activity in this assay correlated with small dissociation constants. When administered in utero in mice or at birth in dogs, agonist antibodies reverted several ectodermal dysplasia features, including tooth morphology. These antibodies are therefore predicted to efficiently trigger EDAR signaling in many vertebrate species and will be particularly suited for long term treatments.

  3. LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone

    International Nuclear Information System (INIS)

    Bian, Xuting; Zhong, Hongyu; Li, Fen; Cai, Yulong; Li, Xin; Wang, Lian; Fan, Xiaotang

    2016-01-01

    Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects.

  4. Individual luteolysis pattern after GnRH-agonist trigger for final oocyte maturation

    Science.gov (United States)

    Garrido, Nicolas; Samir, Suzan; Ruiz, Francisco; Melado, Laura; Fatemi, Human M.

    2017-01-01

    Final oocyte maturation using GnRH-agonist trigger in a GnRH-antagonist protocol is increasingly common, as ovarian hyperstimulation syndrome is almost completely avoided. However, this approach might lead to reduced pregnancy rates due to severe luteolysis. This proof of concept study evaluated the extend of luteolysis by measuring progesterone levels 48 hours after oocyte retrieval in 51 patients, who received GnRH-agonist trigger for final oocyte maturation in a GnRH-antagonist protocol due to the risk of ovarian hyperstimulation syndrome. It was shown, that luteolysis after GnRHa-trigger differs greatly among patients, with progesterone levels ranging from 13.0 ng/ml to ≥ 60.0 ng/ml, 48 hours after oocyte retrieval. Significant positive correlations could be demonstrated between progesterone levels and the number of ovarian stimulation and suppression days (p = 0.006 and p = 0.002 respectively), the total amount of medication used for ovarian suppression (p = 0.015), the level of progesterone on the day of final oocyte maturation (p = 0.008) and the number of retrieved oocytes (p = 0.019). Therefore it was concluded, that luteolysis after GnRH-agonist trigger is patient-specific and also luteal phase support requires individualization. Longer stimulation duration as well as a higher level of progesterone on the day of final oocyte maturation and more retrieved oocytes will result in higher levels of progesterone 48 hours after oocyte retrieval. PMID:28459828

  5. Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors

    Science.gov (United States)

    Jacobson, Kenneth A.; Moro, Stefano; Hoffmann, Carsten; Kim, Yong-Chul; Kim, Hak Sung; Ravi, R. Gnana; Harden, T. Kendall; Boyer, José L.

    2015-01-01

    The P2Y1 receptor responds to adenine nucleotides and is present in platelets, heart, smooth muscles prostate, ovary, and brain. A selective antagonist may be useful as an antithrombotic agent. We have analyzed the binding site of this G protein-coupled receptor using ligand design, site-directed mutagenesis, and homology modeling based on rhodopsin. We have designed and synthesized a series of deoxyadenosine 3′,5′-bisphosphate derivatives that act as antagonists, or, in some cases with small structural changes, as agonists or partial agonists. The 2-position accommodates Cl or thioethers, whereas the N6-position is limited to Me or Et. 2′-Substitution with OH or OMe increases agonist efficacy over 2′-H. Using molecular modeling of the binding site, the oxygen atoms of the ribose moiety were predicted to be non-essential, i.e. no specific H-bonds with the receptor protein appear in the model. We have, therefore, substituted this moiety with carbocylics, smaller and larger rings, conformationally constrained rings, and acyclics, with retention of affinity for the receptor. With simplified pharmacophores we are exploring the steric and electronic requirements of the receptor binding site, and the structural basis of receptor activation. PMID:11347970

  6. Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis.

    Science.gov (United States)

    Zhang, Xue-Qing; Even-Or, Orli; Xu, Xiaoyang; van Rosmalen, Mariska; Lim, Lucas; Gadde, Suresh; Farokhzad, Omid C; Fisher, Edward A

    2015-01-28

    Liver X receptor (LXR) signaling pathways regulate lipid metabolism and inflammation, which has generated widespread interest in developing synthetic LXR agonists as potential therapeutics for the management of atherosclerosis. In this study, it is demonstrated that nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (NP-LXR) exert anti-inflammatory effects and inhibit the development of atherosclerosis without causing hepatic steatosis. These NPs are engineered through self-assembly of a biodegradable diblock poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) copolymer. NP-LXR is significantly more effective than free GW3965 at inducing LXR-target gene expression and suppressing inflammatory factors in macrophages in vitro and in vivo. Additionally, the NPs elicit negligible lipogenic gene stimulation in the liver. Using the Ldlr (-/-) mouse model of atherosclerosis, abundant colocalization of fluorescently labeled NPs within plaque macrophages following systemic administration is seen. Notably, six intravenous injections of NP-LXR over 2 weeks markedly reduce the CD68-positive cell (macrophage) content of plaques (by 50%) without increasing total cholesterol or triglycerides in the liver and plasma. Together, these findings identify GW3965-encapsulated PLGA-b-PEG NPs as a promising nanotherapeutic approach to combat atherosclerosis, providing the benefits of LXR agonists without their adverse effects on hepatic and plasma lipid metabolism. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Anticancer Role of PPARγ Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

    Directory of Open Access Journals (Sweden)

    P. J. Simpson-Haidaris

    2010-01-01

    Full Text Available The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR-γ agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARγ agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARγ agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARγ and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow.

  8. Structure-Based Screening of Uncharted Chemical Space for Atypical Adenosine Receptor Agonists.

    Science.gov (United States)

    Rodríguez, David; Chakraborty, Saibal; Warnick, Eugene; Crane, Steven; Gao, Zhan-Guo; O'Connor, Robert; Jacobson, Kenneth A; Carlsson, Jens

    2016-10-21

    Small molecule screening libraries cover only a small fraction of the astronomical number of possible drug-like compounds, limiting the success of ligand discovery efforts. Computational screening of virtual libraries representing unexplored chemical space could potentially bridge this gap. Drug development for adenosine receptors (ARs) as targets for inflammation and cardiovascular diseases has been hampered by the paucity of agonist scaffolds. To identify novel AR agonists, a virtual library of synthetically tractable nucleosides with alternative bases was generated and structure-based virtual screening guided selection of compounds for synthesis. Pharmacological assays were carried out at three AR subtypes for 13 ribosides. Nine compounds displayed significant activity at the ARs, and several of these represented atypical agonist scaffolds. The discovered ligands also provided insights into receptor activation and revealed unknown interactions of endogenous and clinical compounds with the ARs. The results demonstrate that virtual compound databases provide access to bioactive matter from regions of chemical space that are sparsely populated in commercial libraries, an approach transferrable to numerous drug targets.

