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  1. Expression profiling in APP23 mouse brain: inhibition of Aβ amyloidosis and inflammation in response to LXR agonist treatment

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    Mangelsdorf David

    2007-10-01

    Full Text Available Abstract Background Recent studies demonstrate that in addition to its modulatory effect on APP processing, in vivo application of Liver X Receptor agonist T0901317 (T0 to APP transgenic and non-transgenic mice decreases the level of Aβ42. Moreover, in young Tg2576 mice T0 completely reversed contextual memory deficits. Compared to other tissues, the regulatory functions of LXRs in brain remain largely unexplored and our knowledge so far is limited to the cholesterol transporters and apoE. In this study we applied T0 to APP23 mice for various times and examined gene and protein expression. We also performed a series of experiments with primary brain cells derived from wild type and LXR knockout mice subjected to various LXR agonist treatments and inflammatory stimuli. Results We demonstrate an upregulation of genes related to lipid metabolism/transport, metabolism of xenobiotics and detoxification. Downregulated genes are involved in immune response and inflammation, cell death and apoptosis. Additional treatment experiments demonstrated an increase of soluble apolipoproteins E and A-I and a decrease of insoluble Aβ. In primary LXRwt but not in LXRα-/-β-/- microglia and astrocytes LXR agonists suppressed the inflammatory response induced by LPS or fibrillar Aβ. Conclusion The results show that LXR agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation. An increased understanding of the LXR controlled regulation of Aβ aggregation and clearance systems will lead to the development of more specific and powerful agonists targeting LXR for the treatment of AD.

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

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    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.

  3. LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone

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    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.

  4. Identification of biological markers of liver X receptor (LXR activation at the cell surface of human monocytes.

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    Cédric Rébé

    Full Text Available BACKGROUND: Liver X receptor (LXR α and LXR β (NR1H3 and NR1H2 are oxysterol-activated nuclear receptors involved in the control of major metabolic pathways such as cholesterol homeostasis, lipogenesis, inflammation and innate immunity. Synthetic LXR agonists are currently under development and could find applications in various fields such as cardiovascular diseases, cancer, diabetes and neurodegenerative diseases. The clinical development of LXR agonists requires the identification of biological markers for pharmacodynamic studies. In this context, monocytes represent an attractive target to monitor LXR activation. They are easily accessible cells present in peripheral blood; they express LXR α and β and respond to LXR agonist stimulation in vitro. The aim of our study was to identify cell surface markers of LXR agonists on monocytes. For this, we focused on clusters of differentiation (CD markers because they are well characterized and accessible cell surface molecules allowing easy immuno-phenotyping. METHODOLOGY/PRINCIPAL FINDINGS: By using microarray analysis of monocytes treated or not with an LXR agonist in vitro, we selected three CD, i.e. CD82, CD226, CD244 for further analysis by real time PCR and flow cytometry. The three CD were up-regulated by LXR agonist treatment in vitro in a time- and dose- dependent manner and this induction was LXR specific as assessed by a SiRNA or LXR antagonist strategy. By using flow cytometry, we could demonstrate that the expression of these molecules at the cell surface of monocytes was significantly increased after LXR agonist treatment. CONCLUSIONS/SIGNIFICANCE: We have identified three new cell surface markers that could be useful to monitor LXR activation. Future studies will be required to confirm the biological and diagnostic significance of the markers.

  5. LXR agonist increases apoE secretion from HepG2 spheroid, together with an increased production of VLDL and apoE-rich large HDL

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    Koike Kazuhiko

    2011-08-01

    Full Text Available Abstract Background The physiological regulation of hepatic apoE gene has not been clarified, although the expression of apoE in adipocytes and macrophages has been known to be regulated by LXR. Methods and Results We investigated the effect of TO901317, a LXR agonist, on hepatic apoE production utilizing HepG2 cells cultured in spheroid form, known to be more differentiated than HepG2 cells in monolayer culture. Spheroid HepG2 cells were prepared in alginate-beads. The secretions of albumin, apoE and apoA-I from spheroid HepG2 cells were significantly increased compared to those from monolayer HepG2 cells, and these increases were accompanied by increased mRNA levels of apoE and apoA-I. Several nuclear receptors including LXRα also became abundant in nuclear fractions in spheroid HepG2 cells. Treatment with TO901317 significantly increased apoE protein secretion from spheroid HepG2 cells, which was also associated with the increased expression of apoE mRNA. Separation of the media with FPLC revealed that the production of apoE-rich large HDL particles were enhanced even at low concentration of TO901317, and at higher concentration of TO901317, production of VLDL particles increased as well. Conclusions LXR activation enhanced the expression of hepatic apoE, together with the alteration of lipoprotein particles produced from the differentiated hepatocyte-derived cells. HepG2 spheroids might serve as a good model of well-differentiated human hepatocytes for future investigations of hepatic lipid metabolism.

  6. Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core.

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    Tice, Colin M; Noto, Paul B; Fan, Kristi Yi; Zhao, Wei; Lotesta, Stephen D; Dong, Chengguo; Marcus, Andrew P; Zheng, Ya-Jun; Chen, Guozhou; Wu, Zhongren; Van Orden, Rebecca; Zhou, Jing; Bukhtiyarov, Yuri; Zhao, Yi; Lipinski, Kerri; Howard, Lamont; Guo, Joan; Kandpal, Geeta; Meng, Shi; Hardy, Andrew; Krosky, Paula; Gregg, Richard E; Leftheris, Katerina; McKeever, Brian M; Singh, Suresh B; Lala, Deepak; McGeehan, Gerard M; Zhuang, Linghang; Claremon, David A

    2016-10-15

    Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aβ) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aβ levels was detected.

  7. Identification of phenylsulfone-substituted quinoxaline (WYE-672) as a tissue selective liver X-receptor (LXR) agonist.

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    Hu, Baihua; Unwalla, Rayomand J; Goljer, Igor; Jetter, James W; Quinet, Elaine M; Berrodin, Thomas J; Basso, Michael D; Feingold, Irene B; Nilsson, Annika Goos; Wilhelmsson, Anna; Evans, Mark J; Wrobel, Jay E

    2010-04-22

    A series of phenyl sulfone substituted quinoxaline were prepared and the lead compound 13 (WYE-672) was shown to be a tissue selective LXR Agonist. Compound 13 demonstrated partial agonism for LXRbeta in kidney HEK-293 cells but did not activate Gal4 LXRbeta fusion proteins in huh-7 liver cells. Although 13 showed potent binding affinity to LXRbeta (IC(50) = 53 nM), it had little binding affinity for LXRalpha (IC(50) > 1.0 microM) and did not recruit any coactivator/corepressor peptides in the LXRalpha multiplex assay. However, compound 13 showed good agonism in THP-1 cells with respect to increasing ABCA1 gene expression and good potency on cholesterol efflux in THP-1 foam cells. In an eight-week lesion study in LDLR -/- mice, compound 13 showed reduction of aortic arch lesion progression and no plasma or hepatic triglyceride increase. These results suggest quinoxaline 13 may have an improved biological profile for potential use as a therapeutic agent.

  8. The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism

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    Jonathan Matalonga

    2017-01-01

    Full Text Available Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.

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

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

    2016-07-01

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

  10. The medicinal chemistry of liver X receptor (LXR) modulators.

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    Tice, Colin M; Noto, Paul B; Fan, Kristi Yi; Zhuang, Linghang; Lala, Deepak S; Singh, Suresh B

    2014-09-11

    LXRs have been of interest as targets for the treatment of atherosclerosis for over a decade. In recent years, LXR modulators have also garnered interest for potential use in the treatment of inflammation, Alzheimer's disease (AD), dermatological conditions, hepatic steatosis, and oncology. To date, no LXR modulator has successfully progressed beyond phase I clinical trials. In this Perspective, we summarize published medicinal chemistry efforts in the context of the available crystallographic data, druglikeness, and isoform selectivity. In addition, we discuss the challenges that need to be overcome before an LXR modulator can reach clinical use.

  11. LXR driven induction of HDL-cholesterol is independent of intestinal cholesterol absorption and ABCA1 protein expression.

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    Kannisto, Kristina; Gåfvels, Mats; Jiang, Zhao-Yan; Slätis, Katharina; Hu, Xiaoli; Jorns, Carl; Steffensen, Knut R; Eggertsen, Gösta

    2014-01-01

    We investigated whether: (1) liver X receptor (LXR)-driven induction of high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal ATP-binding cassette (ABC) A1 or ABCG5 protein expression were observed, despite increased mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal cholesterol levels. GW3965 did not affect the intestinal cholesterol absorption, but increased serum HDL-C and ApoAI levels. GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1-6 cells. Ezetimibe reduced the intestinal cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of cholesterol via NPC1L1 and/or low levels of intracellular cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased mRNA levels. Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol.

  12. Regulation of LXR by fatty acids, insulin, growth hormone and tumor necrosis factor-α in rainbow trout myocytes.

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    Cruz-Garcia, Lourdes; Sánchez-Gurmaches, Joan; Gutiérrez, Joaquim; Navarro, Isabel

    2011-10-01

    The liver X receptor (LXR) has recently been described in salmonids. In mammals, this receptor is already known as a transcriptional factor that regulates diverse aspects of cholesterol, fatty acid and carbohydrate metabolism in various tissues, including muscle. Here we examined LXR in trout myocytes. For this purpose, we analyzed LXR target gene expression and gene profile during myocyte development. In addition, we studied the transcriptional regulation of LXR by hormones, a pro-inflammatory mediator and unsaturated fatty acids. Trout myocytes were incubated with LXR agonists (T091317, 22(R)-hydroxycholesterol) and unsaturated fatty acids for 24h. Furthermore, differentiated myocytes were incubated with insulin and growth hormone (GH) for 3h, 6h and 18h, and with tumor necrosis factor-α (TNFα) for 24h. Samples were also obtained in various stages of cell differentiation. Our results demonstrate that lipoprotein lipase (LPL), fatty acid synthase (FAS), ATP-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-α and β (PPARα, β) are target genes of LXR in trout muscle. LXR agonists increased LXR expression, thereby indicating that this receptor is autoregulated. Unsaturated fatty acids downregulated LXR gene expression. This observation suggests a regulatory mechanism of these molecules on LXR-mediated fatty acid synthesis and uptake. TNFα did not modulate LXR gene transcription. Expression of the LXR gene was activated by insulin and GH. These results suggest that LXR may play a lipogenic role through insulin stimulation and a tendency to promote anabolic effects through GH on trout myocytes.

  13. LXR signaling pathways and atherosclerosis

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    Calkin, Anna; Tontonoz, Peter

    2010-01-01

    First discovered as orphan receptors, liver X receptors (LXRs) were subsequently identified as the nuclear receptor target of the cholesterol metabolites, oxysterols.1 There are 2 LXR receptors encoded by distinct genes: LXRα is most highly expressed in the liver, adipose, kidney, adrenal tissues and macrophages, and LXRβ is ubiquitously expressed. Despite differential tissue distribution, these isoforms have 78% homology in their ligand-binding domain and appear to respond to the same endogenous ligands. Work over the past 10 years has shown that the LXR pathway regulates lipid metabolism and inflammation via both the induction and repression of target genes. Given the importance of cholesterol regulation and inflammation in the development of cardiovascular disease, it is not surprising that activation of the LXR pathway attenuates various mechanisms underlying atherosclerotic plaque development.2 In this minireview we will discuss the impact of the LXR pathway on both cholesterol metabolism and atherosclerosis. PMID:20631351

  14. Fasting-Induced FGF21 Is Repressed by LXR Activation via Recruitment of an HDAC3 Corepressor Complex in Mice

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    Archer, Amena; Venteclef, Nicolas; Mode, Agneta; Pedrelli, Matteo; Gabbi, Chiara; Clément, Karine; Parini, Paolo; Gustafsson, Jan-Åke

    2012-01-01

    The liver plays a pivotal role in the physiological adaptation to fasting and a better understanding of the metabolic adaptive responses may give hints on new therapeutic strategies to control the metabolic diseases. The liver X receptors (LXRs) are well-established regulators of lipid and glucose metabolism. More recently fibroblast growth factor 21 (FGF21) has emerged as an important regulator of energy homeostasis. We hypothesized that the LXR transcription factors could influence Fgf21 expression, which is induced in response to fasting. Wild-type, LXRα−/−, and LXRβ−/− mice were treated for 3 d with vehicle or the LXR agonist GW3965 and fasted for 12 h prior to the killing of the animals. Interestingly, serum FGF21 levels were induced after fasting, but this increase was blunted when the mice were treated with GW3965 independently of genotypes. Compared with wild-type mice, GW3965-treated LXRα−/− and LXRβ−/− mice showed improved insulin sensitivity and enhanced ketogenic response at fasting. Of note is that during fasting, GW3965 treatment tended to reduce liver triglycerides as opposed to the effect of the agonist in the fed state. The LXR-dependent repression of Fgf21 seems to be mainly mediated by the recruitment of LXRβ onto the Fgf21 promoter upon GW3965 treatment. This repression by LXRβ occurs through the recruitment and stabilization of the repressor complex composed of retinoid-related orphan receptor-α/Rev-Erbα/histone deacetylase 3 onto the Fgf21 promoter. Our data clearly demonstrate that there is a cross talk between the LXR and FGF21 signaling pathways in the adaptive response to fasting. PMID:23073827

  15. CCAAT/enhancer binding protein {beta} deletion increases mitochondrial function and protects mice from LXR-induced hepatic steatosis

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    Rahman, Shaikh M., E-mail: rmizanoor@hotmail.com [Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, CO 80045 (United States); Choudhury, Mahua; Janssen, Rachel C.; Baquero, Karalee C. [Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, CO 80045 (United States); Miyazaki, Makoto [Division of Renal Diseases and Hypertension, School of Medicine, University of Colorado Denver, Aurora, CO 80045 (United States); Friedman, Jacob E. [Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, CO 80045 (United States); Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, Aurora, CO 80045 (United States)

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer LXR agonist activation increases liver TG accumulation by increasing lipogenesis. Black-Right-Pointing-Pointer C/EBP{beta}{sup -/-} mouse prevents LXR activation-mediated induction of hepatic lipogenesis. Black-Right-Pointing-Pointer C/EBP{beta} deletion increases mitochondrial transport chain function. Black-Right-Pointing-Pointer Beneficial effects of LXR activation on liver cholesterol metabolism did not change. Black-Right-Pointing-Pointer C/EBP{beta} inhibition might have important therapeutic potential. -- Abstract: Drugs designed specifically to activate liver X receptors (LXRs) have beneficial effects on lowering cholesterol metabolism and inflammation but unfortunately lead to severe hepatic steatosis. The transcription factor CCAAT/enhancer binding protein beta (C/EBP{beta}) is an important regulator of liver gene expression but little is known about its involvement in LXR-based steatosis and cholesterol metabolism. The present study investigated the role of C/EBP{beta} expression in LXR agonist (T0901317)-mediated alteration of hepatic triglyceride (TG) and lipogenesis in mice. C/EBP{beta} deletion in mice prevented LXR agonist-mediated induction of lipogenic gene expression in liver in conjunction with significant reduction of liver TG accumulation. Surprisingly, C/EBP{beta}{sup -/-} mice showed a major increase in liver mitochondrial electron chain function compared to WT mice. Furthermore, LXR activation in C/EBP{beta}{sup -/-} mice increased the expression of liver ATP-binding cassette transporter ABCG1, a gene implicated in cholesterol efflux and reducing blood levels of total and LDL-cholesterol. Together, these findings establish a central role for C/EBP{beta} in the LXR-mediated steatosis and mitochondrial function, without impairing the influence of LXR activation on lowering LDL and increasing HDL-cholesterol. Inactivation of C/EBP{beta} might therefore be an important therapeutic strategy to prevent LXR

  16. A systems biology approach to the hepatic role of the oxysterol receptor LXR in the regulation of lipogenesis highlights a cross-talk with PPARα.