  9. Vaginal Expulsion of a Submucosal Myoma During Treatment with Long-Acting Gonadotropin-Releasing Hormone Agonist

    Directory of Open Access Journals (Sweden)

    Lily Wen

    2006-06-01

    Conclusion: Spontaneous expulsion of submucosal myomas might occur after the administration of GnRH agonist; hence, it may be an acceptable alternative for symptomatic females without sexual exposure.

  10. The case for cannabinoid CB1 receptors as a target for bronchodilator therapy for β-agonist resistant asthma.

    Science.gov (United States)

    Ashton, John; Hancox, Robert J

    2017-06-15

    Although b2-receceptor agonists are powerful bronchodilators and are at the forefront of asthma symptom relief, patients who use them frequently develop partial resistance to them. This can be a particularly serious problem during severe attacks, where high dose b2-agonist treatment is the front line therapy. Alternative bronchodilators are urgently needed. In this article we review the evidence for the bronchodilator effects of the cannabinoid CB1 receptor tetrahydrocannabinol (THC) and suggest that the mechanism of action for these effects are sufficiently independent of the mechanisms of standard bronchodilators to warrant clinical investigation. Specifically, clinical trials testing the bronchodilator effects of THC in b2 agonist resistant asthmatic patients would show whether THC could fill the role of rescue bronchodilator in cases of b2 agonist resistance. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Switching from high doses of pure μ-opioid agonists to transdermal buprenorphine in patients with cancer

    DEFF Research Database (Denmark)

    Lundorff, Lena; Sjøgren, Per; Hansen, Ole Bo

    2013-01-01

    BACKGROUND: Several myths on buprenorphine's pharmacology exist: possible analgesic ceiling effect, feasibility of combination with other opioid agonists, and the reversibility of side effects. Aim to evaluate: 1) if cancer patients receiving high doses of pure agonists could obtain adequate pain...... with moderate-to-severe cancer pain satisfactorily controlled. SETTING: Patients were switched from the usual pure agonist to TD buprenorphine and were titrated to a stable dose. The assessments were: 1) daily self-assessment of pain intensity, numbers of rescue medications, and pain interference with sleep; 2...... relief after switching to transdermal (TD) buprenorphine and 2) whether the numbers of breakthrough pain episodes after switching increased and whether they could be treated with the same doses of pure agonist as before switching. DESIGN: The prospective open multicenter study included outpatients...

  12. Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors with core hopping approach.

    Directory of Open Access Journals (Sweden)

    Ying Ma

    Full Text Available Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones, the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful "core hopping" and "glide docking" techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the "core hopping" technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

  13. Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway.

    Science.gov (United States)

    Thompson, Aiysha; Kanamarlapudi, Venkateswarlu

    2015-01-01

    The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) and an important target in the treatment of type 2 diabetes mellitus (T2DM). Upon stimulation with agonist, the GLP-1R signals through both Gαs and Gαq coupled pathways to stimulate insulin secretion. The agonist-induced GLP-1R internalisation has recently been shown to be important for insulin secretion. However, the molecular mechanisms underlying GLP-1R internalisation remain unknown. The aim of this study was to determine the role of GLP-1R downstream signalling pathways in its internalisation. Agonist-induced human GLP-1R (hGLP-1R) internalisation and activity were examined using a number of techniques including immunoblotting, ELISA, immunofluorescence and luciferase assays to determine cAMP production, intracellular Ca(2+) accumulation and ERK phosphorylation. Agonist-induced hGLP-1R internalisation is dependent on caveolin-1 and dynamin. Inhibition of the Gαq pathway but not the Gαs pathway affected hGLP-1R internalisation. Consistent with this, hGLP-1R mutant T149M and small-molecule agonists (compound 2 and compound B), which activate only the Gαs pathway, failed to induce internalisation of the receptor. Chemical inhibitors of the Gαq pathway, PKC and ERK phosphorylation significantly reduced agonist-induced hGLP-1R internalisation. These inhibitors also suppressed agonist-induced ERK1/2 phosphorylation demonstrating that the phosphorylated ERK acts downstream of the Gαq pathway in the hGLP-1R internalisation. In summary, agonist-induced hGLP-1R internalisation is mediated by the Gαq pathway. The internalised hGLP-1R stimulates insulin secretion from pancreatic β-cells, indicating the importance of GLP-1 internalisation for insulin secretion. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Interaction between corticosteroid and beta-agonist drugs. Biochemical and cardiovascular effects in normal subjects.

    Science.gov (United States)

    Taylor, D R; Wilkins, G T; Herbison, G P; Flannery, E M

    1992-08-01

    The aim of this study was to investigate whether the administration of prednisone potentiates any of the acute biochemical and cardiovascular effects of high-dose inhaled beta-agonist drugs. These agents are known to cause dose-related changes in plasma potassium and glucose, as well as ECG changes in heart rate, corrected QT interval (QTc), T wave, and U wave. On theoretical grounds, the concomitant use of systemic corticosteroids might enhance these actions. Twenty-four healthy subjects were randomized to receive one of three treatments: salbutamol 5 mg or fenoterol 5 mg or normal saline solution. Each drug was administered twice, 30 min apart by nebulizer, and the procedure was repeated after each subject had received prednisone 30 mg daily for one week. Plasma potassium and glucose levels were measured, and ECGs were obtained after each treatment, together with 12-h Holter monitoring for arrhythmias. Changes in plasma potassium and glucose following nebulized beta-agonist were significantly greater after treatment with prednisone. Baseline potassium level fell from 3.75 mmol/L (95 percent CI 3.61, 3.89) to 3.50 mmol/L (95 percent CI 3.36, 3.64), and thereafter all values were significantly lower at each time point (p = 0.003). The lowest mean plasma potassium was obtained 90 min after fenoterol administration with prednisone pretreatment: 2.78 mmol/L (95 percent CI 2.44, 3.13). Increases in heart rate and QTc interval following both beta-agonist drugs were significant, but T-wave amplitude reductions did not reach significance. Prednisone treatment did not significantly alter the cardiovascular responses. Supraventricular and ventricular ectopic activity was related to beta-agonist use, but no potentiating effect was noted following steroid treatment. We conclude that the acute biochemical effects of beta-agonist administration are augmented by prior treatment with prednisone, but this is not the case for ECG effects. However, the degree of hypokalemia noted as

  15. Design and Synthesis of Selective Estrogen Receptor beta Agonists and Their Pharmacology

    Science.gov (United States)

    Perera, K. L. Iresha Sampathi

    Estrogens (17beta-estradiol, E2) have garnered considerable attention in influencing cognitive process in relation to phases of the menstrual cycle, aging and menopausal symptoms. However, hormone replacement therapy can have deleterious effects leading to breast and endometrial cancer, predominantly mediated by estrogen receptor-alpha (ERalpha) the major isoform present in the mammary gland and uterus. Further evidence supports a dominant role of estrogen receptor-beta (ERbeta) for improved cognitive effects such as enhanced hippocampal signaling and memory consolidation via estrogen activated signaling cascades. Creation of the ERbeta selective ligands is challenging due to high structural similarity of both receptors. Thus far, several ERbeta selective agonists have been developed, however, none of these have made it to clinical use due to their lower selectivity or considerable side effects. The research in this dissertation involved the design of non-steroidal ERbeta selective agonists for hippocampal memory consolidation. The step-wise process to achieve the ultimate goal of this research includes: (1) design and synthesis of (4-hydroxyphenyl)cyclohexyl or cycloheptyl derivatives, (2) in vitro biological evaluation of synthesized compounds to identify highly potent and selective candidates, and (3) in vivo biological evaluation of selected candidates for hippocampal memory consolidation. Several (4-hydroxyphenyl)cyclohexyl or cycloheptyl derivatives were synthesized having structural alterations on both aromatic and cyclohexyl/heptyl ring scaffolds. ERbeta agonist potency was initially evaluated in TR-FRET ERbeta ligand binding assay and compounds having high potency were re-evaluated in functional cell based assays for potency and ERbeta vs. ERalpha selectivity. Two compounds from each series, ISP 163-PK4 and ISP 358-2 were identified as most selective ERbeta agonists. Both compounds revealed high metabolic stability, solubility and no cross reactivity

  16. Beyond glucose lowering: glucagon-like peptide-1 receptor agonists, body weight and the cardiovascular system.

    Science.gov (United States)

    Vergès, B; Bonnard, C; Renard, E

    2011-12-01

    Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family: in the presence of elevated blood glucose, it stimulates insulin secretion and inhibits glucagon production. In addition, GLP-1 slows gastric emptying. GLP-1 secretion has also been reported to potentially affect patients with type 2 diabetes (T2DM) compared with non-diabetics and, as enzymatic inactivation by dipeptidyl peptidase-4 (DPP-4) shortens the GLP-1 half-life to a few minutes, GLP-1 receptor agonists such as exenatide twice daily (BID) and liraglutide have been developed, and have become part of the management of patients with T2DM. This review focuses on the potential beneficial effects of these compounds beyond those associated with improvements in blood glucose control and weight loss, including changes in the cardiovascular and central nervous systems. This was a state-of-the-art review of the literature to evaluate the relationships between GLP-1, GLP-1 receptor agonists, weight and the cardiovascular system. GLP-1 receptor agonists improve glucose control and do not significantly increase the risk of hypoglycaemia. Also, this new class of antidiabetic drugs was shown to favour weight loss. Mechanisms may involve central action, direct action by reduction of food intake and probably indirect action through slowing of gastric emptying. The relative importance of each activity remains unclear. Weight loss may improve cardiovascular outcomes in patients with T2DM, although GLP-1 receptor agonists may have other direct and indirect effects on the cardiovascular system. Reductions in myocardial infarct size and improvements in cardiac function have been seen in animal models. Beneficial changes in cardiac function were also demonstrated in patients with myocardial infarcts or heart failure. Indirect effects could involve a reduction in blood pressure and potential effects on oxidation. However, the mechanisms involved in the pleiotropic effects of GLP-1 receptor agonists have yet to

  17. Alpha-2 adrenergic agonists for the prevention of shivering following general anaesthesia.

    Science.gov (United States)

    Lewis, Sharon R; Nicholson, Amanda; Smith, Andrew F; Alderson, Phil

    2015-08-10

    Shivering after general anaesthesia is common. It is unpleasant but can also have adverse physiological effects. Alpha-2 (α-2) adrenergic agonist receptors, which can lead to reduced sympathetic activity and central regulation of vasoconstrictor tone, are a group of drugs that have been used to try to prevent postoperative shivering. To assess the following: the effects of α-2 agonists on the prevention of shivering and subsequent complications after general anaesthesia in people undergoing surgery; the effects of α-2 agonists on the risk of inadvertent perioperative hypothermia; and whether any adverse effects are associated with these interventions. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE on 13 June 2014. Our search terms were relevant to the review question and limited to studies that assessed shivering or hypothermia. We also carried out searches of clinical trials registers, and forward and backward citation tracking. We considered all randomized controlled trials, quasi-randomized studies, and cluster-randomized studies with adult participants undergoing surgery with general anaesthesia in which an α-2 agonist was compared with another α-2 agonist or a placebo for the prevention of shivering. Two review authors independently assessed trial quality and extracted data, consulting a third review author in the case of disagreements. We used standard Cochrane methodological procedures, including an assessment of risk of bias and use of GRADEpro software to interpret findings. We included 20 studies with 1401 surgical participants comparing an α-2 agonist against a control. Thirteen studies compared clonidine with a control, whilst seven compared dexmedetomidine with a control. The doses, methods, and time of administration varied between studies: three studies gave the drug orally or as an intravenous bolus preoperatively and nine intraoperatively; one study gave the drug as an infusion starting

  18. Pharmacological activation of the bile acid nuclear farnesoid X receptor is feasible in patients with quiescent Crohn's colitis.

    Directory of Open Access Journals (Sweden)

    Fiona D M van Schaik

    Full Text Available BACKGROUND: The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC. METHODS: Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF 19. Since FGF19 induces gallbladder (GB refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined. RESULTS: At baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups. CONCLUSIONS: Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients. TRIAL REGISTRATION: TrialRegister.nl NTR2009.

  19. FXR induces the UGT2B4 enzyme in hepatocytes : A potential mechanism of negative feedback control of FXR activity

    NARCIS (Netherlands)

    Barbier, O; Pineda Torra, I.; Sirvent, A; Claudel, T; Blanquart, C; Duran-Sandoval, D; Kuipers, F; Kosykh, V.; Fruchart, JC; Staels, B

    Background & Aims: Bile acids are essential for bile formation and Intestinal absorption of lipids and fat-soluble vitamins. However, the intrinsic toxicity of hydrophobic bile acids demands a tight control of their intracellular concentrations. Bile acids are ligands for the farnesoid X receptor

  20. Water exposure assessment of aryl hydrocarbon receptor agonists in Three Gorges Reservoir, China using SPMD-based virtual organisms.