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    Ducheix, Simon; Podechard, Normand; Lasserre, Frédéric; Polizzi, Arnaud; Pommier, Aurélien; Murzilli, Stefania; Di Lisio, Chiara; D'Amore, Simona; Bertrand-Michel, Justine; Montagner, Alexandra; Pineau, Thierry; Loiseau, Nicolas; Lobaccaro, Jean-Marc; Martin, Pascal G P; Guillou, Hervé

    2013-03-01

    The Liver X Receptors (LXRs) α and β and the Peroxisome Proliferator-Activated Receptor α (PPARα) are transcription factors that belong to class II nuclear receptors. They drive the expression of genes involved in hepatic lipid homeostasis and therefore are important targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). LXRs and PPARα are regulated by endogenous ligands, oxysterols and fatty acid derived molecules, respectively. In the liver, pharmacological activation of LXRs leads to the over-expression of genes involved in de novo lipogenesis, while PPARα is critical for fatty acid catabolism in nutrient deprivation. Even if these two nuclear receptors seemed to play opposite parts, recent studies have highlighted that PPARα also influence the expression of genes involved in fatty acids synthesis. In this study, we used pharmacological approaches and genetically engineered mice to investigate the cross-talk between LXRs and PPARα in the regulation of genes responsible for lipogenesis. We first investigated the effect of T0901317 and fenofibrate, two synthetic agonists of LXRs and PPARα, respectively. As expected, T0901317 and fenofibrate induce expression of genes involved LXR-dependent and PPARα-dependent lipogenic responses. Considering such overlapping effect, we then tested whether LXR agonist may influence PPARα driven response and vice versa. We show that the lack of PPARα does not influence the effects of T0901317 on lipogenic genes expression. However, PPARα deficiency prevents the up-regulation of genes involved in ω-hydroxylation that are induced by the LXR agonist. In addition, over-expression of lipogenic genes in response to fenofibrate is decreased in LXR knockout mice as well as the expression of PPARα target genes involved in fatty acid oxidation. Altogether, our work provides in vivo evidence for a central interconnection between nuclear receptors that drive hepatic lipid metabolism in response to

  17. 肝X受体激动剂上调人肾小球内皮细胞血栓调节蛋白表达的机制和作用%Mechanism and role of LXR agonist upregulating thrombo-modulin expression in human glomerular endothelial cells

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    丁涵露; 李怡; 冯韵霖; 陈瑾; 钟翔; 王楠; 汪伟; 张萍; 王莉

    2016-01-01

    目的:探讨肝X受体(LXR)激动剂T0901317上调人肾小球内皮细胞(HRGEC)血栓调节蛋白(TM)表达的机制和作用。方法 Western blot检测25 mmol高糖和2μmol T0901317刺激后的HRGEC上IκBα、磷酸化IκBα、核转录因子-κB(NF-κB)p65、磷酸化NF-κB p65表达;免疫共沉淀法检测LXR与P300之间有无结合;重组腺病毒AdTMshRNA转染HRGEC,观察其对高糖下HRGEC分泌炎症介质的影响。结果T0901317能显著降低高糖刺激后的IκBα和NF-κB p65磷酸化(0.05)。结论LXR可能通过与P300发生相互作用阻断了NF-κB与P300之间的竞争性结合而提高TM的表达并抑制炎症介质的分泌。%Objective To explore the effect of liver X receptor (LXR) agonist T0901317 on thrombomodulin (TM) expression in human glomerular endothelial cells (HUGECs) and its mechanism. Methods Western blot was used to detect the expressions of IκBα, p-IκBα, nuclear transcription factor-κB (NF-κβ) p65 and p-NF-κB p65 in HUGECs stimulated by 25 mmol high glucose and 2μmol T0901317. The interaction between LXR and the transcriptional coactivator p300 in HUGECs was detected using co-immunoprecipitation (Co-IP) assay. The concentrations of IL-1β and TNF-α in the supernatant of HUGECs transfected with or without AdTMshRNA were determined using commercially available ELISA kits. Results T0901317 (2 μmol) significantly reduced the phosphorylation of IκBα and NF-κB p65 in the HUGECs stimulated by high glucose ( 0.05). Conclusions LXR agonist increases TM expression and inhibits secretion of inflammatory mediators probably by competitively blocking the interaction between NF-κB and p300 through interaction with p300.

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

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

    2016-04-14

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

  19. Effect of LXR/RXR agonism on brain and CSF Aβ40 levels in rats [version 2; referees: 1 approved, 2 approved with reservations

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    Songli Wang

    2016-04-01

    Full Text Available Alzheimer's disease (AD is characterized pathologically by the presence of amyloid plaques and neurofibrillary tangles. The amyloid hypothesis contends that the abnormal accumulation of Aβ, the principal component of amyloid plaques, plays an essential role in initiating the disease. Impaired clearance of soluble Aβ from the brain, a process facilitated by apolipoprotein E (APOE, is believed to be a contributing factor in plaque formation. APOE expression is transcriptionally regulated through the action of a family of nuclear receptors including the peroxisome proliferator-activated receptor gamma and liver X receptors (LXRs in coordination with retinoid X receptors (RXRs. It has been previously reported that various agonists of this receptor family can influence brain Aβ levels in rodents. In this study we investigated the effects of LXR/RXR agonism on brain and cerebrospinal fluid (CSF levels of Aβ40 in naïve rats. Treatment of rats for 3 days or 7 days with the LXR agonist, T0901317 or the RXR agonist, bexarotene did not result in significant changes in brain or CSF Aβ40 levels.

  20. Sterol-dependent nuclear import of ORP1S promotes LXR regulated trans-activation of apoE

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    Lee, Sungsoo, E-mail: sungsoo.lee@utsouthwestern.edu [Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039 (United States); Wang, Ping-Yuan [Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039 (United States); Jeong, Yangsik; Mangelsdorf, David J. [Departments of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041 (United States); Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041 (United States); Anderson, Richard G.W. [Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039 (United States); Michaely, Peter, E-mail: peter.michaely@utsouthwestern.edu [Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039 (United States)

    2012-10-01

    Oxysterol binding protein related protein 1S (ORP1S) is a member of a family of sterol transport proteins. Here we present evidence that ORP1S translocates from the cytoplasm to the nucleus in response to sterol binding. The sterols that best promote nuclear import of ORP1S also activate the liver X receptor (LXR) transcription factors and we show that ORP1S binds to LXRs, promotes binding of LXRs to LXR response elements (LXREs) and specifically enhances LXR-dependent transcription via the ME.1 and ME.2 enhancer elements of the apoE gene. We propose that ORP1S is a cytoplasmic sterol sensor, which transports sterols to the nucleus and promotes LXR-dependent gene transcription through select enhancer elements. -- Highlights: Black-Right-Pointing-Pointer ORP1S translocates to the nucleus in response to sterol binding. Black-Right-Pointing-Pointer The sterols that best promote nuclear import of ORP1S are LXR agonists. Black-Right-Pointing-Pointer ORP1S binds to LXRs, enhances binding of LXRs to LXREs and promotes LXR-dependent transcription of apoE.

  1. LXR/RXR ligand activation enhances basolateral efflux of beta-sitosterol in CaCo-2 cells.

    Science.gov (United States)

    Field, F Jeffrey; Born, Ella; Mathur, Satya N

    2004-05-01

    To examine whether intestinal ABCA1 was responsible for the differences observed between cholesterol and beta-sitosterol absorption, ABCA1-facilitated beta-sitosterol efflux was investigated in CaCo-2 cells following liver X receptor/retinoid X receptor (LXR/RXR) activation. Both the LXR agonist T0901317 and the natural RXR/LXR agonists 22-hydroxycholesterol and 9-cis retinoic acid enhanced the basolateral efflux of beta-sitosterol without altering apical efflux. LXR-mediated enhanced beta-sitosterol efflux occurred between 6 h and 12 h after activation, suggesting that transcription, protein synthesis, and trafficking was likely necessary prior to facilitating efflux. The transcription inhibitor actinomycin D prevented the increase in beta-sitosterol efflux by T0901317. Glybenclamide, an inhibitor of ABCA1 activity, and arachidonic acid, a fatty acid that interferes with LXR activation, also prevented beta-sitosterol efflux in response to the LXR ligand activation. Influx of beta-sitosterol mass did not alter the basolateral or apical efflux of the plant sterol, nor did it alter ABCA1, ABCG1, ABCG5, or ABCG8 gene expression or ABCA1 mass. Similar to results observed with intestinal ABCA1-facilitated cholesterol efflux, LXR/RXR ligand activation enhanced the basolateral efflux of beta-sitosterol without affecting apical efflux. The results suggest that ABCA1 does not differentiate between cholesterol and beta-sitosterol and thus is not responsible for the selectivity of sterol absorption by the intestine. ABCA1, however, may play a role in beta-sitosterol absorption.

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

    Science.gov (United States)

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

    2011-12-01

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

  3. Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids.

    Science.gov (United States)

    Cruz-Garcia, Lourdes; Schlegel, Amnon

    2014-09-01

    Liver X receptors (Lxrs) are master regulators of cholesterol catabolism, driving the elimination of cholesterol from the periphery to the lumen of the intestine. Development of pharmacological agents to activate Lxrs has been hindered by synthetic Lxr agonists' induction of hepatic lipogenesis and hypertriglyceridemia. Elucidating the function of Lxrs in regulating enterocyte lipid handling might identify novel aspects of lipid metabolism that are pharmacologically amenable. We took a genetic approach centered on the single Lxr gene nr1h3 in zebrafish to study the role of Lxr in enterocyte lipid metabolism. Loss of nr1h3 function causes anticipated gene regulatory changes and cholesterol intolerance, collectively reflecting high evolutionary conservation of zebrafish Lxra function. Intestinal nr1h3 activation delays transport of absorbed neutral lipids, with accumulation of neutral lipids in enterocyte cytoplasmic droplets. This delay in transport of ingested neutral lipids protects animals from hypercholesterolemia and hepatic steatosis induced by a high-fat diet. On a gene regulatory level, Lxra induces expression of acsl3a, which encodes acyl-CoA synthetase long-chain family member 3a, a lipid droplet-anchored protein that directs fatty acyl chains into lipids. Forced overexpression of acls3a in enterocytes delays, in part, the appearance of neutral lipids in the vasculature of zebrafish larvae. Activation of Lxr in the intestine cell-autonomously regulates the rate of delivery of absorbed lipids by inducting a temporary lipid intestinal droplet storage depot.

  4. Susceptibility of pancreatic beta cells to fatty acids is regulated by LXR/PPARalpha-dependent stearoyl-coenzyme A desaturase.

    Directory of Open Access Journals (Sweden)

    Karine H Hellemans

    Full Text Available Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARalpha-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRbeta(-/- and LXRalphabeta(-/-, beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARalpha agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARalpha agonists favors their desaturation and subsequent incorporation in neutral lipids.

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

    Science.gov (United States)

    Lepor, Herbert; Shore, Neal D

    2012-01-01

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

  6. Lxrα regulates the androgen response in prostate epithelium.

    Science.gov (United States)

    Viennois, Emilie; Esposito, Teresa; Dufour, Julie; Pommier, Aurélien; Fabre, Stephane; Kemeny, Jean-Louis; Guy, Laurent; Morel, Laurent; Lobaccaro, Jean-Marc; Baron, Silvère

    2012-07-01

    Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.

  7. Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Xiaolin [Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200032 (China); Li, Qian [Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai (China); Pang, Liewen; Huang, Guoqian; Huang, Jiechun; Shi, Meng; Sun, Xiaotian [Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200032 (China); Wang, Yiqing, E-mail: yiqingwangbiopaper@163.com [Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200032 (China)

    2013-11-15

    Highlights: •Arctigenin enhanced cholesterol efflux in oxLDL-loaded THP-1 macrophages. •The expression of ABCA1, ABCG1 and apoE was upregulated in arctigenin-treated cells. •Arctigenin promoted the expression of PPAR-γ and LXR-α. •Inhibition of PPAR-γ or LXR-α reversed arctigenin-mediated biological effects. •Arctigenin promotes cholesterol efflux via activation of PPAR-γ/LXR-α/ABCA1 pathway. -- Abstract: Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-γ or LXR-α using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-γ and LXR-α.

  8. 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

  9. Ramelteon: A melatonin receptor agonist for the treatment of insomnia

    Directory of Open Access Journals (Sweden)

    Devi V

    2008-01-01

    Full Text Available Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for the treatment of insomnia characterized by difficulty in sleep onset. It is a nonscheduled drug since it lacks the potential for abuse and does not interact with neurotransmitter receptors most associated with these phenomena. Although the effects of ramelteon use> 5 weeks are unknown, the available data confirms its safety and efficacy for short-term use. Clinical use and future research should uncover more information about ramelteon′s properties.

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

    Science.gov (United States)

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

    2015-01-01

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

  11. Effects of Liver × receptor agonist treatment on signal transduction pathways in acute lung inflammation

    Directory of Open Access Journals (Sweden)

    Bramanti Placido

    2010-02-01

    Full Text Available Abstract Background Liver × receptor α (LXRα and β (LXRβ are members of the nuclear receptor super family of ligand-activated transcription factors, a super family which includes the perhaps better known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. There is limited evidence that LXL activation may reduces acute lung inflammation. The aim of this study was to investigate the effects of T0901317, a potent LXR receptor ligand, in a mouse model of carrageenan-induced pleurisy. Methods Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx, tumor necrosis factor-α, (TNF-α and interleukin-1β (IL-1β. Furthermore, carrageenan induced the expression of iNOS, nitrotyrosine and PARP, as well as induced apoptosis (TUNEL staining and Bax and Bcl-2 expression in the lung tissues. Results Administration of T0901317, 30 min after the challenge with carrageenan, caused a significant reduction in a dose dependent manner of all the parameters of inflammation measured. Conclusions Thus, based on these findings we propose that LXR ligand such as T0901317, may be useful in the treatment of various inflammatory diseases.

  12. Liver X receptor agonist T0901317 reduces atherosclerotic lesions in apoE-/- mice by up-regulating NPC1 expression

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    In this study, we studied the effect of liver X receptor (LXR) agonist T0901317 on Niemann-Pick C1 protein (NPC1) expression in apoE-/- mice. Male apoE-/- mice were randomized into 4 groups, baseline group (n=10), control group (n=14), treatment group (n=14) and prevention group (n=14). All of the mice were fed with a high-fat/high-cholesterol (HFHC) diet containing 15% fat and 0.25% cholesterol. The baseline group treated with vehicle was sacrificed after 8 weeks of the diet. The control group and the prevention group were treated with either vehicle or T0901317 daily by oral gavage for 14 weeks. The treatment group was treated with vehicle for 8 weeks, and then was treated with the agonist T0901317 for additional 6 weeks. Gene and protein expression was analyzed by real-time quantitative PCR, immunohistochemistry and Western blotting, respectively. Plasma lipid concentrations were measured by commercially enzymatic methods. We used RNA interference technology to silence NPC1 gene expression in THP-1 macrophage-derived foam cells and then detected the effect of LXR agonist T0901317 on cholesterol efflux. Plasma triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and apoA-I concentrations were markedly increased in T0901317-treated groups. T0901317 treatment reduced the aortic atherosclerotic lesion area by 64.2% in the prevention group and 58.3% in the treatment group. LXR agonist treatment increased NPC1 mRNA expression and protein levels in the small intestine, liver and aorta of apoE-/- mice. Compared with the normal cells, cholesterol efflux of siRNA THP-1 macrophage-derived foam cells was significantly decreased, whereas cholesterol efflux of LXR agonist T0901317-treated THP-1 macrophage-derived foam cells was significantly increased. Our results suggest that LXR agonist T0901317 inhibits atherosclerosis development in apoE-/- mice, which is related to up-regulating NPC1 expression.

  13. 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...

  14. Dopamine Agonist in Treatment of ADHD with Restless Legs Syndrome and ODD

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-05-01

    Full Text Available A 6-year-old male with attention deficit hyperactivity disorder who responded poorly to methylphenidate (MPH was benefited following treatment with the dopamine agonist ropinirole, in a report from the Hopital Robert Debre, Paris, France.

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

    Science.gov (United States)

    Kulka, P J

    1996-04-25

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

  16. Melatonin agonists for treatment of sleep and depressive disorders

    Directory of Open Access Journals (Sweden)

    Seithikurippu R. Pandi-Perumal

    2011-06-01

    Full Text Available Melatonin the hormone secreted by the pineal gland has been effective in improving sleep both in normal sleepers and insomniacs and has been used successfully in treating sleep and circadian rhythm sleep disorders. The lack of consistency in the reports published by the authors is attributed to the differential bioavailabilty and short half-life of melatonin. Sleep disturbances are also prominent features of depressive disorders. To overcome this problem, melatonergic agonists with sleep promoting properties have been introduced in clinical practice. Ramelteon, the MT1/ MT2 melatonergic agonist, has been used in a large number of clinical trials involving chronic insomniacs and has been found effective in improving the total sleep time and sleep efficiency of insomniacs and has not manifested serious adverse effects. The development of another MT1/MT2 melatonergic agonist agomelatine with antagonsim to 5-HT2c serotonin receptors has been found useful not only in treating sleep problems of patients but also as a first line antidepressant with earlier onset of actions in patients with major depressive disorder. An agonist for MT3 melatonin receptor has also been found effective in animal models of depression. [J Exp Integr Med 2011; 1(3.000: 149-158

  17. Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway.

    Science.gov (United States)

    Xu, Xiaolin; Li, Qian; Pang, Liewen; Huang, Guoqian; Huang, Jiechun; Shi, Meng; Sun, Xiaotian; Wang, Yiqing

    2013-11-15

    Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-γ or LXR-α using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-γ and LXR-α.

  18. PPAR GAMMA AGONISTS: AN EFFECTIVE STRATEGY FOR CANCER TREATMENT

    Directory of Open Access Journals (Sweden)

    Divya G.S

    2013-10-01

    Full Text Available PPAR-γ regulates cellular differentiation, development and metabolism. They play these essential roles by functioning as transcription factors regulating the expression of genes. The PPARs mainly are of three types α, β and γ. The PPAR-γ expressed in three forms γ1, γ2 and γ3 present in different tissues. When PPAR binds its ligand, transcription of target gene is increased or decreased. Tzds were able to induce cell differentiation and apoptosis or inhibit cell proliferation both in vitro and in vivo. However, widespread use of thiazolidinediones (TZDs, the clinically used synthetic PPAR gamma agonists, has been limited by adverse effects. So in this review we are suggesting some new molecules other than thiazolidine diones which can act as potential anticancer agents, after explaining the mechanism of action of PPAR-γ agonists as anticancer agents especially thiazolidinediones.

  19. Cloning and Characterization of Lxr and Srebp1, and Their Potential Roles in Regulation of LC-PUFA Biosynthesis in Rabbitfish Siganus canaliculatus.

    Science.gov (United States)

    Zhang, Qinghao; You, Cuihong; Liu, Fang; Zhu, Wendi; Wang, Shuqi; Xie, Dizhi; Monroig, Óscar; Tocher, Douglas R; Li, Yuanyou

    2016-09-01

    Rabbitfish Siganus canaliculatus was the first marine teleost demonstrated to have the ability to biosynthesize C20-22 long-chain polyunsaturated fatty acid (LC-PUFA) from C18 PUFA precursors, which is generally absent or low in marine teleosts. Thus, understanding the molecular basis of LC-PUFA biosynthesis in rabbitfish will contribute to efforts aimed at optimizing LC-PUFA biosynthesis in teleosts, especially marine species. In the present study, the importance of the transcription factors liver X receptor (Lxr) and sterol regulatory element-binding protein 1 (Srebp1) in regulation of LC-PUFA biosynthesis in rabbitfish was investigated. First, full-length cDNA of Lxr and Srebp1 were cloned and characterized. The Lxr mRNA displayed a ubiquitous tissue expression pattern while Srebp1 was highly expressed in eyes, brain and intestine. In rabbitfish primary hepatocytes treated with Lxr agonist T0901317, the expression of Lxr and Srebp1 was activated, accompanied by elevated mRNA levels of Δ4 and Δ6/Δ5 fatty acyl desaturase (Fad), key enzymes of LC-PUFA biosynthesis, as well as peroxisome proliferator-activated receptor γ (PPARγ). In addition, Srebp1 displayed higher expression levels in liver of rabbitfish fed a vegetable oil diet or reared at 10 ppt salinity, which were conditions reported to increase the liver expression of Δ4 and Δ6/Δ5 Fad and LC-PUFA biosynthetic ability, than fish fed a fish oil diet or reared at 32 ppt, respectively. These results suggested that Lxr and Srebp1 are involved in regulation of LC-PUFA biosynthesis probably by promoting the expression of two Fad in rabbitfish liver, which, to our knowledge, is the first report in marine teleosts.

  20. 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

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

    Science.gov (United States)

    Grandas, F; Galiano, M L

    1999-05-01

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

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

    DEFF Research Database (Denmark)

    Mehlsen, J; Trap-Jensen, J

    1986-01-01

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

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

    Science.gov (United States)

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

    2015-06-03

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

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

    Science.gov (United States)

    Guo, Song; Lu, Xiaowei; Gu, Ruihuan; Zhang, Di; Sun, Yijuan; Feng, Yun

    2017-01-01

    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; Ppregnancy outcome of adenomyosis in a mouse model. Besides pituitary down-regulation, other possible mechanisms such as the regulation of cell proliferation may play a role in this. These new insights into GnRH agonist mechanisms will be useful for future adenomyosis treatment. PMID:28331289

  5. National and State Treatment Need and Capacity for Opioid Agonist Medication-Assisted Treatment

    Science.gov (United States)

    Campopiano, Melinda; Baldwin, Grant; McCance-Katz, Elinore

    2015-01-01

    Objectives. We estimated national and state trends in opioid agonist medication-assisted treatment (OA-MAT) need and capacity to identify gaps and inform policy decisions. Methods. We generated national and state rates of past-year opioid abuse or dependence, maximum potential buprenorphine treatment capacity, number of patients receiving methadone from opioid treatment programs (OTPs), and the percentage of OTPs operating at 80% capacity or more using Substance Abuse and Mental Health Services Administration data. Results. Nationally, in 2012, the rate of opioid abuse or dependence was 891.8 per 100 000 people aged 12 years or older compared with national rates of maximum potential buprenorphine treatment capacity and patients receiving methadone in OTPs of, respectively, 420.3 and 119.9. Among states and the District of Columbia, 96% had opioid abuse or dependence rates higher than their buprenorphine treatment capacity rates; 37% had a gap of at least 5 per 1000 people. Thirty-eight states (77.6%) reported at least 75% of their OTPs were operating at 80% capacity or more. Conclusions. Significant gaps between treatment need and capacity exist at the state and national levels. Strategies to increase the number of OA-MAT providers are needed. PMID:26066931

  6. 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.

    2011-01-01

    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

  7. Mycophenolic acid induces ATP-binding cassette transporter A1 (ABCA1) expression through the PPAR{gamma}-LXR{alpha}-ABCA1 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Yanni; Lai, Fangfang; Xu, Yang; Wu, Yexiang; Liu, Qi; Li, Ni; Wei, Yuzhen; Feng, Tingting; Zheng, Zhihui; Jiang, Wei; Yu, Liyan; Hong, Bin [Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050 (China); Si, Shuyi, E-mail: sisyimb@hotmail.com [Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050 (China)

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer Using an ABCA1p-LUC HepG2 cell line, we found that MPA upregulated ABCA1 expression. Black-Right-Pointing-Pointer MPA induced ABCA1 and LXR{alpha} protein expression in HepG2 cells. Black-Right-Pointing-Pointer PPAR{gamma} antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXR{alpha} protein expression. Black-Right-Pointing-Pointer The effect of MPA upregulating ABCA1 was due mainly to activation of the PPAR{gamma}-LXR{alpha}-ABCA1 pathway. -- Abstract: ATP-binding cassette transporter A1 (ABCA1) promotes cholesterol and phospholipid efflux from cells to lipid-poor apolipoprotein A-I and plays an important role in atherosclerosis. In a previous study, we developed a high-throughput screening method using an ABCA1p-LUC HepG2 cell line to find upregulators of ABCA1. Using this method in the present study, we found that mycophenolic acid (MPA) upregulated ABCA1 expression (EC50 = 0.09 {mu}M). MPA upregulation of ABCA1 expression was confirmed by real-time quantitative reverse transcription-PCR and Western blot analysis in HepG2 cells. Previous work has indicated that MPA is a potent agonist of peroxisome proliferator-activated receptor gamma (PPAR{gamma}; EC50 = 5.2-9.3 {mu}M). Liver X receptor {alpha} (LXR{alpha}) is a target gene of PPAR{gamma} and may directly regulate ABCA1 expression. Western blot analysis showed that MPA induced LXR{alpha} protein expression in HepG2 cells. Addition of PPAR{gamma} antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXR{alpha} protein expression. These data suggest that MPA increased ABCA1 expression mainly through activation of PPAR{gamma}. Thus, the effects of MPA on upregulation of ABCA1 expression were due mainly to activation of the PPAR{gamma}-LXR{alpha}-ABCA1 signaling pathway. This is the first report that the antiatherosclerosis activity of MPA is due to this mechanism.

  8. Emerging corticosteroid agonists for the treatment of asthma

    DEFF Research Database (Denmark)

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

    2015-01-01

    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...

  9. Lxr regulates lipid metabolic and visual perception pathways during zebrafish development.

    Science.gov (United States)

    Pinto, Caroline Lucia; Kalasekar, Sharanya Maanasi; McCollum, Catherine W; Riu, Anne; Jonsson, Philip; Lopez, Justin; Swindell, Eric C; Bouhlatouf, Abdel; Balaguer, Patrick; Bondesson, Maria; Gustafsson, Jan-Åke

    2016-01-05

    The Liver X Receptors (LXRs) play important roles in multiple metabolic pathways, including fatty acid, cholesterol, carbohydrate and energy metabolism. To expand the knowledge of the functions of LXR signaling during embryonic development, we performed a whole-genome microarray analysis of Lxr target genes in zebrafish larvae treated with either one of the synthetic LXR ligands T0901317 or GW3965. Assessment of the biological processes enriched by differentially expressed genes revealed a prime role for Lxr in regulating lipid metabolic processes, similarly to the function of LXR in mammals. In addition, exposure to the Lxr ligands induced changes in expression of genes in the neural retina and lens of the zebrafish eye, including the photoreceptor guanylate cyclase activators and lens gamma crystallins, suggesting a potential novel role for Lxr in modulating the transcription of genes associated with visual function in zebrafish. The regulation of expression of metabolic genes was phenotypically reflected in an increased absorption of yolk in the zebrafish larvae, and changes in the expression of genes involved in visual perception were associated with morphological alterations in the retina and lens of the developing zebrafish eye. The regulation of expression of both lipid metabolic and eye specific genes was sustained in 1 month old fish. The transcriptional networks demonstrated several conserved effects of LXR activation between zebrafish and mammals, and also identified potential novel functions of Lxr, supporting zebrafish as a promising model for investigating the role of Lxr during development.

  10. Expansion of opiate agonist treatment: an historical perspective

    Directory of Open Access Journals (Sweden)

    Newman Robert G

    2006-07-01

    Full Text Available Abstract Untreated opiate addiction remains a major health care crisis in New York and in most other urban centers in America. Optimism for closing the gap between need and demand for treatment and its availability has greeted the recent approval of a new opiate medication for addiction, buprenorphine – which unlike methadone may be prescribed by independent, office-based practitioners. The likelihood of buprenorphine fulfilling its potential is assessed in the light of the massive expansion of methadone treatment more than 30 years earlier. It is concluded that the key, indispensable ingredient of success will be true commitment on the part of Government to provide care to all those who need it.

  11. [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.

  12. LHRH agonists in prostate cancer : frequency of treatment, serum testosterone measurement and castrate level: consensus opinion from a roundtable discussion

    NARCIS (Netherlands)

    de Jong, Igle Jan; Eaton, Alan; Bladou, Franck

    2007-01-01

    Background: Options for lowering testosterone in patients with prostate cancer include bilateral orchiectomy, oestrogens and luteinising hormone-releasing hormone (LHRH) agonists. LHRH agonists have become widely used in the treatment of prostate cancer. Roundtable assembly: In May 2006, a team of e

  13. PPAR- γ agonist in treatment of diabetes: cardiovascular safety considerations.

    Science.gov (United States)

    Abbas, Aamer; Blandon, Jimena; Rude, Jennifer; Elfar, Ahmed; Mukherjee, Debabrata

    2012-06-01

    The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed.

  14. 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.

  15. 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.

  16. Navy LX(R) Amphibious Ship Program: Background and Issues for Congress

    Science.gov (United States)

    2016-05-27

    Service Summary The LX(R) program is a program to build a new class of 11 amphibious ships for the Navy. The Navy wants to procure the first LX(R) in...accelerate the procurement of the first LX(R) from FY2020 to an earlier year, so as to reduce the gap in time between the end of LPD-17 production and the

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

    OpenAIRE

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

    2014-01-01

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

  18. Treatment of type 2 diabetes, lifestyle, GLP1 agonists and DPP4 inhibitors

    Institute of Scientific and Technical Information of China (English)

    Gerald; H; Tomkin

    2014-01-01

    In recent years the treatment focus for type 2 diabetes has shifted to prevention by lifestyle change and to more aggressive reduction of blood sugars during the early stage of treatment. Weight reduction is an important goal for many people with type 2 diabetes.Bariatric surgery is no longer considered a last resort treatment. Glucagon-like peptide-1 agonists given by injection are emerging as a useful treatment since they not only lower blood sugar but are associated with a modest weight reduction. The role of the oral dipeptidyl peptidase 4 inhibitors is emerging as second line treatment ahead of sulphonylureas due to a possible beneficial effect on the beta cell and weight neutrality.Drugs which inhibit glucose re-absorption in the kidney,sodium/glucose co-transport 2 inhibitors, may have a role in the treatment of diabetes. Insulin treatment still remains the cornerstone of treatment in many patients with type 2 diabetes.

  19. Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Mayi, Therese Hervee; Rigamonti, Elena [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Pattou, Francois [Univ Lille Nord de France, F-59000 Lille (France); Department of Endocrine Surgery, University Hospital, Lille (France); U859 Biotherapies for Diabetes, INSERM, Lille (France); Staels, Bart, E-mail: bart.staels@pasteur-lille.fr [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Chinetti-Gbaguidi, Giulia [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France)

    2011-01-07

    Research highlights: {yields} Synthetic LXR ligands decreased visfatin expression in human macrophages. {yields} LXR activation leads to a modest and transient decrease of NAD{sup +} concentration. {yields} LXR activation decreased PPAR{gamma}-induced visfatin in human macrophages. -- Abstract: Adipose tissue macrophages (ATM) are the major source of visfatin, a visceral fat adipokine upregulated during obesity. Also known to play a role in B cell differentiation (pre-B cell colony-enhancing factor (PBEF)) and NAD biosynthesis (nicotinamide phosphoribosyl transferase (NAMPT)), visfatin has been suggested to play a role in inflammation. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR){gamma} are nuclear receptors expressed in macrophages controlling the inflammatory response. Recently, we reported visfatin as a PPAR{gamma} target gene in human macrophages. In this study, we examined whether LXR regulates macrophage visfatin expression. Synthetic LXR ligands decreased visfatin gene expression in a LXR-dependent manner in human and murine macrophages. The decrease of visfatin mRNA was paralleled by a decrease of protein secretion. Consequently, a modest and transient decrease of NAD{sup +} concentration was observed. Interestingly, LXR activation decreased the PPAR{gamma}-induced visfatin gene and protein secretion in human macrophages. Our results identify visfatin as a gene oppositely regulated by the LXR and PPAR{gamma} pathways in human macrophages.

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

    Science.gov (United States)

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

    2010-11-01

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

  1. Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder.

    Science.gov (United States)

    Belkin, Molly R; Schwartz, Thomas L

    2015-01-01

    Clonidine and guanfacine are alpha-2 receptor agonists that decrease sympathetic outflow from the central nervous system. Posttraumatic stress disorder (PTSD) is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system. Currently, the only US Food and Drug Administration (FDA)-approved medications for PTSD are the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. Sometimes use of the SSRIs may not lead to full remission and symptoms of hyperarousal often persist. This article specifically reviews the literature on alpha-2 receptor agonist use for the treatment of PTSD and concludes that while the evidence base is limited, these agents might be considered useful when SSRIs fail to treat symptoms of agitation and hyperarousal in patients with PTSD.

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

    DEFF Research Database (Denmark)

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

    2009-01-01

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

  3. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Østergaard, L; Frandsen, Christian S.; Madsbad, S

    2016-01-01

    Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases...... gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA....

  4. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method

    Science.gov (United States)

    Hämmig, Robert; Kemter, Antje; Strasser, Johannes; von Bardeleben, Ulrich; Gugger, Barbara; Walter, Marc; Dürsteler, Kenneth M; Vogel, Marc

    2016-01-01

    Background Buprenorphine is a partial µ-opioid receptor agonist used for maintenance treatment of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate withdrawal symptoms during induction in persons on full µ-opioid receptor agonists. Therefore, current guidelines and drug labels recommend leaving a sufficient time period since the last full agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full agonist therapies before administering buprenorphine. However, even with these precautions, for many patients the induction of buprenorphine is a difficult experience, due to withdrawal symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use. Cases We present two cases of successful initiation of buprenorphine treatment with the Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, withdrawal, and trauma reactivation symptoms during conventional induction. The second patient was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin) and methadone during induction. Both patients tolerated the induction procedure well and reported only mild withdrawal symptoms. Discussion Overlapping induction of buprenorphine maintenance treatment with full µ-opioid receptor agonist use is feasible and may be associated with better tolerability and acceptability in some patients compared to the conventional method of induction. PMID:27499655

  5. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method.

    Science.gov (United States)

    Hämmig, Robert; Kemter, Antje; Strasser, Johannes; von Bardeleben, Ulrich; Gugger, Barbara; Walter, Marc; Dürsteler, Kenneth M; Vogel, Marc

    2016-01-01

    Buprenorphine is a partial µ-opioid receptor agonist used for maintenance treatment of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate withdrawal symptoms during induction in persons on full µ-opioid receptor agonists. Therefore, current guidelines and drug labels recommend leaving a sufficient time period since the last full agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full agonist therapies before administering buprenorphine. However, even with these precautions, for many patients the induction of buprenorphine is a difficult experience, due to withdrawal symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use. We present two cases of successful initiation of buprenorphine treatment with the Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, withdrawal, and trauma reactivation symptoms during conventional induction. The second patient was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin) and methadone during induction. Both patients tolerated the induction procedure well and reported only mild withdrawal symptoms. Overlapping induction of buprenorphine maintenance treatment with full µ-opioid receptor agonist use is feasible and may be associated with better tolerability and acceptability in some patients compared to the conventional method of induction.

  6. Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus.

    Science.gov (United States)

    Yoshimoto, Ryo; Miyamoto, Yasuhisa; Shimamura, Ken; Ishihara, Akane; Takahashi, Kazuhiko; Kotani, Hidehito; Chen, Airu S; Chen, Howard Y; Macneil, Douglas J; Kanatani, Akio; Tokita, Shigeru

    2006-09-12

    Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.