    Science.gov (United States)

    Wang, Jingxian; Bernhöft, Silke; Pfister, Gerd; Schramm, Karl-Werner

    2014-10-15

    SPMD-based virtual organisms (VOs) were deployed at five to eight sites in the Three Gorges Reservoir (TGR), China for five periods in 2008, 2009 and 2011. The water exposure of aryl hydrocarbon receptor (AhR) agonists was assessed by the VOs. The chosen bioassay response for the extracts of the VOs, the induction of 7-ethoxyresorufin-O-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The results show that the extracts from the VOs could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) accounted for effects in the mixture. The levels of AhR agonists in VOs from upstream TGR were in general higher than those from downstream reservoir, indicating urbanization effect on AhR agonist pollution. The temporal variation showed that levels of AhR agonists in 2009 and 2011 were higher than those in 2008, and the potential non-additive effects in the area close to the dam were also obviously higher in 2009 and 2011 than in 2008, indicating big changes in the composition of pollutants in the area after water level reached a maximum of 175 m. Although the aqueous concentration of AhR agonists of 0.8-4.8 pg TCDDL(-1) in TGR was not alarming, the tendency of accumulating high concentration of AhR agonists in VO lipid and existence of possible synergism or antagonism in the water may exhibit a potential hazard to local biota being exposed to AhR agonists. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Agonist pharmacology at recombinant α1A - and α1L -adrenoceptors and in lower urinary tract α1 -adrenoceptors.

    Science.gov (United States)

    Yoshiki, Hatsumi; Uwada, Junsuke; Umada, Hidenori; Kobayashi, Tadashi; Takahashi, Toshihiro; Yamakawa, Tomio; Yamaguchi, Akio; Yokoyama, Osamu; Muramatsu, Ikunobu

    2013-11-01

    Two distinct α1 -adrenoceptor phenotypes (α1A and α1L ) have recently been demonstrated to originate from a single α1A -adrenoceptor gene. Here, we examined the agonist profiles of recombinant α1A and α1L phenotypes and of lower urinary tract (LUT) α1 -adrenoceptors. A series of drugs (A61603, Ro 115-1240, NS-49 , MK017 and ESR1150) originally developed for stress urinary incontinence (SUI) therapy were used to stimulate recombinant α1A - and α1L -adrenoceptor phenotypes, and their potencies and intrinsic activity estimated from Ca(2+) responses. Agonist-induced contractions were also examined in LUT tissues of rats and humans and in human mesenteric artery and rat tail artery. All the drugs were potent agonists of the α1A -adrenoceptor compared with the α1L -adrenoceptor phenotype. Among them, Ro 115-1240 was shown to be an α1A -specific partial agonist that produced partial contractions through α1A -adrenoceptors in rat prostate and tail artery, but not in the other LUT tissues and human mesenteric artery. In contrast, P-come 102 showed full agonist activity at α1A - and α1L -adrenoceptors, but was less selective than noradrenaline for α1A -adrenoceptors. Like noradrenaline, P-come 102 was highly potent at inducing contractions in all of the LUT tissues tested. However, the potency and intrinsic activity of P-come 102 were significantly lower than those of noradrenaline in human mesenteric artery. The α1A - and α1L -adrenoceptor phenotypes and LUT α1 -adrenoceptors were demonstrated to have distinct agonist profiles. As adrenergic contractions in LUT are predominantly mediated through α1L -adrenoceptors, the development of α1L -selective agonists may provide clinically useful drugs for SUI therapy. © 2013 The British Pharmacological Society.

  2. 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.

  3. Detecting associations between behavioral addictions and dopamine agonists in the Food & Drug Administration’s Adverse Event database

    Science.gov (United States)

    Gendreau, Katherine E.; Potenza, Marc N.

    2014-01-01

    Background/Aims: Studies have reported higher prevalences of four behavioral addictions (binge eating, compulsive shopping, hypersexuality, and pathological gambling) in dopamine agonist-treated Parkinson’s disease relative to non-dopamine agonist-treated Parkinson’s. However, recent case-control and epidemiological studies suggest that prevalences of behavioral addictions in dopamine agonist-treated Parkinson’s may be similar to background population rates. This study tests that hypothesis by examining the FDA Adverse Event Reporting System (FAERS) for evidence of these associations, taking into account the potential impact of publicity on reporting rates. Methods: FAERS reports in 2004 (pre-publicity for all but pathological gambling) and 2007 (post-publicity for all four behaviors) were analyzed. A threshold consisting of ≥3 cases, proportional reporting ratio ≥2, and χ2 with Yates’ correction ≥4 was used to detect signals (drug-associated adverse reactions) involving any of five dopamine agonists and any of four behavioral addictions. Results: No reports containing compulsive shopping and no signal for binge eating and dopamine agonists were found in either year. A weak signal was found for hypersexuality in 2004, with a stronger signal in 2007. A robust signal was found for pathological gambling in 2004, with a more robust signal in 2007. Discussion/Conclusions: These results suggest that publicity may increase reporting rates in the FAERS. Findings for binge eating, compulsive shopping, and hypersexuality suggest that prevalences of these behaviors among those treated with dopamine agonists may be similar to background population rates and thus may not reflect an adverse safety signal. Further investigation of the relationship between dopamine agonists and behavioral addictions is warranted. PMID:25215211

  4. Ractopamine, a Livestock Feed Additive, Is a Full Agonist at Trace Amine–Associated Receptor 1

    Science.gov (United States)

    Grandy, David K.; Janowsky, Aaron

    2014-01-01

    Ractopamine (RAC) is fed to an estimated 80% of all beef, swine, and turkey raised in the United States. It promotes muscle mass development, limits fat deposition, and reduces feed consumption. However, it has several undesirable behavioral side effects in livestock, especially pigs, including restlessness, agitation, excessive oral-facial movements, and aggressive behavior. Numerous in vitro and in vivo studies suggest RAC’s physiological actions begin with its stimulation of β1- and β2-adrenergic receptor–mediated signaling in skeletal muscle and adipose tissue; however, the molecular pharmacology of RAC’s psychoactive effects is poorly understood. Using human cystic fibrosis transmembrane conductance regulator (hCFTR) chloride channels as a sensor for intracellular cAMP, we found that RAC and p-tyramine (TYR) produced concentration-dependent increases in chloride conductance in oocytes coexpressing hCFTR and mouse trace amine–associated receptor 1 (mTAAR1), which was completely reversed by the trace amine–associated receptor 1 (TAAR1)–selective antagonist EPPTB [N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide]. Oocytes coexpressing hCFTR and the human β2-adrenergic receptor showed no response to RAC or TYR. These studies demonstrate that, contrary to expectations, RAC is not an agonist of the human β2-adrenergic receptor but rather a full agonist for mTAAR1. Since TAAR1-mediated signaling can influence cardiovascular tone and behavior in several animal models, our finding that RAC is a full mTAAR1 agonist supports the idea that this novel mechanism of action influences the physiology and behavior of pigs and other species. These findings should stimulate future studies to characterize the pharmacological, physiological, and behavioral actions of RAC in humans and other species exposed to this drug. PMID:24799633