  7. Efficacy and safety of gonadotropin-releasing hormone agonists used in the treatment of prostate cancer

    Directory of Open Access Journals (Sweden)

    Choi S

    2011-12-01

    Full Text Available Seungtaek Choi, Andrew K LeeDepartment of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USAAbstract: Androgen deprivation therapy (ADT is the most effective systemic treatment for prostate cancer. ADT has been shown to have a high rate of response and to improve overall survival in patients with metastatic prostate cancer. In addition, multiple studies have shown that adding ADT to external beam radiation therapy leads to improvement in cure rates and overall survival in prostate cancer patients. The most commonly used ADT is gonadotropin-releasing hormone (GnRH agonist therapy. Although GnRH agonist therapy has significant benefits for patients with prostate cancer, it has also been shown to have significant side effects, including fatigue, hot flashes, decreased libido, decreased quality of life, obesity, diabetes mellitus, coronary artery disease, decreased bone mineral density, and increased risk of fractures. Therefore, it is crucial that the benefits of ADT be weighed against its potential adverse effects before its use.Keywords: androgen deprivation therapy, gonadotropin-releasing hormone agonists, prostate cancer

  8. 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.

  9. Perivagal antagonist treatment in rats selectively blocks the reflex and afferent responses of vagal lung C fibers to intravenous agonists.

    Science.gov (United States)

    Lin, Yu-Jung; Lin, You Shuei; Lai, Ching Jung; Yuan, Zung Fan; Ruan, Ting; Kou, Yu Ru

    2013-02-01

    The terminals of vagal lung C fibers (VLCFs) express various types of pharmacological receptors that are important to the elicitation of airway reflexes and the development of airway hypersensitivity. We investigated the blockade of the reflex and afferent responses of VLCFs to intravenous injections of agonists using perivagal treatment with antagonists (PAT) targeting the transient receptor potential vanilloid 1, P2X, and 5-HT(3) receptors in anesthetized rats. Blockading these responses via perivagal capsaicin treatment (PCT), which blocks the neural conduction of C fibers, was also studied. We used capsaicin, α,β-methylene-ATP, and phenylbiguanide as the agonists, and capsazepine, iso-pyridoxalphosphate-6-azophenyl-2',5'-disulfonate, and tropisetron as the antagonists of transient receptor potential vanilloid 1, P2X, and 5-HT(3) receptors, respectively. We found that each of the PATs abolished the VLCF-mediated reflex apnea evoked by the corresponding agonist, while having no effect on the response to other agonists. Perivagal vehicle treatment failed to produce any such blockade. These blockades had partially recovered at 3 h after removal of the PATs. In contrast, PCT abolished the reflex apneic response to all three agonists. Both PATs and PCT did not affect the myelinated afferent-mediated apneic response to lung inflation. Consistently, our electrophysiological studies revealed that each of the PATs prevented the VLCF responses to the corresponding agonist, but not to any other agonist. PCT inevitably prevented the VLCF responses to all three agonists. Thus these PATs selectively blocked the stimulatory action of corresponding agonists on the VLCF terminals via mechanisms that are distinct from those of PCT. PAT may become a novel intervention for studying the pharmacological modulation of VLCFs.

  10. Efficacy of a triple treatment with irradiation, agonistic TRAIL receptor antibodies and EGFR blockade

    Energy Technology Data Exchange (ETDEWEB)

    Niyazi, Maximilian; Marini, Patrizia [Dept. of Radiation Oncology, CCC Tuebingen (Germany); Daniel, Peter T. [Clinical and Molecular Oncology, Charite, Humboldt Univ., Berlin (Germany); Humphreys, Robin [Oncology Research Dept., Human Genome Sciences Inc., Rockville, MD (United States); Jendrossek, Verena [Dept. of Radiation Oncology, CCC Tuebingen (Germany); Dept. of Molecular Cell Biology, Essen (Germany); Belka, Claus [Dept. of Radiation Oncology, CCC Tuebingen (Germany); Dept. of Radiation Oncology, Ludwig Maximilian Univ., Munich (Germany)

    2009-01-15

    Background and purpose: since the efficacy of a single targeted agent in combination with ionizing radiation is limited by putative treatment resistances, a rationally designed triple treatment consisting of an agonistic antibody targeting either TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab), radiation and an epidermal growth factor receptor-(EGFR-)inhibiting antibody (cetuximab) was tested. Material and methods: induction of apoptosis after triple treatment was determined in Colo205, HCT116 and FaDu cells by Hoechst 33342 stain. The degree of interaction was determined by isobologram analysis. A knockout variant of HCT116 was used to examine Bax dependence of the triple treatment. The role of Akt/PKB signaling was analyzed using the phosphatidylinositol 3-kinase inhibitor LY294002. Clonogenic assays were performed to examine the effect on clonogenic survival of tumor cells. Results: a synergistic effect of radiation, cetuximab and agonistic TRAIL-R antibodies was demonstrated in cell lines derived from colorectal tumors or head-and-neck cancers. The efficacy of this multimodal approach was dependent on Bax and inhibition of Akt/PKB in the cell systems used. The results also show a positive impact on clonogenic cell death in several cell lines. Conclusion: these data suggest that rationally designed multimodal therapy approaches integrating radiation with more than one targeted agent will open new perspectives in radiation oncology. (orig.)

  11. Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice

    Directory of Open Access Journals (Sweden)

    Stevens Paula J

    2007-07-01

    Full Text Available Abstract Background Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy. Methods Using the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R agonist treatment has on diaphragm function, morphology and gene expression. Results We have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression. Conclusion Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.

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

    DEFF Research Database (Denmark)

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2010-01-01

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

  14. Hepatic AQP9 expression in male rats is reduced in response to PPARα agonist treatment.

    Science.gov (United States)

    Lebeck, Janne; Cheema, Muhammad Umar; Skowronski, Mariusz T; Nielsen, Søren; Praetorius, Jeppe

    2015-02-01

    The peroxisome proliferator receptor α (PPARα) is a key regulator of the hepatic response to fasting with effects on both lipid and carbohydrate metabolism. A role in hepatic glycerol metabolism has also been found; however, the results are somewhat contradictive. Aquaporin 9 (AQP9) is a pore-forming transmembrane protein that facilitates hepatic uptake of glycerol. Its expression is inversely regulated by insulin in male rodents, with increased expression during fasting. Previous results indicate that PPARα plays a crucial role in the induction of AQP9 mRNA during fasting. In the present study, we use PPARα agonists to explore the effect of PPARα activation on hepatic AQP9 expression and on the abundance of enzymes involved in glycerol metabolism using both in vivo and in vitro systems. In male rats with free access to food, treatment with the PPARα agonist WY 14643 (3 mg·kg(-1)·day(-1)) caused a 50% reduction in hepatic AQP9 abundance with the effect being restricted to AQP9 expressed in periportal hepatocytes. The pharmacological activation of PPARα had no effect on the abundance of GlyK, whereas it caused an increased expression of hepatic GPD1, GPAT1, and L-FABP protein. In WIF-B9 and HepG2 hepatocytes, both WY 14643 and another PPARα agonist GW 7647 reduced the abundance of AQP9 protein. In conclusion, pharmacological PPARα activation results in a marked reduction in the abundance of AQP9 in periportal hepatocytes. Together with the effect on the enzymatic apparatus for glycerol metabolism, our results suggest that PPARα activation in the fed state directs glycerol into glycerolipid synthesis rather than into de novo synthesis of glucose. Copyright © 2015 the American Physiological Society.

  15. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review.

    Science.gov (United States)

    Østergaard, L; Frandsen, Christian S; Madsbad, S

    2016-01-01

    Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.

  16. 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

    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...... developed. At the moment four different compounds are available for the treatment of T2D and many more are in clinical development. These compounds, although all based on the effects of native GLP-1, differ with regards to structure, pharmacokinetics and size, which ultimately leads to different clinical...... 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...

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

    Directory of Open Access Journals (Sweden)

    Yifei Zhong

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

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

    Science.gov (United States)

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

    2011-01-01

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

  19. Navy LX(R) Amphibious Ship Program: Background and Issues for Congress

    Science.gov (United States)

    2016-01-08

    unaffordable for the purposes of the LX(R) program), 11 a modified (reduced capability/reduced-cost) version of the LPD-17 design, brand new (i.e...Solicitation Limited to Two Builders16 On June 25, 2015, the Navy, as part of its acquisition strategy for LX(R) program, issued a combined solicitation...estimated cost of the 12 th LPD-17 class ship by incorporating design innovations and cost-reduction strategies intended for the LX(R). 20 This will make

  20. Mechanisms of anorexia-cachexia syndrome and rational for treatment with selective ghrelin receptor agonist.

    Science.gov (United States)

    Esposito, Angela; Criscitiello, Carmen; Gelao, Lucia; Pravettoni, Gabriella; Locatelli, Marzia; Minchella, Ida; Di Leo, Maria; Liuzzi, Rita; Milani, Alessandra; Massaro, Mariangela; Curigliano, Giuseppe

    2015-11-01

    Cancer cachexia is a multi-organ, multifactorial and often irreversible syndrome affecting many patients with cancer. Cancer cachexia is invariably associated with weight loss, mainly from loss of skeletal muscle and body fat, conditioning a reduced quality of life due to asthenia, anorexia, anaemia and fatigue. Treatment options for treating cancer cachexia are limited. The approach is multimodal and may include: treatment of secondary gastrointestinal symptoms, nutritional treatments, drug, and non-drug treatments. Nutritional counselling and physical training may be beneficial in delaying or preventing the development of anorexia-cachexia. However, these interventions are limited in their effect, and no definitive pharmacological treatment is available to address the relevant components of the syndrome. Anamorelin is a first-in-class, orally active ghrelin receptor agonist that binds and stimulates the growth hormone secretagogue receptor centrally, thereby mimicking the appetite-enhancing and anabolic effects of ghrelin. It represents a new class of drug and an additional treatment option for this patient group, whose therapeutic options are currently limited. In this review we examine the mechanisms of anamorelin by which it contrasts catabolic states, its role in regulation of metabolism and energy homeostasis, the data of recent trials in the setting of cancer cachexia and its safety profile.

  1. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the “Bernese method”

    Directory of Open Access Journals (Sweden)

    Hämmig R

    2016-07-01

    Full Text Available Robert Hämmig,1 Antje Kemter,2 Johannes Strasser,2 Ulrich von Bardeleben,1 Barbara Gugger,1 Marc Walter,2 Kenneth M Dürsteler,2 Marc Vogel2 1Division of Addiction, University Psychiatric Services Bern, Bern, Switzerland; 2Division of Substance Use and Addictive Disorders, University of Basel Psychiatric Hospital, Basel, Switzerland Background: Buprenorphine is a partial µ-opioid receptor agonist used for maintenance treatment of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate withdrawal symptoms during induction in persons on full µ-opioid receptor agonists. Therefore, current guidelines and drug labels recommend leaving a sufficient time period since the last full agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full agonist therapies before administering buprenorphine. However, even with these precautions, for many patients the induction of buprenorphine is a difficult experience, due to withdrawal symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use.Cases: We present two cases of successful initiation of buprenorphine treatment with the ­Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, withdrawal, and trauma reactivation symptoms during conventional induction. The second patient was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin and methadone during induction. Both patients tolerated the induction procedure well and reported only mild withdrawal symptoms.Discussion: Overlapping induction of buprenorphine maintenance treatment with full µ-opioid receptor agonist use is feasible and may be associated with better tolerability and acceptability in some patients compared to the conventional method of induction. Keywords: subutex, suboxone, heroin

  2. Perspectives on mirabegron in the treatment of overactive bladder syndrome: A new beta-3 adrenoceptor agonist

    Directory of Open Access Journals (Sweden)

    Chia-Hao Kuei

    2015-03-01

    Full Text Available Mirabegron, the first β3-adrenoceptor agonist introduced for use in clinical practice, differs from antimuscarinic agents in terms of mechanism of action. This review discusses various perspectives on mirabegron in terms of efficacy, mechanism of action, pharmacokinetics, safety, and tolerability for overactive bladder syndrome in studies conducted thus far. Mirabegron administered at daily doses of 25 mg, 50 mg, and 100 mg demonstrated significant improvements in micturition frequency, urgency incontinence, and mean volume voided/micturition as early as the first assessment, and these were maintained throughout the treatment course. Mirabegron seemed well tolerated. The most common adverse events observed with mirabegron in clinical trials were hypertension, nasopharyngitis, and urinary tract infection. The incidence of dry mouth was similar to that with placebo, between 3- and 5-fold lower than with 4 mg tolterodine extended release. Considering that dry mouth is the most bothersome adverse event associated with antimuscarinic drugs and often a reason for treatment discontinuation, mirabegron may be a valuable treatment option for these patients. The benefit of mirabegron (at doses of 50 mg and 100 mg was also evident in elderly patients and in both treatment-naive patients and those who previously discontinued antimuscarinic therapy. Mirabegron can also be used in combination with antimuscarinics or in addition to alpha blockers. Mirabegron may quickly become a standard treatment of overactive bladder syndrome.

  3. [Treatment strategy for elderly diabetic patient with insulin or GLP-1 receptor agonist].

    Science.gov (United States)

    Ando, Yasuyo

    2013-11-01

    It has been established that diabetes is an independent risk factor for microvascular and macrovascular complications, and many studies indicate that diabetic subjects are at greater risk of dementia, depression and fracture. Risk reductions for microvascular, macrovascular and death were observed by intensive therapy using insulin or oral diabetic agents. But a history of hypoglycemia was increased myocardial infarction, mortality, dementia and fracture. So it is important that optimum glycemic control has to be achieved without hypoglycemia. Treatment with a long-acting basal insulin analogue or glucagon-like peptide-1(GLP-1) receptor agonist, provide effective glycemic control without serious hypoglycemia in elderly patients. Self-monitoring of blood glucose might be effective in improving glycemic control in elderly patients, and it is useful for the diagnosis of hypoglycemia.

  4. Treatment of type 2 diabetes by free Fatty Acid receptor agonists

    DEFF Research Database (Denmark)

    Watterson, Kenneth R; Hudson, Brian D; Ulven, Trond

    2014-01-01

    Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for free fatty acid receptors (FFA1-4) have consequently...... been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long-chain FFA receptor, FFA1, improved glycemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand...... was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss, and reduces inflammation and the metabolic and anti...

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

    Directory of Open Access Journals (Sweden)

    Bhaven C. Kataria

    2012-02-01

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

  6. Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study.

    Science.gov (United States)

    Marcus, Monica M; Björkholm, Carl; Malmerfelt, Anna; Möller, Annie; Påhlsson, Ninni; Konradsson-Geuken, Åsa; Feltmann, Kristin; Jardemark, Kent; Schilström, Björn; Svensson, Torgny H

    2016-09-01

    Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.

  7. Classification of chronic cough by systematic treatment cascade trial starting with beta agonist

    Science.gov (United States)

    2013-01-01

    Background Chronic cough is one of the most challenging symptoms to diagnose and treat, not only because of the variety of underlying disorders but also its varying susceptibility to treatments. Etiological studies of chronic cough vary depending on the clinical settings and the particular interests of investigators. Objectives The purposes of this study were first to categorize the etiology of chronic cough by its response to systematic diagnostic treatments starting from the β2 agonist and second to sub-categorize β2 agonist responsive cough (BRC) by the airway hyperresponsiveness. Methods One hundred and eighty-four never-smokers received the maximal dose of procaterol to diagnose BRC. BRC was sub-categorized into two groups with or without airway hyperresponsiveness measured by the methacholine challenge test. Sinobronchial syndrome (SBS) was diagnosed by postnasal drip symptoms and by the response to clarythromycin and carbocysteine. Atopic cough (AC) was diagnosed by the evidence of atopy and the response to cetirizine hydrochloride. Gastroesophageal reflux disease (GERD) was diagnosed by the response to rabeprazole sodium. Since we did not investigate eosinophil counts in the tissue or in the induced sputum, no diagnosis of eosinophilic bronchitis was made. Results One hundred and nine patients had BRC. Twenty-three of them had bronchial asthma (BA), 53 had cough variant asthma (CVA) and 33 had non-hyperresponsive BRC (NHBRC). Thirty-one patients had GERD, 27 had AC and 14 had SBS. Twenty-five patients had more than one diagnosis in combination, while 6 had other miscellaneous diseases. Twelve patients were undiagnosed and 11 dropped out of the study. Conclusions The majority of chronic cough was BRC. NHBRC was a new chronic cough entity. GERD is a common cause of chronic cough in Japan, as in Western countries. AC and SBS are also causes of chronic cough in Japan. Trial registration University hospital medical information network (UMIN 000007483) PMID

  8. [Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes].

    Science.gov (United States)

    Salvador, Javier; Andrada, Patricia

    2014-01-01

    The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy.

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

    Science.gov (United States)

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

    2015-07-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  11. Tasimelteon, a melatonin agonist for the treatment of insomnia and circadian rhythm sleep disorders.

    Science.gov (United States)

    Hardeland, Rüdiger

    2009-07-01

    Tasimelteon, developed by Vanda Pharmaceuticals Inc under license from Bristol-Myers Squibb Co, is a melatonin receptor agonist. Because of the high density of melatonin receptors in the circadian pacemaker, the suprachiasmatic nucleus, melatonergic actions can phase-shift circadian rhythms and promote sleep. Tasimelteon was effective in reducing sleep onset latency (in phase II and III clinical trials) and in resetting the circadian melatonin rhythm (in phase II trials), which indicated its potential suitability as treatment for jet lag, shift work and circadian rhythm sleep disorders. Statistically significant improvements in sleep maintenance have also been observed with the drug. Tasimelteon has been claimed to be useful in the treatment of depression, and preclinical evidence in this respect is to be confirmed in a phase II clinical trial, which was ready to be initiated at the time of publication. It is plausible that the drug may be effective in the treatment of depressive disorders, at least those that are related to circadian dysfunction, and that it may attenuate sleep problems in depressed patients of different subtypes. A general suitability in mitigating other symptoms of major depressive disorder cannot be deduced from the actions of tasimelteon via the melatonin receptors MT1 and MT2. The drug is well tolerated, does not induce impairment of next-day functioning or dependence, and seems to be safe in short-term treatment; however, toxicological data would be required for assessing its long-term safety.

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

    Science.gov (United States)

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

    2014-01-01

    Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for free fatty acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long-chain FFA receptor, FFA1, improved glycemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss, and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programs within industry and academia aimed at improving the safety and effectiveness of these potential treatments. PMID:25221541

  13. [The effect of oxcarbamazepine on the clinical effectiveness of dopamine agonists in the treatment of prolactinoma].

    Science.gov (United States)

    Krysiak, Robert; Kedzia, Agnieszka; Okopień, Bogusław

    2011-01-01

    The CYP450 enzyme family plays a very important role in the biotransformation of many drugs with a different chemical structure. Therefore, the inhibition or induction of CYP enzymes may be responsible for the development of numerous drug interactions. Moreover, a peculiarity of constitution causes that some persons in particular situations may respond differently to a drug or treatment than do most people. In this article, we show a case of a young woman diagnosed with prolactinoma who was initially successfully treated with bromocriptine. Two years later she developed epilepsy secondary to brain trauma and as a result, she started receiving oxcarbamazepine treatment. Unfortunately, the treatment led to a deterioration of prolactinoma control. To normalize plasma prolactin levels, bromocriptine dose had to be increased and then replaced, initially with cabergoline and later with quinagolide. Only the latter drug effectively reduced plasma prolactin levels and tumor size. This case shows for the first time the existence of a drug interaction between dopamine agonists and any anti-epileptic drug in patients with prolactinoma.

  14. The conjugated linoleic acid isomer trans-9,trans-11 is a dietary occurring agonist of liver X receptor {alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Ecker, Josef; Liebisch, Gerhard [Institute of Clinical Chemistry, University of Regensburg (Germany); Patsch, Wolfgang [Department of Laboratory Medicine, Hospital of Salzburg (Austria); Schmitz, Gerd, E-mail: gerd.schmitz@klinik.uni-regensburg.de [Institute of Clinical Chemistry, University of Regensburg (Germany)

    2009-10-30

    Conjugated linoleic acid (CLA) isomers are dietary fatty acids that modulate gene expression in many cell types. We have previously reported that specifically trans-9,trans-11 (t9,t11)-CLA induces expression of genes involved in lipid metabolism of human macrophages. To elucidate the molecular mechanism underlying this transcriptional activation, we asked whether t9,t11-CLA affects activity of liver X receptor (LXR) {alpha}, a major regulator of macrophage lipid metabolism. Here we show that t9,t11-CLA is a regulator of LXR{alpha}. We further demonstrate that the CLA isomer induces expression of direct LXR{alpha} target genes in human primary macrophages. Knockdown of LXR{alpha} with RNA interference in THP-1 cells inhibited t9,t11-CLA mediated activation of LXR{alpha} including its target genes. To evaluate the effective concentration range of t9,t11-CLA, human primary macrophages were treated with various doses of CLA and well known natural and synthetic LXR agonists and mRNA expression of ABCA1 and ABCG1 was analyzed. Incubation of human macrophages with 10 {mu}M t9,t11-CLA led to a significant modulation of ABCA1 and ABCG1 transcription and caused enhanced cholesterol efflux to high density lipoproteins and apolipoprotein AI. In summary, these data show that t9,t11-CLA is an agonist of LXR{alpha} in human macrophages and that its effects on macrophage lipid metabolism can be attributed to transcriptional regulations associated with this nuclear receptor.

  15. BMI and metabolic profile in patients with prolactinoma before and after treatment with dopamine agonists.

    Science.gov (United States)

    dos Santos Silva, Cintia M; Barbosa, Flavia R P; Lima, Giovanna A B; Warszawski, Leila; Fontes, Rosita; Domingues, Romeu C; Gadelha, Mõnica R

    2011-04-01

    Hyperprolactinemia might be related to weight gain, metabolic syndrome (MS), and insulin resistance (IR). Treatment with dopamine agonist (DA) has been shown to reduce body weight and improve metabolic parameters. The objectives of this study were to determine the prevalence of obesity, overweight, MS, and IR in patients with prolactinoma before and after therapy with DA and to evaluate the relation between prolactin (PRL), body weight, fat distribution, leptin levels, IR, and lipid profile before treatment. In addition, we investigated the correlation of the reduction in PRL levels with weight loss and metabolic profile improvement. Twenty-two patients with prolactinoma completed 6 months of treatment with DA. These patients were submitted to clinical (BMI, waist circumference, blood pressure (BP)), laboratory evaluation (leptin, glucose, low-density lipoprotein (LDL)-cholesterol, and triglyceride (TG) levels) and abdominal computed tomography (CT) before and after treatment. The statistical analyses were done by nonparametric tests. At the beginning of the study, the prevalence of obesity, overweight, MS, and IR was 45, 27, 27, and 18%, respectively. After 6 months of treatment with DA, PRL levels normalized, but no significant difference in BMI was observed. However, there was a significant decrease on homeostasis model assessment of insulin resistance (HOMA(IR)) index, glucose, LDL-cholesterol, and TG levels. This study suggests a possible involvement of prolactinoma on the prevalence of obesity. We should consider that DA may be effective on improving metabolic parameters, and we speculate that a period longer than 6 months of treatment is necessary to conclude whether this drug can interfere in the body weight of patients with prolactinoma.

  16. The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes.

    Science.gov (United States)

    Moon, Ho-Sang; Kim, Mi-Kyung; Son, Moon-Ho

    2011-07-01

    Glucagon-like peptide-1 (GLP-1) is the main member of the incretin family and stimulates insulin secretion by binding with its specific receptor on pancreatic β-cells. In addition, GLP-1 exerts broad beneficial effects on the glucose regulation by suppressing food intake and delaying stomach emptying. Now, long acting GLP-1 analogs including exenatide and liraglutide have been approved for the treatment of diabetes mellitus type 2, however long-term injection can limit their use for these chronic patients. In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864.

  17. Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis

    NARCIS (Netherlands)

    M.A.F.M. Youssef; M. van Wely; M.A. Hassan; H.G. Al-Inany; M. Mochtar; S. Khattab; F. van der Veen

    2010-01-01

    Recently, dopamine agonists were proposed as a prophylactic treatment for ovarian hyperstimulation syndrome (OHSS) in women at high risk in IVF/ICSI treatment cycles. We conducted a systematic review and meta-analysis of randomized trials comparing the prophylactic effect of the dopamine agonist, ca

  18. 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

    groups, P  = .03). We found no significant differences in heart rate, left ventricular (LV) structure or function within or between the groups. In conclusion, the addition of liraglutide to exercise in sedentary patients with dysregulated type 2 diabetes may blunt the suggested beneficial effect......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......, combined with supervised exercise, in 33 dysregulated patients with type 2 diabetes on diet and/or metformin. Early diastolic myocardial tissue velocity was improved by exercise in the placebo group (mean ± standard deviation [s.d.] -7.1 ± 1.6 to -7.7 ± 1.8 cm/s, P  = .01), but not in the liraglutide group...

  19. GNRH-agonist or antagonist in the treatment of prostate cancer: a comparision based on oncological results.

    Science.gov (United States)

    Salciccia, Stefano; Gentilucci, Alessandro; Cattarino, Susanna; Sciarra, Alessandro

    2016-11-18

    On the basis of the trials available, are we ready to consider GnRH antagonists better than agonists? Is there a population of patients who may benefit from antagonists more than agonists?We specifically focused our analysis on the significance of oncological results obtained in phase III trials directly comparing Degarelix with GnRH agonists. Oncological results were evaluated only in 1 trial (CS21) with some subanalysis and they were not the primary endpoints of the study. The follow-up duration was 364 days, and therefore, the number of events (all causes deaths and prostate cancer (PC), Prostate Specific Antigen (PSA), Hazard ratio (HR)-related deaths) was very low in both groups and this aspect strongly reduces the significance of overall survival evaluation. In our opinion, the CS21A open-label extension does not consent to obtain useful clinical data and the design of the study loses the possibility to have a longer randomized comparison between degarelix and agonist. Moreover, the fact that the crossover from leuprolide to degarelix was pre-defined at 12 months and not at agonist failure does not allow to gather data also on the effect of sequential treatment.The answer to the question whether we are ready to consider antagonists better than agonists, based on oncological results, is probably no. We have data in terms of testosterone suppression and PSA control rather than overall survival or clinical progression free survival. A PSA progression-free survival is a secondary endpoint that in our opinion is not sufficient. Large prospective comparative trials with long-term follow-up are needed to clarify this critical clinical question.

  20. Effects of neonatal treatment with the TRPV1 agonist, capsaicin, on adult rat brain and behaviour.

    Science.gov (United States)

    Newson, Penny N; van den Buuse, Maarten; Martin, Sally; Lynch-Frame, Ann; Chahl, Loris A

    2014-10-01

    Treatment of neonatal rats with the transient receptor potential vanilloid 1 (TRPV1) channel agonist, capsaicin, produces life-long loss of sensory neurons expressing TRPV1 channels. Previously it was shown that rats treated on day 2 of life with capsaicin had behavioural hyperactivity in a novel environment at 5-7 weeks of age and brain changes reminiscent of those found in subjects with schizophrenia. The objective of the present study was to investigate brain and behavioural responses of adult rats treated as neonates with capsaicin. It was found that the brain changes found at 5-7 weeks in rats treated as neonates with capsaicin persisted into adulthood (12 weeks) but were less in older rats (16-18 weeks). Increased prepulse inhibition (PPI) of acoustic startle was found in these rats at 8 and 12 weeks of age rather than the deficit commonly found in animal models of schizophrenia. Subjects with schizophrenia also have reduced flare responses to niacin and methylnicotinate proposed to be mediated by prostaglandin D2 (PGD2). Flare responses are accompanied by cutaneous plasma extravasation. It was found that the cutaneous plasma extravasation responses to methylnicotinate and PGD2 were reduced in capsaicin-treated rats. In conclusion, several neuroanatomical changes observed in capsaicin-treated rats, as well as the reduced cutaneous plasma extravasation responses, indicate that the role of TRPV1 channels in schizophrenia is worthy of investigation.

  1. Regulation of prostaglandin F2α against β amyloid clearance and its inflammation induction through LXR/RXR heterodimer antagonism in microglia.

    Science.gov (United States)

    Zhuang, Jingjing; Zhang, Haikun; Zhou, Rong; Chen, Lili; Chen, Jing; Shen, Xu

    2013-10-01

    Alzheimer's disease (AD) is characterized by extracellular deposit of β-amyloid (Aβ) and accumulation of intracellular neurofibrillary tangles in the brain. Prostaglandin F2α (PGF2α) is one of the major metabolites of arachidonic acid (AA), and plays essential roles in a series of key physiological processes like luteolysis and parturition. Additionally, PGF2α is also involved in the regulation of chronic and acute inflammation processes. Recent clinical studies have revealed the high content of PGF2α metabolite, 15-keto-dihydro-PGF2α in AD patients, implying the activation of in vivo PGF2α biosynthesis. However, the mechanism underlying the involvement of PGF2α in the progression of AD still remains unclear. Here we discovered that PGF2α selectively antagonized LXR (liver X receptors)/RXR (retinoid X receptor α) and RXR/RXR dimers. Cell based assays indicated that PGF2α effectively antagonized the activation of LXR agonist (t0901317) on Aβ clearance via inhibiting apolipoprotein E (apoE) expression, and cell apoptosis alleviation by accelerating inflammatory response to Aβ or Lipopolysaccharide (LPS) in microglia. Therefore, our current findings have addressed the potential association of PGF2α with AD progression, and highlighted that inhibition of PGF2α biosynthesis might be a useful therapeutic strategy against AD. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. EFFECTS OF 22 MONTHS OF TREATMENT WITH INHALED CORTICOSTEROIDS AND OR BETA-2-AGONISTS ON LUNG-FUNCTION, AIRWAY RESPONSIVENESS, AND SYMPTOMS IN CHILDREN WITH ASTHMA

    NARCIS (Netherlands)

    VANESSENZANDVLIET, EE; HUGHES, MD; WAALKENS, HJ; DUIVERMAN, EJ; POCOCK, SJ; KERREBIJN, KF

    1992-01-01

    In a randomized double-blind multicenter clinical study, 116 children with asthma were randomly assigned to treatment with an inhaled beta-2-agonist (salbutamol 0.2 mg) plus an inhaled corticosteroid (budesonide 0.2 mg) three times a day (BA + CS) or to an inhaled beta-2-agonist (salbutamol 0.2 mg)

  3. Inhalation by design: dual pharmacology β-2 agonists/M3 antagonists for the treatment of COPD.

    Science.gov (United States)

    Jones, Lyn H; Baldock, Helen; Bunnage, Mark E; Burrows, Jane; Clarke, Nick; Coghlan, Michele; Entwistle, David; Fairman, David; Feeder, Neil; Fulton, Craig; Hilton, Laura; James, Kim; Jones, Rhys M; Kenyon, Amy S; Marshall, Stuart; Newman, Sandra D; Osborne, Rachel; Patel, Sheena; Selby, Matthew D; Stuart, Emilio F; Trevethick, Michael A; Wright, Karen N; Price, David A

    2011-05-01

    This paper describes the successful design and development of dual pharmacology β-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum. Copyright © 2010 Elsevier Ltd. All rights reserved.

  4. Treatment of cocaine craving with as-needed nalmefene, a partial κ opioid receptor agonist: first clinical experience.

    Science.gov (United States)

    Grosshans, Martin; Mutschler, Jochen; Kiefer, Falk

    2015-07-01

    The treatment of cocaine dependence is difficult as no approved pharmacotherapy is available as yet. However, in preclinical and clinical trials, a variety of compounds were tested for suitability as inhibitors of craving for and relapse into the use of cocaine, among these antidepressants, antiepileptics, dopamine agonists, disulfiram, and naltrexone. Nalmefene, a structural derivative of naltrexone, shares with its parent compound approval (granted by the European Medical Agency in 2013) as a medication for the treatment of alcohol addiction in the European Union. It differs from naltrexone by a higher affinity for the δ opioid-receptors and a partial agonistic affinity to the κ opioid-receptors. It should be noted that patients addicted to cocaine show a considerable increase in κ receptors in the nucleus accumbens. This report describes the case of an abstinent cocaine-addicted patient regularly afflicted with cravings for cocaine. The patient took as-needed nalmefene for 5 months whenever she developed a craving for cocaine. For most of these interventions, the patient reported an abatement of craving and could avoid relapsing into cocaine consumption. This effect may be accounted for by nalmefene acting, other than naltrexone, as a partial agonist of the κ opioid-receptors. Therefore, nalmefene might be a promising new option in the pharmacological repertoire for the treatment of cocaine addiction.