  5. Chronic levodopa treatment alters basal and dopamine agonist-stimulated cerebral glucose utilization

    Energy Technology Data Exchange (ETDEWEB)

    Engber, T.M.; Susel, Z.; Kuo, S.; Chase, T.N. (National Institute of Neurological Disorders and Stroke, Bethesda, MD (USA))

    1990-12-01

    The effect of chronic levodopa administration on the functional activity of the basal ganglia and its output regions was evaluated by means of the 2-deoxyglucose (2-DG) autoradiographic technique in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The rates of local cerebral glucose utilization were studied under basal conditions as well as in response to challenge with a selective D1 or D2 dopamine-receptor agonist. Levodopa (100 mg/kg/d, i.p.) was administered for 19 d either continuously via infusion with an osmotic pump or intermittently by twice-daily injections. Following a 3-d washout, glucose utilization was found to be decreased by both levodopa regimens in the nucleus accumbens; intermittent levodopa also decreased glucose utilization in the entopeduncular nucleus, subthalamic nucleus, ventrolateral thalamus, ventromedial thalamus, ventroposterolateral thalamus, and lateral habenula. In control (lesioned and treated chronically with saline) rats, the D1 agonist SKF 38393 (5 mg/kg, i.v.) increased 2-DG uptake in the substantia nigra pars reticulata and entopeduncular nucleus ipsilateral to the lesion by 84% and 56%, respectively. Both continuous and intermittent levodopa blunted the SKF 38393-induced elevation in glucose metabolism in the substantia nigra pars reticulata, while intermittent levodopa also attenuated the increase in the entopeduncular nucleus. The D2 agonist quinpirole (0.4 mg/kg, i.v.) did not increase glucose utilization in any brain region in control animals; following intermittent levodopa treatment, however, quinpirole increased 2-DG uptake by 64% in the subthalamic nucleus and by 39% in the deep layers of the superior colliculus on the ipsilateral side.

  6. Ractopamine, a livestock feed additive, is a full agonist at trace amine-associated receptor 1.

    Science.gov (United States)

    Liu, Xuehong; Grandy, David K; Janowsky, Aaron

    2014-07-01

    Ractopamine (RAC) is fed to an estimated 80% of all beef, swine, and turkey raised in the United States. It promotes muscle mass development, limits fat deposition, and reduces feed consumption. However, it has several undesirable behavioral side effects in livestock, especially pigs, including restlessness, agitation, excessive oral-facial movements, and aggressive behavior. Numerous in vitro and in vivo studies suggest RAC's physiological actions begin with its stimulation of β1- and β2-adrenergic receptor-mediated signaling in skeletal muscle and adipose tissue; however, the molecular pharmacology of RAC's psychoactive effects is poorly understood. Using human cystic fibrosis transmembrane conductance regulator (hCFTR) chloride channels as a sensor for intracellular cAMP, we found that RAC and p-tyramine (TYR) produced concentration-dependent increases in chloride conductance in oocytes coexpressing hCFTR and mouse trace amine-associated receptor 1 (mTAAR1), which was completely reversed by the trace amine-associated receptor 1 (TAAR1)-selective antagonist EPPTB [N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide]. Oocytes coexpressing hCFTR and the human β2-adrenergic receptor showed no response to RAC or TYR. These studies demonstrate that, contrary to expectations, RAC is not an agonist of the human β2-adrenergic receptor but rather a full agonist for mTAAR1. Since TAAR1-mediated signaling can influence cardiovascular tone and behavior in several animal models, our finding that RAC is a full mTAAR1 agonist supports the idea that this novel mechanism of action influences the physiology and behavior of pigs and other species. These findings should stimulate future studies to characterize the pharmacological, physiological, and behavioral actions of RAC in humans and other species exposed to this drug. U.S. Government work not protected by U.S. copyright.

  7. Investigations into factors determining the duration of action of the beta 2-adrenoceptor agonist, salmeterol.

    Science.gov (United States)

    Nials, A T; Sumner, M J; Johnson, M; Coleman, R A

    1993-02-01

    1. This study has explored the mechanism underlying the long duration of action of the beta 2-adrenoceptor agonist, salmeterol. 2. Salmeterol, salbutamol and isoprenaline caused a concentration-related inhibition of electrically-induced contractile responses of the guinea-pig superfused trachea preparation. The effects of both isoprenaline and salbutamol were rapid in onset and rapidly reversed upon removal of the agonist. In contrast, the effects of salmeterol were slower in onset and could not be reversed by superfusion of the tissue with agonist-free Krebs solution even for periods of up to 10 h. 3. The effects of salmeterol were, however, readily reversed by a number of beta-adrenoceptor blocking drugs, as was the effect of a continuous infusion of isoprenaline. Upon removal of the antagonist, however, the effects of salmeterol and of the isoprenaline infusion were reasserted at a rate which was inversely related to the lipophilicity of a beta-adrenoceptor blocking drugs. 4. Salmeterol inhibited the binding of [125I]-(-)-iodopindolol (100 pM) to rat lung membranes (pIC50 7.1), with isoprenaline (pIC50 6.2) and salbutamol (pIC50 5.1) having lower potencies. The inhibition of binding by salmeterol was apparently non-competitive, whereas that produced by salbutamol and isoprenaline was competitive in nature. 5. Isoprenaline and salbutamol rapidly dissociated from their binding sites, whereas in marked contrast, the binding of salmeterol showed no dissociation for periods of up to 1 h. 6. These data are consistent with the mechanism in which salmeterol binds adjacent to the active site of the beta 2-adrenoceptor, such that the drug cannot be washed out of the tissue, yet can interact with and activate the receptor. This latter property is susceptible to antagonism by beta-adrenoceptor blocking drugs but is reassured when the antagonists are removed.

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

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    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.

  9. Preventing or attenuating amphotericin B nephrotoxicity with dopamine receptor agonists: a literature review

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    Iman Karimzadeh

    2016-09-01

    Full Text Available Nephrotoxicity is generally considered as the most clinically significant and dose-limiting adverse reaction of amphotericin B. Currently, only the clinical effectiveness of salt loading and administering lipid formulations of amphotericin B have been clearly demonstrated to prevent its nephrotoxicity. In this review, we collected the published data related to dopamine receptor agonists in preventing amphotericin B nephrotoxicity. A literature search was conducted by the relevant keywords like ‘‘amphotericin B”, “nephrotoxicity’’, and ‘‘dopamine’’in databases such as Scopus, Medline, Embase and ISI Web of Knowledge. Four relevant articles were considered. Results of all the 3 experimental studies demonstrated that co-administration of dopamine (0.5-10 μg/kg/min as continuous intravenous infusion, SK&F R-105058, a prodrug of fenoldopam (10 mg/kg twice daily, orally or fenoldopam, a relatively selective dopamine receptor type 1 agonist, (0.5 or 1 μg/kg/min as continuous intravenous infusion can at least significantly mitigate the decrease in creatinine clearance caused by amphotericin B. Furthermore, fenoldopam and SK&F R-105058 can also protect against or delay amphotericin B-induced tubular damage. In contrast, the only clinical trial published until now found that simultaneous continuous intravenous infusion of low dose dopamine (3 μg/kg/min had no beneficial effect on the incidence, severity and time onset of developing amphotericin B-induced nephrotoxicity in autologous bone marrow transplant and leukemia patients. Considering the lack of beneficial effects in different settings such as acute kidney injury of any cause, negative results of the only clinical trial, and risk of significant adverse reactions, continuous intravenous infusion of low dose dopamine (1-3 μg/kg/min or selective dopamine receptor type 1 agonists (e.g., fenoldopam currently appears to have no promising clinical role in preventing or attenuating

  10. Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels.

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    Xiao-Fei Gao

    Full Text Available (+-SKF 10047 (N-allyl-normetazocine is a prototypic and specific sigma-1 receptor agonist that has been used extensively to study the function of sigma-1 receptors. (+-SKF 10047 inhibits K(+, Na(+ and Ca2+ channels via sigma-1 receptor activation. We found that (+-SKF 10047 inhibited Na(V1.2 and Na(V1.4 channels independently of sigma-1 receptor activation. (+-SKF 10047 equally inhibited Na(V1.2/1.4 channel currents in HEK293T cells with abundant sigma-1 receptor expression and in COS-7 cells, which barely express sigma-1 receptors. The sigma-1 receptor antagonists BD 1063,BD 1047 and NE-100 did not block the inhibitory effects of (+-SKF-10047. Blocking of the PKA, PKC and G-protein pathways did not affect (+-SKF 10047 inhibition of Na(V1.2 channel currents. The sigma-1 receptor agonists Dextromethorphan (DM and 1,3-di-o-tolyl-guanidine (DTG also inhibited Na(V1.2 currents through a sigma-1 receptor-independent pathway. The (+-SKF 10047 inhibition of Na(V1.2 currents was use- and frequency-dependent. Point mutations demonstrated the importance of Phe(1764 and Tyr(1771 in the IV-segment 6 domain of the Na(V1.2 channel and Phe(1579 in the Na(V1.4 channel for (+-SKF 10047 inhibition. In conclusion, our results suggest that sigma-1 receptor agonists directly inhibit Na(V1.2/1.4 channels and that these interactions should be given special attention for future sigma-1 receptor function studies.

  11. Metabolic markers following beta-adrenoceptor agonist infusion in footshock-stressed rats

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    J.L. Verago

    2001-09-01

    Full Text Available Stress hormones can alter metabolic functions in adipose tissue and liver, as well as the sensitivity of rat white adipocytes and rat atrial responses to ß-adrenergic agonists. In this study, we examined the effects of three daily footshock stress sessions on the plasma corticosterone, glucose, glycerol and triacylglycerol levels of fed, conscious male rats, and on the plasma glucose, glycerol and triacylglycerol levels of the same rats following iv infusions of ß-adrenergic agonists (isoproterenol: 0.4 nmol kg-1 min-1, noradrenaline: 5.0 µg kg-1 day-1, and BRL 37344 ([±]-[4-(2-[(2-[3-chlorophenyl]-2-hydroxyethylamino]propylphenoxy]acetic acid, a selective ß3-adrenoceptor agonist: 0.4 nmol kg-1 min-1. Plasma corticosterone levels increased significantly after each stress session, while triacylglycerol levels increased after the first session and glucose increased after the second and third sessions. Glycerol levels were unaltered after stress. These results suggest that repeated footshock stress may induce a metabolic shift from triacylglycerol biosynthesis to glucose release by hepatic tissue, with glycerol serving as one of the substrates in both pathways. Stressed rats were more sensitive to infusion of noradrenaline plus prazosin and to infusion of isoproterenol, with elevated plasma glucose, glycerol and triacylglycerol levels. The higher sensitivity of stressed rats to isoproterenol and noradrenaline was probably related to the permissive effect of plasma corticosterone. Only BRL 37344 increased plasma glycerol levels in stressed rats, probably because ß3-adrenoceptors are not involved in hepatic triacylglycerol synthesis, thus allowing glycerol to accumulate in plasma.

  12. Liver X receptors agonists impede hepatitis C virus infection in an Idol-dependent manner.

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    Zeng, Jing; Wu, Yang; Liao, Qingjiao; Li, Lixia; Chen, Xinwen; Chen, Xulin

    2012-09-01

    Hepatitis C virus (HCV) is a major human pathogen that causes many serious diseases, including acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. Treatments for this virus are inadequate, and improved antiviral therapies are necessary. Although the precise mechanisms regulating HCV entry into hepatic cells are still unknown, the low-density lipoprotein receptor (LDLR) has been shown to be essential for entry of infectious HCV particles. Liver X receptors (LXR) were recently reported to control LDLR expression through the regulation of the expression of the Idol (inducible degrader of the LDLR) protein, which could trigger the ubiquitination and degradation of LDLR. In this study, we analyzed the antiviral effect of Idol in vitro. The results demonstrated that Huh7.5.1 cells that exogenously expressed Idol were resistant to HCV infection. Next, the treatment of HCV-infected Huh7.5.1 cells with either synthetic LXR agonists (GW3965 or T0901317) or the natural LXR ligand 24(S),25-epoxycholesterol inhibited HCV infection in a dose-dependent manner. Furthermore, a combination of LXR agonists and HCV RNA replication inhibitors exerted additive effects against HCV, as revealed by isobologram analysis. In conclusion, our data indicate that molecules such as LXR agonists, which could stimulate the expression of Idol, represent a new class of potential anti-HCV compounds, and these compounds could be developed for therapeutic use against HCV infection, either as a monotherapy, or in combination with other anti-HCV drugs. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist

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    Doi, Seira; Mori, Tomohisa; Uzawa, Naoki; Arima, Takamichi; Takahashi, Tomoyuki; Uchida, Masashi; Yawata, Ayaka; Narita, Michiko; Uezono, Yasuhito; Suzuki, Tsutomu