  5. Functionalized Ergot-alkaloids as potential dopamine D3 receptor agonists for treatment of schizophrenia

    Science.gov (United States)

    Ivanova, Bojidarka; Spiteller, Michael

    2012-12-01

    The relationship between the molecular structure and physical properties of functionalized naturally occurred Ergot-alkaloids as potential dopamine D3 receptor agonists is presented. The molecular modeling of the ergoline-skeleton is based on the comprehensive theoretical study of the binding affinity of the isolated chemicals towards the active sites of the D3 sub-type receptor (D3R) loops. The studied proton accepting ability under physiological conditions allows classifying four types of monocationics, characterizing with the different binding modes to D3R involving selected amino acid residues to the active sites. These results marked the pharmaceutical potential and clinical usage of the reported compounds as antipsychotic drugs for Schizophrenia treatment, since they allowed evaluating the highlights of the different hypothesizes of the biochemical causes the illness. The applied complex approach for theoretical and experimental elucidation, including quantum chemistry method, electrospray ionization (ESI) and matrix assisted laser desorption/ionization (MALDI) mass spectrometric (MS) methods, nuclear magnetic resonance and vibrational IR and Raman spectroscopy on the isolated fifteen novel derivatives (1)-(15) and their different protonated forms (1a)-(15a) evidenced a strong dependence of molecular conformation, physical properties and binding affinity. Thus, the semi-synthetic functionalization of the naturally occurred products (NPs), provided significant possibilities to further molecular drugs-design and development of novel derivatives with wanted biological function, using the established profile of selected classes/families of NPs. The work described chiefly the non-linear (NL) approach for the interpretation of the mass chromatograms on the performed hybrid high performance liquid chromatography (HPLC) tandem MS/MS and MS/MS/MS experiments, discussing the merits and great diversity of instrumentation flexibility, thus achieving fundamental

  6. The Hypocrea jecorina (syn. Trichoderma reesei) lxr1 gene encodes a D-mannitol dehydrogenase and is not involved in L-arabinose catabolism

    NARCIS (Netherlands)

    Metz, Benjamin; de Vries, Ronald P; Polak, Stefan; Seidl, Verena; Seiboth, Bernhard

    2009-01-01

    The Hypocrea jecorina LXR1 was described as the first fungal L-xylulose reductase responsible for NADPH dependent reduction of L-xylulose to xylitol in L-arabinose catabolism. Phylogenetic analysis now reveals that LXR1 forms a clade with fungal D-mannitol 2-dehydrogenases. Lxr1 and the orthologous

  7. The Hypocrea jecorina (syn. Trichoderma reesei) lxr1 gene encodes a D-mannitol dehydrogenase and is not involved in L-arabinose catabolism

    NARCIS (Netherlands)

    Metz, Benjamin; de Vries, Ronald P; Polak, Stefan; Seidl, Verena; Seiboth, Bernhard

    2009-01-01

    The Hypocrea jecorina LXR1 was described as the first fungal L-xylulose reductase responsible for NADPH dependent reduction of L-xylulose to xylitol in L-arabinose catabolism. Phylogenetic analysis now reveals that LXR1 forms a clade with fungal D-mannitol 2-dehydrogenases. Lxr1 and the orthologous

  8. Pregnancy rate in women with adenomyosis undergoing fresh or frozen embryo transfer cycles following gonadotropin-releasing hormone agonist treatment.

    Science.gov (United States)

    Park, Chan Woo; Choi, Min Hye; Yang, Kwang Moon; Song, In Ok

    2016-09-01

    To determine the preferred regimen for women with adenomyosis undergoing in vitro fertilization (IVF), we compared the IVF outcomes of fresh embryo transfer (ET) cycles with or without gonadotropin-releasing hormone (GnRH) agonist pretreatment and of frozen-thawed embryo transfer (FET) cycles following GnRH agonist treatment. This retrospective study included 241 IVF cycles of women with adenomyosis from January 2006 to January 2012. Fresh ET cycles without (147 cycles, group A) or with (105 cycles, group B) GnRH agonist pretreatment, and FET cycles following GnRH agonist treatment (43 cycles, group C) were compared. Adenomyosis was identified by using transvaginal ultrasound at the initial workup and classified into focal and diffuse types. The IVF outcomes were also subanalyzed according to the adenomyotic region. GnRH agonist pretreatment increased the stimulation duration (11.5±2.1 days vs. 9.9±2.0 days) and total dose of gonadotropin (3,421±1,141 IU vs. 2,588±1,192 IU), which resulted in a significantly higher number of retrieved oocytes (10.0±8.2 vs. 7.9±6.8, p=0.013) in group B than in group A. Controlled ovarian stimulation for freezing resulted in a significantly higher number of retrieved oocytes (14.3±9.2 vs. 10.0±8.2, p=0.022) with a lower dose of gonadotropin (2,974±1,112 IU vs. 3,421±1,141 IU, p=0.037) in group C than in group B. The clinical pregnancy rate in group C (39.5%) tended to be higher than those in groups B (30.5%) and A (25.2%) but without a significant difference. FET following GnRH agonist pretreatment tended to increase the pregnancy rate in patients with adenomyosis. Further large-scale prospective studies are required to confirm this result.

  9. Virtual screening studies of Chinese medicine Coptidis Rhizoma as alpha7 nicotinic acetylcholine receptor agonists for treatment of Alzheimer's disease

    Science.gov (United States)

    Xiang, Li; Xu, Youdong; Zhang, Yan; Meng, Xianli; Wang, Ping

    2015-04-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease. Extensive in vitro and in vivo experiments have proved that the decreased activity of the cholinergic neuron is responsible for the memory and cognition deterioration. The alpha7 nicotinic acetylcholine receptor (α7-nAChR) is proposed to a drug target of AD, and compounds which acting as α7-nAChR agonists are considered as candidates in AD treatment. Chinese medicine CoptidisRhizoma and its compounds are reported in various anti-AD effects. In this study, virtual screening, docking approaches and hydrogen bond analyses were applied to screen potential α7-nAChR agonists from CoptidisRhizome. The 3D structure of the protein was obtained from PDB database. 87 reported compounds were included in this research and their structures were accessed by NCBI Pubchem. Docking analysis of the compounds was performed using AutoDock 4.2 and AutoDock Vina. The images of the binding modes hydrogen bonds and the hydrophobic interaction were rendered with PyMOL1.5.0.4. and LigPlot+ respectively. Finally, N-tran-feruloyltyramine, isolariciresinol, flavanone, secoisolariciresinol, (+)-lariciresinol and dihydrochalcone, exhibited the lowest docking energy of protein-ligand complex. The results indicate these 6 compounds are potential α7 nAChR agonists, and expected to be effective in AD treatment.

  10. Dual-pharmacology muscarinic antagonist and β₂ agonist molecules for the treatment of chronic obstructive pulmonary disease.

    Science.gov (United States)

    Hughes, Adam D; Jones, Lyn H

    2011-10-01

    Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world today. Bronchodilators, particularly muscarinic antagonists and β(2) agonists, are recommended for patients with moderate to severe COPD. Dual-pharmacology muscarinic antagonist- β(2) agonist (MABA) molecules present an exciting new approach to the treatment of COPD by combining muscarinic antagonism and β(2) agonism in a single entity. They have the potential to demonstrate additive or synergistic bronchodilation over either pharmacology alone. Due to this enticing prospect, several companies have now reported MABA discovery efforts through a conjugated/linked strategy with one candidate (GSK-961081) demonstrating clinical proof of concept. Several MABA crystal forms have been identified, satisfying the requirements for inhaled dosing devices. There are significant challenges in designing MABAs, but the potential to achieve enhanced bronchoprotection in patients and facilitate 'triple therapy' makes this an extremely important and exciting area of pharmaceutical research.

  11. Coordinated Actions of FXR and LXR in Metabolism: From Pathogenesis to Pharmacological Targets for Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Lin Ding

    2014-01-01

    Full Text Available Type 2 diabetes (T2D is the most prevalent metabolic disease, and many people are suffering from its complications driven by hyperglycaemia and dyslipidaemia. Nuclear receptors (NRs are ligand-inducible transcription factors that mediate changes to metabolic pathways within the body. As metabolic regulators, the farnesoid X receptor (FXR and the liver X receptor (LXR play key roles in the pathogenesis of T2D, which remains to be clarified in detail. Here we review the recent progress concerning the physiological and pathophysiological roles of FXRs and LXRs in the regulation of bile acid, lipid and glucose metabolism and the implications in T2D, taking into account that these two nuclear receptors are potential pharmaceutical targets for the treatment of T2D and its complications.

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

    NARCIS (Netherlands)

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

    2013-01-01

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

  13. Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists.

    Science.gov (United States)

    Farzin, Davood; Asghari, Ladan; Nowrouzi, Mahvash

    2002-06-01

    The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.

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

    Science.gov (United States)

    Wilding, J P H

    2012-11-01

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

  15. Synthetic liver X receptor agonist T0901317 inhibits semicarbazide-sensitive amine oxidase gene expression and activity in apolipoprotein E knockout mice

    Institute of Scientific and Technical Information of China (English)

    Xiaoyan Dai; Xiang Ou; Xinrui Hao; Dongli Cao; Yaling Tang; Yanwei Hu; Xiaoxu Li; Chaoke Tang

    2008-01-01

    Semicarbazide-sensitive amine oxidase(SSAO)catalyzes oxidative deamination of primary aromatic and aliphatic amines.Increased SSAO activity has been found in atherosclerosis and diabetes mellitus.We hypothesize that the anti-atherogenic effect of liver X receptors(LXRs)might be related to the inhibition of SSAD gene expression and its activity.In this study,we investigated the effect of LXR agonist T0901317 on SSAO gene expression and its activity in apolipoprotein E knockout(apoE-/-)mice.Male apoE-/-mice(8 weeks old) were randomly divided into four groups:basal control group;vehicle group;prevention group;and treatment group.SSAO gene expression was analyzed by real-time quantitative polymerase chain reaction and its activity was determined.The activity of superoxide dismutase and content of malondialdehy de in the aorta and liver were also determined.In T0901317-treated mice,SSAO gene expression was significantly decreased in the aorta,liver,small intestine,and brain.SSAO activities in serum and in these tissues were also inhibited.The amount of superoxide dismutase in the aorta and liver of the prevention group and treatment group was significantly higher compared with the vehicle group(P<0.05).Malondialdehyde in the tissues of these two groups was significantly lower compared with the vehicle group(P<0.05).Our results showed that T0901317 inhibits SSAO gene expression and its activity in atherogenic apoE-/-mice.The atheroprotective effect of LXR agonist T0901317 is related to the inhibition of SSAO gene expression and its activity.

  16. QT interval prolongation in opioid agonist treatment: analysis of continuous 12-lead electrocardiogram recordings.

    Science.gov (United States)

    Isbister, Geoffrey K; Brown, Amanda L; Gill, Anthony; Scott, Alexander J; Calver, Leonie; Dunlop, Adrian J

    2017-10-01

    Methadone is a widely used opioid agonist treatment associated with QT prolongation and torsades de pointes. We investigated the QT interval in patients treated with methadone or buprenorphine using continuous 12-lead Holter recordings. We prospectively made 24-h Holter recordings in patients prescribed methadone or buprenorphine, compared to controls. After their normal dose a continuous 12-lead Holter recorder was attached for 24 h. Digital electrocardiograms were extracted hourly from the Holter recordings. The QT interval was measured automatically (H-scribe software, Mortara Pty Ltd) and checked manually. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine abnormality. Demographics, dosing, medical history and laboratory investigations were recorded. There were 58 patients (19 methadone, 20 buprenorphine and 19 control); median age 35 years (20-56 years); 33 males. Baseline characteristics were similar. Median dose of methadone was 110 mg day(-1) (70-170 mg day(-1) ) and buprenorphine was 16 mg day(-1) (12-32 mg day(-1) ). Seven participants had abnormal QT intervals. There was a significant difference in the proportion of prescribed methadone with abnormal QT intervals, 7/19 (37%; 95% confidence interval: 17-61%), compared to controls 0/19 (0%; 95% confidence interval: 0-21%; P = 0.008), but no difference between buprenorphine and controls (0/20). QT vs. HR plots showed patients prescribed methadone had higher QT-HR pairs over 24 h compared to controls. There was no difference in dose for patients prescribed methadone with abnormal QT intervals and those without. Methadone is associated with prolonged QT intervals, but there was no association with dose. Buprenorphine did not prolong the QT interval. Twenty four-hour Holter recordings using the QT nomogram is a feasible method to assess the QT interval in patients prescribed methadone. © 2017 The Authors. British Journal of Clinical Pharmacology published by John

  17. A liver X receptor (LXR)-{beta} alternative splicing variant (LXRBSV) acts as an RNA co-activator of LXR-{beta}

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Koshi, E-mail: khashi@med.gunma-u.ac.jp [Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511 (Japan); Ishida, Emi; Matsumoto, Shunichi; Shibusawa, Nobuyuki; Okada, Shuichi [Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511 (Japan); Monden, Tsuyoshi [Department of Endocrinology and Metabolism, Dokkyo Medical College, Mibu, Tochigi (Japan); Satoh, Tetsurou; Yamada, Masanobu; Mori, Masatomo [Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511 (Japan)

    2009-12-25

    We report the isolation and functional characterization of a novel transcriptional co-activator, termed LXRBSV. LXRBSV is an alternative splicing variant of liver X receptor (LXR)-{beta} LXRBSV has an intronic sequence between exons 2 and 3 in the mouse LXR-{beta} gene. The LXRBSV gene is expressed in various tissues including the liver and brain. We sub-cloned LXRBSV into pSG5, a mammalian expression vector, and LXRBSV in pSG5 augmented human Sterol Response Element Binding Protein (SREBP)-1c promoter activity in HepG2 cells in a ligand (TO901317) dependent manner. The transactivation mediated by LXRBSV is selective for LXR-{beta}. The LXRBSV protein was deduced to be 64 amino acids in length; however, a GAL4-LXRBSV fusion protein was not able to induce transactivation. Serial deletion constructs of LXRBSV demonstrated that the intronic sequence inserted in LXRBSV is required for its transactivation activity. An ATG mutant of LXRBSV was able to induce transactivation as wild type. Furthermore, LXRBSV functions in the presence of cycloheximide. Taken together, we have concluded that LXRBSV acts as an RNA transcript not as a protein. In the current study, we have demonstrated for the first time that an alternative splicing variant of a nuclear receptor acts as an RNA co-activator.

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

    Science.gov (United States)

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

    2017-01-01

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

  19. Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder

    OpenAIRE

    Belkin, Molly R; Schwartz, Thomas L.

    2015-01-01

    Clonidine and guanfacine are alpha-2 receptor agonists that decrease sympathetic outflow from the central nervous system. Posttraumatic stress disorder (PTSD) is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system. Currently, the only US Food and Drug Administration (FDA)-approved medications for PTSD are the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. Sometimes use of the SSRIs may not lead to full remission and sympt...

  20. LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2.

    Directory of Open Access Journals (Sweden)

    Maryem A Hussein

    Full Text Available High cholesterol and diabetes are major risk factors for atherosclerosis. Regression of atherosclerosis is mediated in part by the Liver X Receptor (LXR through the induction of genes involved in cholesterol transport and efflux. In the context of diabetes, regression of atherosclerosis is impaired. We proposed that changes in glucose levels modulate LXR-dependent gene expression. Using a mouse macrophage cell line (RAW 264.7 and primary bone marrow derived macrophages (BMDMs cultured in normal or diabetes relevant high glucose conditions we found that high glucose inhibits the LXR-dependent expression of ATP-binding cassette transporter A1 (ABCA1, but not ABCG1. To probe for this mechanism, we surveyed the expression of a host of chromatin-modifying enzymes and found that Protein Arginine Methyltransferase 2 (PRMT2 was reduced in high compared to normal glucose conditions. Importantly, ABCA1 expression and ABCA1-mediated cholesterol efflux were reduced in Prmt2-/- compared to wild type BMDMs. Monocytes from diabetic mice also showed decreased expression of Prmt2 compared to non-diabetic counterparts. Thus, PRMT2 represents a glucose-sensitive factor that plays a role in LXR-mediated ABCA1-dependent cholesterol efflux and lends insight to the presence of increased atherosclerosis in diabetic patients.

  1. LXRß is the dominant LXR subtype in skeletal muscle regulating lipogenesis and cholesterol efflux

    NARCIS (Netherlands)

    Hessvik, N.P.; Boekschoten, M.V.; Baltzersen, M.A.; Kersten, A.H.; Xu, X.; Andersen, H.E.; Rustan, A.C.; Thoresen, G.H.

    2010-01-01

    Liver X receptors (LXRs) are important regulators of cholesterol, lipid, and glucose metabolism and have been extensively studied in liver, macrophages, and adipose tissue. However, their role in skeletal muscle is poorly studied and the functional role of each of the LXR and LXRß subtypes in skelet

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

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  3. In vivo pharmacological characterization of AC-3933, a benzodiazepine receptor partial inverse agonist for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Hatayama, Y; Hashimoto, T; Kohayakawa, H; Kiyoshi, T; Nakamichi, K; Kinoshita, T; Yoshida, N

    2014-04-18

    GABAergic neurons are known to inhibit neural transduction and therefore negatively affect excitatory neural circuits in the brain. We have previously reported that 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1,6-naphthyridin-2(1H)-one (AC-3933), a partial inverse agonist for the benzodiazepine receptor (BzR), reverses GABAergic inhibitory effect on cholinergic neurons, and thus enhances acetylcholine release from these neurons in rat hippocampal slices. In this study, we evaluated AC-3933 potential for the treatment of Alzheimer's disease, a disorder characterized by progressive decline mainly in cholinergic function. Oral administration of AC-3933 (0.01-0.03mg/kg) resulted in the amelioration of scopolamine-induced amnesia, as well as a shift in electroencephalogram (EEG) relative power characteristic of pro-cognitive cholinergic activators, such as donepezil. In addition, treatment with AC-3933 even at the high dose of 100mg/kg p.o. produced no seizure or anxiety, two major adverse effects of BzR inverse agonists developed in the past. These findings indicate that AC-3933 with its low risk for side effects may be useful in the treatment of Alzheimer's disease.

  4. Liver X receptor agonist prevents LPS-induced mastitis in mice.

    Science.gov (United States)

    Fu, Yunhe; Tian, Yuan; Wei, Zhengkai; Liu, Hui; Song, Xiaojing; Liu, Wenbo; Zhang, Wenlong; Wang, Wei; Cao, Yongguo; Zhang, Naisheng

    2014-10-01

    Liver X receptor-α (LXR-α) which belongs to the nuclear receptor superfamily, is a ligand-activated transcription factor. Best known for its ability to regulate lipid metabolism and transport, LXRs have recently also been implicated in regulation of inflammatory response. The aim of this study was to investigate the preventive effects of synthetic LXRagonist T0901317 on LPS-induced mastitis in mice. The mouse model of mastitis was induced by injection of LPS through the duct of mammary gland. T0901317 was injected 1h before and 12h after induction of LPS intraperitoneally. The results showed that T0901317 significantly attenuated the infiltration of neutrophilic granulocytes, and the activation of myeloperoxidase (MPO); down-regulated the level of pro-inflammatory mediators including TNF-α, IL-1β, IL-6, COX-2 and PEG2; inhibited the phosphorylation of IκB-α and NF-κB p65, caused by LPS. Moreover, we report for the first time that LXR-α activation impaired LPS-induced mastitis. Taken together, these data indicated that T0901317 had protective effect on mastitis and the anti-inflammatory mechanism of T0901317 on LPS induced mastitis in mice may be due to its ability to inhibit NF-κB signaling pathway. LXR-α activation can be used as a therapeutic approach to treat mastitis. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. In vitro evidence in rainbow trout supporting glucosensing mediated by sweet taste receptor, LXR, and mitochondrial activity in Brockmann bodies, and sweet taste receptor in liver.

    Science.gov (United States)

    Otero-Rodiño, Cristina; Velasco, Cristina; Álvarez-Otero, Rosa; López-Patiño, Marcos A; Míguez, Jesús M; Soengas, José L

    2016-10-01

    We previously obtained evidence in rainbow trout peripheral tissues such as liver and Brockmann bodies (BB) for the presence and response to changes in circulating levels of glucose (induced by intraperitoneal hypoglycaemic and hyperglycaemic treatments) of glucosensing mechanisms others than that mediated by glucokinase (GK). There were based on mitochondrial production of reactive oxygen species (ROS) leading to increased expression of uncoupling protein 2 (UCP2), and sweet taste receptor in liver and BB, and on liver X receptor (LXR) and sodium/glucose co-transporter 1 (SGLT-1) in BB. We aimed in the present study to obtain further in vitro evidence for the presence and functioning of these systems. In a first experiment, pools of sliced liver and BB were incubated for 6h at 15°C in modified Hanks' medium containing 2, 4, or 8mM d-glucose, and we assessed the response of parameters related to these glucosensing mechanisms. In a second experiment, pools of sliced liver and BB were incubated for 6h at 15°C in modified Hanks' medium with 8mM d-glucose alone (control) or containing 1mM phloridzin (SGLT-1 antagonist), 20μM genipin (UCP2 inhibitor), 1μM trolox (ROS scavenger), 100μM bezafibrate (T1R3 inhibitor), and 50μM geranyl-geranyl pyrophosphate (LXR inhibitor). The results obtained in both experiments support the presence and functioning of glucosensor mechanisms in liver based on sweet taste receptor whereas in BB the evidence support those based on LXR, mitochondrial activity and sweet taste receptor.

  6. D-cycloserin, a NMDA-agonist may be a treatment option for anti-NMDAR encephalitis

    Institute of Scientific and Technical Information of China (English)

    Hong-Zhi Guan; Tie-Kuan Du; Jin Xu; Xia Lv; Hua-Dong Zhu; Yi-Cheng Zhu; Bin Peng; Li-Ying Cui

    2016-01-01

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is caused by reversible neuron dysfunction associated an autoantibody-mediated decrease of NMDAR in the entire brain. A N-methyl-D-aspartate (NMDA) -agonist treatment for anti-NMDAR encephalitis might have a role considering its speciifc mechanism. The authors used D-cycloserine, a partial NMDA-agonist in a refractory case with prolonged intensive care unit duration. A 13-year-old female presented with headache, cognitive deterioration, generalized seizures, coma and hypoventilation with required mechanical ventilation. Anti-NMDAR antibodies were identiifed in cerebrospinal lfuid and serum conifrming anti-NMDAR encephalitis. The patient was refractory to ifrst-line and second-line immunotherapy and removal of ovary teratoma. D-cycloserine was then administered and her symptoms improved gradually and signiifcantly. This is the ifrst reported case in which D-cycloserine was applied to this disease. D-cycloserine might be a potential option as speciifc treatment in anti-NMDAR encephalitis.

  7. Phosphorylation and chronic agonist treatment atypically modulate GABAB receptor cell surface stability.

    Science.gov (United States)

    Fairfax, Benjamin P; Pitcher, Julie A; Scott, Mark G H; Calver, Andrew R; Pangalos, Menelas N; Moss, Stephen J; Couve, Andrés

    2004-03-26

    GABA(B) receptors are heterodimeric G protein-coupled receptors that mediate slow synaptic inhibition in the central nervous system. The dynamic control of the cell surface stability of GABA(B) receptors is likely to be of fundamental importance in the modulation of receptor signaling. Presently, however, this process is poorly understood. Here we demonstrate that GABA(B) receptors are remarkably stable at the plasma membrane showing little basal endocytosis in cultured cortical and hippocampal neurons. In addition, we show that exposure to baclofen, a well characterized GABA(B) receptor agonist, fails to enhance GABA(B) receptor endocytosis. Lack of receptor internalization in neurons correlates with an absence of agonist-induced phosphorylation and lack of arrestin recruitment in heterologous systems. We also demonstrate that chronic exposure to baclofen selectively promotes endocytosis-independent GABA(B) receptor degradation. The effect of baclofen can be attenuated by activation of cAMP-dependent protein kinase or co-stimulation of beta-adrenergic receptors. Furthermore, we show that increased degradation rates are correlated with reduced receptor phosphorylation at serine 892 in GABA(B)R2. Our results support a model in which GABA(B)R2 phosphorylation specifically stabilizes surface GABA(B) receptors in neurons. We propose that signaling pathways that regulate cAMP levels in neurons may have profound effects on the tonic synaptic inhibition by modulating the availability of GABA(B) receptors.

  8. The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Weight Loss in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Jessica E Potts

    Full Text Available To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus.Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo in adults with type 2 diabetes and a mean body mass index ≥ 25 kg/m2. Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator.In the mixed treatment comparison (27 trials, the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2 mg/week: -1.62 kg (95% CrI: -2.95 kg, -0.30 kg, exenatide 20 μg: -1.37 kg (95% CI: -222 kg, -0.52 kg, liraglutide 1.2 mg: -1.01 kg (95%CrI: -2.41 kg, 0.38 kg and liraglutide 1.8 mg: -1.51 kg (95% CI: -2.67 kg, -0.37 kg compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss.This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed.

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

    Directory of Open Access Journals (Sweden)

    Ferreira Leonardo F

    2011-01-01

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

  10. Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists

    Science.gov (United States)

    Murányi, Marianna; Cinar, Resat; Kékesi, Orsolya; Birkás, Erika; Fábián, Gabriella; Bozó, Beáta; Zentai, András; Tóth, Géza; Kicsi, Emese Gabriella; Mácsai, Mónika; Szabó, Gyula; Szücs, Mária

    2013-01-01

    Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid2-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the “so-called biased agonism” or “functional selectivity”. PMID:24350273

  11. Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists

    Directory of Open Access Journals (Sweden)

    Marianna Murányi

    2013-01-01

    Full Text Available Since the discovery of the endomorphins (EM, the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid2-endomorphin-2 (ACHC-EM2, had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60% acute antinociceptive response than the parent peptide, EM2 (45%, which peaked at 10 min after intracerebroventricular (icv administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the “so-called biased agonism” or “functional selectivity”.

  12. Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic triglyceride synthesis.

    Science.gov (United States)

    Wrobel, Jay; Steffan, Robert; Bowen, S Marc; Magolda, Ronald; Matelan, Edward; Unwalla, Rayomand; Basso, Michael; Clerin, Valerie; Gardell, Stephen J; Nambi, Ponnal; Quinet, Elaine; Reminick, Jason I; Vlasuk, George P; Wang, Shuguang; Feingold, Irene; Huselton, Christine; Bonn, Tomas; Farnegardh, Mathias; Hansson, Tomas; Nilsson, Annika Goos; Wilhelmsson, Anna; Zamaratski, Edouard; Evans, Mark J

    2008-11-27

    A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.

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

    Directory of Open Access Journals (Sweden)

    Decramer ML

    2013-01-01

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

  14. A new era of targeting the ancient gatekeepers of the immune system: toll-like agonists in the treatment of allergic rhinitis and asthma.

    Science.gov (United States)

    Aryan, Zahra; Holgate, Stephen T; Radzioch, Danuta; Rezaei, Nima

    2014-01-01

    Toll-like receptors (TLR) belong to a large family of pattern recognition receptors known as the ancient 'gatekeepers' of the immune system. TLRs are located at the first line of defense against invading pathogens as well as aeroallergens, making them interesting targets to modulate the natural history of respiratory allergy. Agonists of TLRs have been widely employed in therapeutic or prophylactic preparations useful for asthma/allergic rhinitis (AR) patients. MPL® (a TLR4 agonist) and the CpG oligodeoxynucleotide of 1018 ISS, a TLR9 agonist, show strong immunogenicity effects that make them appropriate adjuvants for allergy vaccines. Targeting the TLRs can enhance the efficacy of specific allergen immunotherapy, currently the only available 'curative' treatment for respiratory allergies. In addition, intranasal administration of AZD8848 (a TLR7 agonist) and VTX-1463 (a TLR8 agonist) as stand-alone therapeutics have revealed efficacy in the relief of the symptoms of AR patients. No anaphylaxis has been so far reported with such compounds targeting TLRs, with the most common adverse effects being transient and local irritation (e.g. redness, swelling and pruritus). Many other compounds that target TLRs have been found to suppress airway inflammation, eosinophilia and airway hyper-responsiveness in various animal models of allergic inflammation. Indeed, in the future a wide variability of TLR agonists and even antagonists that exhibit anti-asthma/AR effects are likely to emerge.

  15. Magnetic resonance guided focused ultrasound surgery of uterine fibroids-The tissue effects of GnRH agonist pre-treatment

    Energy Technology Data Exchange (ETDEWEB)

    Smart, O.C. [Department of Academic Obstetrics and Gynaecology, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom); Department of Magnetic Resonance Imaging, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom); Hindley, J.T. [Department of Academic Obstetrics and Gynaecology, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom); Regan, L. [Department of Academic Obstetrics and Gynaecology, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom); Gedroyc, W.M.W. [Department of Magnetic Resonance Imaging, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom)]. E-mail: w.gedroyc@imperial.ac.uk

    2006-08-15

    Objective: The purpose of this study was to determine the ablative effect of magnetic resonance guided focused ultrasound (MRgFUS) on fibroid tissue following the administration of gonadotrophin releasing hormone (GnRH) agonist. Study design: Fifty women with clinically symptomatic uterine fibroids were treated. Those with uterine diameter of 10 cm or greater were given 3 months pre-treatment with GnRH agonists. Data regarding number of ultrasound sonications, Joules of energy delivered and volume of thermal destruction was recorded. Results: Twenty-seven subjects were given GnRH agonist therapy before MRgFUS and 23 women underwent MRgFUS without pre-treatment. All patients in both study groups completed MR guided FUS as an outpatient procedure with no device related adverse events reported. In the group of women who received GnRH agonists, the volume of ablation was significantly larger than that in the control group (0.06 cm{sup 3} versus 0.03 cm{sup 3}, P < 0.05), per Joule of energy applied. Conclusion: The use of GnRH agonists potentiates the thermal effects of MRgFUS in women undergoing treatment of uterine fibroids.

  16. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss

    DEFF Research Database (Denmark)

    Iepsen, E W; Lundgren, J; Dirksen, C

    2015-01-01

    BACKGROUND: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin...... receptors thereby preserving free leptin levels and preventing weight regain. METHODS: In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case...... of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor...

  17. A systematic review of health economic models of opioid agonist therapies in maintenance treatment of non-prescription opioid dependence.

    Science.gov (United States)

    Chetty, Mersha; Kenworthy, James J; Langham, Sue; Walker, Andrew; Dunlop, William C N

    2017-02-24

    Opioid dependence is a chronic condition with substantial health, economic and social costs. The study objective was to conduct a systematic review of published health-economic models of opioid agonist therapy for non-prescription opioid dependence, to review the different modelling approaches identified, and to inform future modelling studies. Literature searches were conducted in March 2015 in eight electronic databases, supplemented by hand-searching reference lists and searches on six National Health Technology Assessment Agency websites. Studies were included if they: investigated populations that were dependent on non-prescription opioids and were receiving opioid agonist or maintenance therapy; compared any pharmacological maintenance intervention with any other maintenance regimen (including placebo or no treatment); and were health-economic models of any type. A total of 18 unique models were included. These used a range of modelling approaches, including Markov models (n = 4), decision tree with Monte Carlo simulations (n = 3), decision analysis (n = 3), dynamic transmission models (n = 3), decision tree (n = 1), cohort simulation (n = 1), Bayesian (n = 1), and Monte Carlo simulations (n = 2). Time horizons ranged from 6 months to lifetime. The most common evaluation was cost-utility analysis reporting cost per quality-adjusted life-year (n = 11), followed by cost-effectiveness analysis (n = 4), budget-impact analysis/cost comparison (n = 2) and cost-benefit analysis (n = 1). Most studies took the healthcare provider's perspective. Only a few models included some wider societal costs, such as productivity loss or costs of drug-related crime, disorder and antisocial behaviour. Costs to individuals and impacts on family and social networks were not included in any model. A relatively small number of studies of varying quality were found. Strengths and weaknesses relating to model structure, inputs and approach were identified across

  18. Effects of PPAR-γ agonist treatment on LPS-induced mastitis in rats.

    Science.gov (United States)

    Mingfeng, Ding; Xiaodong, Ming; Yue, Liu; Taikui, Piao; Lei, Xiao; Ming, Liu

    2014-12-01

    PPAR-γ, a member of the nuclear receptor superfamily, plays an important role in lipid metabolism and inflammation. The aim of this study was to investigate the preventive effects of synthetic PPAR-γ agonist rosiglitazone on lipopolysaccharide (LPS)-induced mastitis in rats. The mouse model of mastitis was induced by the injection of LPS through the duct of the mammary gland. Rosiglitazone was injected 1 h before the induction of LPS intraperitoneally. The results showed that rosiglitazone attenuated the infiltration of inflammatory cells, the activity of myeloperoxidase (MPO), and the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in a dose-dependent manner. Additionally, Western blotting showed that rosiglitazone inhibited the phosphorylation of IκB-α and NF-κB p65. These results indicated that rosiglitazone has a protective effect on mastitis, and the anti-inflammatory mechanism of rosiglitazone on LPS-induced mastitis in rats may be due to its ability to inhibit NF-κB signaling pathways. PPAR-γ may be a potential therapeutic target against mastitis.

  19. Screening of agonistic activities against four nuclear receptors in wastewater treatment plants in Japan using a yeast two-hybrid assay

    Institute of Scientific and Technical Information of China (English)

    Daisuke Inoue; Koki Nakama; Kazuko Sawada; Taro Watanabe; Hisae Matsui; Kazunari Sei; Tsuyoshi Nakanishi; Michihiko Ike

    2011-01-01

    To assess the potential endocrine disruptive effects through multiple nuclear receptors (NRs), especially non-steroidal NRs, in municipal wastewater, we examined the agonistic activities on four NRs (estrogen receptor c, thyroid hormone receptor α, retinoic acid receptor α and retinoid X receptor α) of untreated and treated wastewater from municipal wastewater treatment plants (WWTPs) in Japan using a yeast two-hybrid assay.Investigation of the infiuent and effluent of seven WWTPs revealed that agonistic activities against steroidal and non-steroidal NRs were always detected in the infiuents and partially remained in the effluents.Further investigation of four WWTPs employing conventional activated sludge, pseudo-anoxic-oxic, anoxic-oxic and anaerobic-anoxic-oxic processes revealed that the ability to reduce the agonistic activity against each of the four NRs varies depending on the treatment process.These results indicated that municipal wastewater in Japan commonly contains endocrine disrupting chemicals that exert agonistic activities on steroidal and non-steroidal NRs, and that some of these chemicals are released into the natural aquatic environment.Although the results obtained in yeast assays suggested that measured levels of non-steroidal NR agonists in the effluent of WWTPs were not likely to cause any biological effect, further study is required to assess their possible risks in detail.