    2016-01-01

    Background Methadone is a unique µ-opioid receptor agonist. Although several researchers have insisted that the pharmacological effects of methadone are mediated through the blockade of NMDA receptor, the underlying mechanism by which methadone exerts its distinct pharmacological effects compared to those of other µ-opioid receptor agonists is still controversial. In the present study, we further investigated the pharmacological profile of methadone compared to those of fentanyl and morphine as measured mainly by the discriminative stimulus effect and in vitro assays for NMDA receptor binding, µ-opioid receptor-internalization, and µ-opioid receptor-mediated β-arrestin recruitment. Results We found that fentanyl substituted for the discriminative stimulus effects of methadone, whereas a relatively high dose of morphine was required to substitute for the discriminative stimulus effects of methadone in rats. Under these conditions, the non-competitive NMDA receptor antagonist MK-801 did not substitute for the discriminative stimulus effects of methadone. In association with its discriminative stimulus effect, methadone failed to displace the receptor binding of MK801 using mouse brain membrane. Methadone and fentanyl, but not morphine, induced potent µ-opioid receptor internalization accompanied by the strong recruitment of β-arrestin-2 in µ-opioid receptor-overexpressing cells. Conclusions These results suggest that methadone may, at least partly, produce its pharmacological effect as a β-arrestin-biased µ-opioid receptor agonist, similar to fentanyl, and NMDA receptor blockade is not the main contributor to the pharmacological profile of methadone. PMID:27317580

  14. Regression of cardiac valvulopathy related to ergot-derived dopamine agonists.

    Science.gov (United States)

    Zanettini, Renzo; Antonini, Angelo; Gatto, Gemma; Gentile, Rosa; Tesei, Silvana; Pezzoli, Gianni

    2011-12-01

    In a previous echocardiographic prevalence study we reported a significant increase in the frequency of heart valve regurgitation in patients with Parkinson's disease taking the ergot-derived dopamine agonists pergolide and cabergoline versus controls. We followed-up our original cohort of patients to ascertain whether valvulopathy regressed after discontinuation of treatment and/or its incidence increased over time. Prospective follow-up of 101 patients treated with ergot-derived dopamine agonists included in the prevalence study: 53 given pergolide and 48 cabergoline (64% male; 66.4 ± 8.7 years of age, 11.5 ± 5.9 years of disease, 21.8 ± 5.9 months of follow-up); 55 stopped treatment while 46 continued. The main outcomes measures, were: echocardiographic quantification of regurgitant valve disease, abnormal leaflet, or cusp thickening and measurement of mitral valve tenting area. Valve abnormalities regressed in about one third of patients with significant multivalvular and in about half of the patients with monovalvular regurgitation who withdrew; no progression was observed in remaining patients. Patients continuing ergot-derived dopamine agonists showed progression of cardiac valvulopathy: seven new cases with three to four regurgitation grade of any valve occurred during follow-up; this regarded also patients who had been on pergolide for many years. Owing to the persistence of risk of heart valve damage over time and the lack of its mid-term reversibility in many patients, we believe that pergolide and cabergoline should be prescribed only when therapeutic alternatives with a better risk/benefit ratio are unavailable and the patient has access to echocardiography. © 2010 Blackwell Publishing Ltd.

  15. A selective beta2-adrenergic agonist, terbutaline, improves sepsis-induced diaphragmatic dysfunction in the rat.

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    Ito, Tetsuo; Fujimura, Naoyuki; Omote, Keiichi; Namiki, Akiyoshi

    2006-07-24

    Sepsis causes diaphragmatic dysfunction, which can lead to the development of respiratory failure. We previously reported that isoproterenol, non-selective beta-adrenergic agonist, improved contractility of the diaphragm in a septic rat model. Since beta(2)-adrenoceptor agonists are widely used in the treatment of chronic respiratory disease, we investigated the effect of terbutaline, a selective beta(2)-adrenergic agonist, on contractility of the septic rat diaphragm and the contribution of intracellular Ca(2+) to the effect of terbutaline in vitro. Forty-eight rats were divided into a sham group (in which sham laparotomy was performed) and a CLP group (in which peritonitis was induced by cecal ligation and perforation). The left hemidiaphragm was removed at 16 h after the operation. The effect of terbutaline (10(-)(6) M) on contractility of the diaphragm was assessed by twitch characteristics (twitch tension, contraction time and contraction velocity) and force-frequency relationship. In addition, to investigate the role of calcium ions in the effect of terbutaline on contractility of the diaphragm, contractility of the diaphragm was assessed after the pre-incubation of the diaphragm with methoxy-verapamil (10(-)(5) M), Ca(2+)-free Krebs-Ringer's solution buffered with 2 mM of ethylene glycol tetra-acetic acid (EGTA), and ryanodine (10(-)(6) M). Terbutaline significantly improved twitch characteristics and force-frequency relationship of the diaphragm in the CLP group (P<0.01). Incubation with methoxy-verapamil or calcium-free solution with EGTA did not show any changes in the inotropic effect of terbutaline in the CLP group. However, incubation with ryanodine completely abolished the inotropic effect of terbutaline in the CLP group. The present study demonstrated that terbutaline increased contractility of the diaphragm in the septic rats. Since this inotropic effect was abolished by ryanodine administration, calcium release from the sarcoplasmic reticulum may

  16. Progenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion.

    Science.gov (United States)

    Riddell, Natalie E; Burns, Victoria E; Wallace, Graham R; Edwards, Kate M; Drayson, Mark; Redwine, Laura S; Hong, Suzi; Bui, Jack C; Fischer, Johannes C; Mills, Paul J; Bosch, Jos A

    2015-10-01

    Stimuli that activate the sympathetic nervous system, such as acute psychological stress, rapidly invoke a robust mobilization of lymphocytes into the circulation. Experimental animal studies suggest that bone marrow-derived progenitor cells (PCs) also mobilize in response to sympathetic stimulation. Here we tested the effects of acute psychological stress and brief pharmacological β-adrenergic (βAR) stimulation on peripheral PC numbers in humans. In two studies, we investigated PC mobilization in response to an acute speech task (n=26) and βAR-agonist (isoproterenol) infusion (n=20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the βAR-antagonist propranolol. Flow cytometry was used to enumerate lymphocyte subsets, total progenitor cells, total haematopoietic stem cells (HSC), early HSC (multi-lineage potential), late HSC (lineage committed), and endothelial PCs (EPCs). Both psychological stress and βAR-agonist infusion caused the expected mobilization of total monocytes and lymphocytes and CD8(+) T lymphocytes. Psychological stress also induced a modest, but significant, increase in total PCs, HSCs, and EPC numbers in peripheral blood. However, infusion of a βAR-agonist did not result in a significant change in circulating PCs. PCs are rapidly mobilized by psychological stress via mechanisms independent of βAR-stimulation, although the findings do not exclude βAR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress-induced PC mobilization seems warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Selectivity optimization of substituted 1,2,3-triazoles as α7 nicotinic acetylcholine receptor agonists.

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    Arunrungvichian, Kuntarat; Fokin, Valery V; Vajragupta, Opa; Taylor, Palmer

    2015-08-19

    Three series of substituted anti-1,2,3-triazoles (IND, PPRD, and QND), synthesized by cycloaddition from azide and alkyne building blocks, were designed to enhance selectivity and potency profiles of a lead α7 nicotinic acetylcholine receptor (α7-nAChR) agonist, TTIn-1. Designed compounds were synthesized and screened for affinity by a radioligand binding assay. Their functional characterization as agonists and antagonists was performed by fluorescence resonance energy transfer assay using cell lines expressing transfected cDNAs, α7-nAChRs, α4β2-nAChRs, and 5HT3A receptors, and a fluorescence cell reporter. In the IND series, a tropane ring of TTIn-1, substituted at N1, was replaced by mono- and bicyclic amines to vary length and conformational flexibility of a carbon linker between nitrogen atom and N1 of the triazole. Compounds with a two-carbon atom linker optimized binding with Kd's at the submicromolar level. Further modification at the hydrophobic indole of TTIn-1 was made in PPRD and QND series by fixing the amine center with the highest affinity building blocks in the IND series. Compounds from IND and PPRD series are selective as agonists for the α7-nAChRs over α4β2-nAChRs and 5HT3A receptors. Lead compounds in the three series have EC50's between 28 and 260 nM. Based on the EC50, affinity, and selectivity determined from the binding and cellular responses, two of the leads have been advanced to behavioral studies described in the companion article (DOI: 10.1021/acschemneuro.5b00059).

  18. Adverse reactions of α2-adrenoceptor agonists in cats reported in 2003-2013 in Finland.

    Science.gov (United States)

    Raekallio, Marja R; Virtanen, Marika; Happonen, Irmeli; Vainio, Outi M

    2017-07-01

    To describe suspected adverse drug reactions in cats associated with use of α 2 -adrenoceptor agonists. Retrospective study. A total of 90 cats. Data were collected from reports on adverse reactions to veterinary medicines sent to the Finnish Medicines Agency during 2003-2013. All reports of suspected adverse reactions associated with use of α 2 -adrenoceptor agonists in cats were included. Probable pulmonary oedema was diagnosed based on post mortem or radiological examination, or presence of frothy or excess fluid from the nostrils or trachea. If only dyspnoea and crackles on auscultation were reported, possible pulmonary oedema was presumed. Pulmonary oedema was suspected in 61 cases. Of these cats, 37 were categorised as probable and 24 as possible pulmonary oedema. The first clinical signs had been noted between 1 minute and 2 days (median, 15 minutes) after α 2 -adrenoceptor agonist administration. Many cats probably had no intravenous overhydration when the first clinical signs were detected, as either they presumably had no intravenous cannula or the signs appeared before, during or immediately after cannulation. Of the 61 cats, 43 survived, 14 died and for four the outcome was not clearly stated. Pulmonary oedema is a perilous condition that may appear within minutes of an intramuscular administration of sedative or anaesthetic agent in cats. The symptoms were not caused by intravenous overhydration, at least in cats having no venous cannula when the first clinical signs were detected. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

  19. Effects of Peroxisome Proliferator-Activated Receptor-δ Agonist on Cardiac Healing after Myocardial Infarction.

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    Jeong Rang Park

    Full Text Available Peroxisome proliferator-activated receptor-delta (PPAR-δ-dependent signaling is associated with rapid wound healing in the skin. Here, we investigated the therapeutic effects of PPAR-δ-agonist treatment on cardiac healing in post-myocardial infarction (MI rats. Animals were assigned to the following groups: sham-operated control group, left anterior descending coronary artery ligation (MI group, or MI with administration of the PPAR-δ agonist GW610742 group. GW610742 (1 mg/kg was administrated intraperitoneally after the operation and repeated every 3 days. Echocardiographic data showed no differences between the two groups in terms of cardiac function and remodeling until 4 weeks. However, the degrees of angiogenesis and fibrosis after MI were significantly higher in the GW610742-treated rats than in the untreated MI rats at 1 week following MI, which changes were not different at 2 weeks after MI. Naturally, PPAR-δ expression in infarcted myocardium was highest increased in 3 day after MI and then disappeared in 14 day after MI. GW610742 increased myofibroblast differentiation and transforming growth factor-beta 2 expression in the infarct zone at 7 days after MI. GW610742 also increased bone marrow-derived mesenchymal stem cell (MSC recruitment in whole myocardium, and increased serum platelet-derived growth factor B, stromal-derived factor-1 alpha, and matrix metallopeptidase 9 levels at day 3 after MI. PPAR-δ agonists treatment have the temporal effect on early fibrosis of infarcted myocardium, which might not sustain the functional and structural beneficial effect.

  20. Effect of Agonist and Antagonist on the In Vitro Contractility of Inflamed Vermiform Appendix.

    Science.gov (United States)

    Singh, Phani Bhushan; Tiwary, Pushpakant; Singh, Sanjeev K; Pandey, Ratna; Roy, Atanu; Kar, Amrita Ghosh; Basu, Somprakas; Tiwari, Anil Kumar

    2017-06-01

    Appendicitis poses a great health problem worldwide. Previous studies demonstrated structural damage to neuronal network and interstitial cell of Cajal in appendicitis. Above observations suggest for the alterations in appendicular motility/contractility in appendicitis. But the mechanisms involved in mediating the contractility in inflamed vermiform appendix is not known till date. The present in vitro study was performed to find out the mechanisms responsible for contractility in the inflamed human vermiform appendix. Contractions of the longitudinal muscle strips of inflamed appendix were recorded in vitro at 37±0.5°C. Control contractions were recorded for 30 min after an initial tension of 0.5 gram. Initially dose-response experiments of agonists (acetylcholine, serotonin and histamine) were performed separately and the dose that produced maximum contraction was determined with each agonist. This maximal dose of agonist was used to elicit contractions in next series of experiments before and after pre-treatment with appropriate antagonists like atropine, ondansetron (5-HT 3 antagonist) and chlorpheniramine maleate respectively. Acetylcholine (ACh) and serotonin (5-HT) elicited maximum amplitude of contraction at 10 µM and 1 µM concentration respectively. These contractions were significantly blocked by prior exposure of muscle strips with atropine (100 µM) and ondansetron (10 µM). Histamine produced very low amplitude of contractions in comparison to ACh or 5-HT and did not exhibit dose-response relations. The histamine induced contractions were blocked by H 1 antagonist chlorpheniramine maleate (100 µM). The observations suggested that the contractility of longitudinal muscle strips of inflamed vermiform appendix in human beings was predominantly mediated by muscarinic and serotonergic (5-HT 3 ) mechanisms, whereas, histaminergic mechanisms played a minor role in mediating the contractility.