  20. Polymorphisms in NF-κB, PXR, LXR, PPARγ and risk of inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Vibeke Andersen; Jane Christensen; Anja Ernst; Bent A Jacobsen; Anne Tj(o)nneland; Henrik B Krarup; Ulla Vogel

    2011-01-01

    AIM: To investigate the contribution of polymorphisms in nuclear receptors to risk of inflammatory bowel disease (IBD).METHODS: Genotypes of nuclear factor (NF)-κB (NFKB1)NFκB -94ins/del (rs28362491); peroxisome proliferatoractivated receptor (PPAR)-γ (PPARγ) PPARγ Pro12Ala (rs 1801282) and C1431T (rs 3856806); pregnane X receptor (PXR) (NR1I2) PXR A-24381C (rs1523127), C8055T (2276707), and A7635G (rs 6785049); and liver X receptor (LXR) (NR1H2) LXR T-rs1405655-C and T-rs2695121-C were assessed in a Danish case-control study of 327 Crohn's disease patients, 495 ulcerative colitis (UC) patients,and 779 healthy controls. Odds ratio (OR) and 95% CI were estimated by logistic regression models.RESULTS: The PXR A7635G variant, the PPARγ Pro-12Ala and LXR T-rs2695121-C homozygous variant genotypes were associated with risk of UC (OR: 1.31, 95% CI: 1.03-1.66, P = 0.03, OR: 2.30, 95% CI: 1.04-5.08,P = 0.04, and OR: 1.41, 95% CI: 1.00-1.98, P = 0.05,respectively) compared to the corresponding homozygous wild-type genotypes. Among never smokers, PXR A7635G and the LXR T-rs1405655-C and T-rs2695121-C variant genotypes were associated ith risk of IBD (OR: 1.41, 95% CI: 1.05-1.91, P = 0.02, OR: 1.63,95% CI: 1.21-2.20, P = 0.001, and OR: 2.02, 95% CI:1.36-2.99, P = 0.0005, respectively) compared to the respective homozygous variant genotypes. PXR A7635G (rs6785049) variant genotype was associated with a higher risk of UC diagnosis before the age of 40 years and with a higher risk of extensive disease (OR: 1.34,95% CI: 1.03-1.75 and OR: 2.49, 95% CI: 1.24-5.03, respectively).CONCLUSION: Common PXR and LXR polymorphisms may contribute to risk of IBD, especially among never smokers.

  1. 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...

  2. Site-specific dephosphorylation of tau of apolipoprotein E-deficient and control mice by M1 muscarinic agonist treatment.

    Science.gov (United States)

    Genis, I; Fisher, A; Michaelson, D M

    1999-01-01

    Apolipoprotein E (apoE)-deficient mice have memory deficits that are associated with synaptic loss of basal forebrain cholinergic projections and with hyperphosphorylation of distinct epitopes of the microtubule-associated protein tau. Furthermore, treatment of apoE-deficient mice with the M1 selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline) [AF150(S)] abolishes their memory deficits and results in recovery of their brain cholinergic markers. In the present study, we used a panel of anti-tau monoclonal antibodies to further map the tau epitopes that are hyperphosphorylated in apoE-deficient mice and examined the effects of prolonged treatment with AF150(S). This revealed that tau of apoE-deficient mice contains a distinct, hyperphosphorylated "hot spot" domain which is localized N-terminally to the microtubule binding domain of tau, and that AF150(S) has an epitope-specific tau dephosphorylating effect whose magnitude is affected by apoE deficiency. Accordingly, epitopes which reside in the hyperphosphorylated "hot spot" are dephosphorylated by AF150(S) in apoE-deficient mice but are almost unaffected in the controls, whereas epitopes which flank this tau domain are dephosphorylated by AF150(S) in both mice groups. In contrast, epitopes located at the N and C terminals of tau are unaffected by AF150(S) in both groups of mice. These findings suggest that apoE deficiency results in hyperphosphorylation of a distinct tau domain whose excess phosphorylation can be reduced by muscarinic treatment.

  3. Treatment of antipsychotic-induced hyperprolactinemia: an update on the role of the dopaminergic receptors D2 partial agonist aripiprazole.

    Science.gov (United States)

    De Berardis, Domenico; Fornaro, Michele; Serroni, Nicola; Marini, Stefano; Piersanti, Monica; Cavuto, Marilde; Valchera, Alessandro; Mazza, Monica; Girinelli, Gabriella; Iasevoli, Felice; Perna, Giampaolo; Martinotti, Giovanni; Di Giannantonio, Massimo

    2014-01-01

    Hyperprolactinemia is an unwanted adverse effect present in several typical and atypical antipsychotics. Aripiprazole is a drug with partial agonist activity at the level of dopamine receptors D2, which may be effective for antipsychotic- induced hyperprolactinemia. Therefore, we analyzed the literature concerning the treatment of antipsychoticinduced hyperprolactinemia with aripiprazole by updating a previous paper written on the same topic. More recent studies were reviewed. They showed that there are two options for the treatment of antipsychotic-induced hyperprolactinemia with aripiprazole. The safest strategy may require the addition of aripiprazole to ongoing treatments, in the case patients had previously responded to antipsychotic drugs and then developed hyperprolactinemia. However, it is advisable to monitor the patients in case relapses and/or side effect, although rare, might occur. Switching drugs should be considered when a patient does not appear to be responding to the previous antipsychotic, thus developing hyperprolactinemia. A cross-taper switch should always be considered, but the risk of a relapse in the disorder may occur more frequently and the patients should be closely monitored. However, limitations must be considered and further studies are needed to definitely elucidate this important issue. Some relevant patents are also described in this review.

  4. Beta-1 adrenergic agonist treatment mitigates negative changes in cancellous bone microarchitecture and inhibits osteocyte apoptosis during disuse.

    Directory of Open Access Journals (Sweden)

    Joshua M Swift

    Full Text Available The sympathetic nervous system (SNS plays an important role in mediating bone remodeling. However, the exact role that beta-1 adrenergic receptors (beta1AR have in this process has not been elucidated. We have previously demonstrated the ability of dobutamine (DOB, primarily a beta1AR agonist, to inhibit reductions in cancellous bone formation and mitigate disuse-induced loss of bone mass. The purpose of this study was to characterize the independent and combined effects of DOB and hindlimb unloading (HU on cancellous bone microarchitecture, tissue-level bone cell activity, and osteocyte apoptosis. Male Sprague-Dawley rats, aged 6-mos, were assigned to either normal cage activity (CC or HU (n = 18/group for 28 days. Animals were administered either daily DOB (4 mg/kg BW/d or an equal volume of saline (VEH (n = 9/gp. Unloading resulted in significantly lower distal femur cancellous BV/TV (-33%, Tb.Th (-11%, and Tb.N (-25% compared to ambulatory controls (CC-VEH. DOB treatment during HU attenuated these changes in cancellous bone microarchitecture, resulting in greater BV/TV (+29%, Tb.Th (+7%, and Tb.N (+21% vs. HU-VEH. Distal femur cancellous vBMD (+11% and total BMC (+8% were significantly greater in DOB- vs. VEH-treated unloaded rats. Administration of DOB during HU resulted in significantly greater osteoid surface (+158% and osteoblast surface (+110% vs. HU-VEH group. Furthermore, Oc.S/BS was significantly greater in HU-DOB (+55% vs. CC-DOB group. DOB treatment during unloading fully restored bone formation, resulting in significantly greater bone formation rate (+200% than in HU-VEH rats. HU resulted in an increased percentage of apoptotic cancellous osteocytes (+85%, reduced osteocyte number (-16%, lower percentage of occupied osteocytic lacunae (-30% as compared to CC-VEH, these parameters were all normalized with DOB treatment. Altogether, these data indicate that beta1AR agonist treatment during disuse mitigates negative changes

  5. Combination PPARγ and RXR Agonist Treatment in Melanoma Cells: Functional Importance of S100A2

    Directory of Open Access Journals (Sweden)

    Joshua P. Klopper

    2010-01-01

    Full Text Available Nuclear hormone receptors, including RXR and PPARγ, represent novel therapeutic targets in melanoma. We have previously shown that the DRO subline of the amelanotic melanoma A375 responds to rexinoid and thiazolidinedione (TZD treatment in vitro and in vivo. We performed microarray analysis of A375(DRO after TZD and combination rexinoid/TZD treatment in which the calcium binding protein S100A2 had increased expression after rexinoid or TZD treatment and a synergistic increase to combination treatment. Increased S100A2 expression is dependent on an intact PPARγ receptor, but it is not sufficient to mediate the antiproliferative effects of rexinoid/TZD treatment. Over expression of S100A2 enhanced the effect of rexinoid and TZD treatment while inhibition of S100A2 expression attenuated the response to rexinoid/TZD treatment, suggesting that S100A2 is necessary for optimal response to RXR and PPARγ activation by respective ligands. In summary, we have identified potential downstream mediators of rexinoid and TZD treatment in a poorly differentiated melanoma and found that alterations in S100A2 expression affect RXR and PPARγ signaling in A375(DRO cells. These studies provide insight into potential mechanisms of tumor response or resistance to these novel therapies.

  6. Design and development of a peptide-based adiponectin receptor agonist for cancer treatment

    Directory of Open Access Journals (Sweden)

    Lovas Sandor

    2011-10-01

    displayed excellent stability (at least 30 min in mouse blood or serum and did not induce gross toxic effects at 5-50 mg/kg bolus doses in normal CBA/J mice. Conclusions ADP 355 is a first-in-class adiponectin receptor agonist. Its biological activity, superior stability in biological fluids as well as acceptable toxicity profile indicate that the peptidomimetic represents a true lead compound for pharmaceutical development to replace low adiponectin levels in cancer and other malignancies.

  7. Pharmacogenetics of β2-Agonists

    OpenAIRE

    Nobuyuki Hizawa

    2011-01-01

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

  8. Randomized Trial of Oxytocin Antagonist Atosiban Versus Beta-adrenergic Agonists in the Treatment of Spontaneous Preterm Labor in Taiwanese Women

    Directory of Open Access Journals (Sweden)

    Chia-Hui Lin

    2009-06-01

    Conclusion: The present study showed similar effectiveness between atosiban and ritodrine, while tachycardia occurred more frequently in women treated with ritodrine. These results indicate that atosiban is an effective tocolytic drug without the conventional cardiovascular side effects often seen with beta-agonist treatment.

  9. Liver X Receptor Agonist Modifies the DNA Methylation Profile of Synapse and Neurogenesis-Related Genes in the Triple Transgenic Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Sandoval-Hernández, A G; Hernández, H G; Restrepo, A; Muñoz, J I; Bayon, G F; Fernández, A F; Fraga, M F; Cardona-Gómez, G P; Arboleda, H; Arboleda, Gonzalo H

    2016-02-01

    The liver X receptor agonist, GW3965, improves cognition in Alzheimer's disease (AD) mouse models. Here, we determined if short-term GW3965 treatment induces changes in the DNA methylation state of the hippocampus, which are associated with cognitive improvement. Twenty-four-month-old triple-transgenic AD (3xTg-AD) mice were treated with GW3965 (50 mg/kg/day for 6 days). DNA methylation state was examined by modified bisulfite conversion and hybridization on Illumina Infinium Methylation BeadChip 450 k arrays. The Morris water maze was used for behavioral analysis. Our results show in addition to improvement in cognition methylation changes in 39 of 13,715 interrogated probes in treated 3xTg-AD mice compared with untreated 3xTg-AD mice. These changes in methylation probes include 29 gene loci. Importantly, changes in methylation status were mainly from synapse-related genes (SYP, SYN1, and DLG3) and neurogenesis-associated genes (HMGB3 and RBBP7). Thus, our results indicate that liver X receptors (LXR) agonist treatment induces rapid changes in DNA methylation, particularly in loci associated with genes involved in neurogenesis and synaptic function. Our results suggest a new potential mechanism to explain the beneficial effect of GW3965.

  10. Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2004-01-01

    analogues of the hormone (or agonists of the GLP-1 receptor) are in development, along with DPP-IV inhibitors, which have been demonstrated to protect the endogenous hormone and enhance its activity. Agonists include both albumin-bound analogues of GLP-1 and exendin-4, a lizard peptide. Clinical studies...

  11. A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep.

    Science.gov (United States)

    Hough, D; Bellingham, M; Haraldsen, I R; McLaughlin, M; Robinson, J E; Solbakk, A K; Evans, N P

    2017-03-01

    Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (Plong lasting effects on other brain areas and aspects of cognitive function. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction.

    Science.gov (United States)

    Johnson, Matthew W; Garcia-Romeu, Albert; Cosimano, Mary P; Griffiths, Roland R

    2014-11-01

    Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.

  13. In Vivo Efficacy of HD0471953: A Novel GPR119 Agonist for the Treatment of Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    So Ra Kim

    2013-01-01

    Full Text Available G-protein coupled receptor 119 (GPR119 has emerged as a promising new target for the treatment of type 2 diabetes mellitus. The expression of GPR119 on the pancreatic B cells and intestinal L cells provides a unique opportunity for a single drug to promote insulin and GLP-1 secretion. In this study, we identified a novel small molecule GPR119 agonist, HD0471953, from our large library of synthetic compounds based on its ability to anti-hyperglycemic effects on T2DM murine models. We have tested the acute efficacy of HD0471953 by the oral glucose tolerance test (OGTT with normal C57BL/6J mice. Then, chronic administrations of HD0471953 were performed to evaluate the efficacy on various diabetic rodent models. Single administration of HD0471953 showed improved glycemic control with a dose-dependent manner in OGTT with normal mice, and the insulin and GLP-1 were also increased. To identify chronic efficacy, we have observed a decline of blood glucose and fasting insulin in a dose-dependent manner of 10, 20, and 50 mpk in db/db mice. The results suggest that HD0471953 may be a potentially promising anti-hyperglycemic agent for the treatment of patients with type 2 diabetes mellitus.

  14. The case for intraocular delivery of PPAR agonists in the treatment of diabetic retinopathy.

    LENUS (Irish Health Repository)

    Treacy, Maxwell P

    2012-09-01

    Systemic therapeutics targeting the peroxisome proliferator-activated receptors have been found to be beneficial in the treatment of diabetic retinopathy. In this paper, we provide a rationale for the use of these therapeutics as intraocular agents. In addition, we introduce the peroxisome proliferator-activated receptors and describe their functions in response to the drugs.

  15. Rexinoid Bexarotene Modulates Triglyceride but not Cholesterol Metabolism via Gene-Specific Permissivity of the RXR/LXR Heterodimer in the Liver

    DEFF Research Database (Denmark)

    Lalloyer, Fanny; Pedersen, Thomas Åskov; Gross, Barbara

    2009-01-01

    of cardiovascular disease. The molecular mechanism behind this hypertriglyceridemia remains poorly understood. METHODS AND RESULTS: Using wild-type and LXRalpha/beta-deficient mice, we show here that bexarotene induces hypertriglyceridemia and activates hepatic LXR-target genes of lipogenesis in an LXR...

  16. The Liver X Receptor (LXR) and its Target Gene ABCA1 are Regulated Upon Low Oxygen in Human Trophoblast Cells : A Reason for Alterations in Preeclampsia?

    NARCIS (Netherlands)

    Plosch, T.; Gellhaus, A.; van Straten, E. M. E.; Wolf, N.; Huijkman, N. C. A.; Schmidt, M.; Dunk, C. E.; Kuipers, F.; Winterhager, E.

    2010-01-01

    Objectives: The Liver X receptors (LXR) alpha and beta and their target genes such as the ATP-binding cassette (ABC) transporters have been shown to be crucially involved in the regulation of cellular cholesterol homeostasis. The aim of this study was to characterize the role of LXR alpha/beta in th

  17. 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...

  18. Gonadothropin-releasing hormone agonist as a treatment of choice for central precocious puberty

    Directory of Open Access Journals (Sweden)

    Jose R.L. Batubara

    2010-11-01

    Full Text Available Precocious puberty is defi ned as pubertal development which occurs too early. The age limit in this term is based on the onset of puberty in normal population. Some points have to be taken into account, such as ethnicity, gender, nutritional conditions, and secular trends. In girls, precocious puberty is defi ned by breast development occured before 8 years old. In boys, precocious puberty is defi ned as gonadarche or pubarche before 9 years of age. The clinical course of precocious puberty varies widely, ranging from alternating, slowly progressive, and rapidly progressive    form. The rapidly progressive forms of idiopathic central precocious puberty need to be treated because it may result in early epiphyseal closure and short fi nal height, and also pyschosocial problems in the affected children and the family. The aims of treatment are to arrest physical maturation, prevent early menarche, and also improve adult height combined with normal body proportions. Gonadotropin releasing hormone analogue is the treatment of choice for central precocious puberty. Gonadotropin releasing horomone analogue has suppressive effect on the pituitarygonadal axis, therefore it suppresses LH secretion. This leads to the return of estradiol and testosterone to prepubertal levels. Treatment using gonadotropin releasing horomone analogue is shown to reduce breast size, pubic hair, ovarian and uterine size in girls, and decrease testicular size in boys. Gonadotropin releasing hormone analogue is effective in halting progression of secondary sexual characteristics development, presenting menstrual cycle, slowing bone-age advancement, and also improving fi nal height. (Med J Indones 2010; 19:287-92Keywords: gonadache, GRH analogue, pubarche , precocious puberty

  19. Neonatal DSP-4 treatment modifies antinociceptive effects of the CB1 receptor agonist methanandamide in adult rats.

    Science.gov (United States)

    Korossy-Mruk, Eva; Kuter, Katarzyna; Nowak, Przemysław; Szkilnik, Ryszard; Rykaczewska-Czerwinska, Monika; Kostrzewa, Richard M; Brus, Ryszard

    2013-01-01

    To study the influence of the central noradrenergic system on antinociceptive effects mediated by the CB(1)-receptor agonist methanandamide, intact rats were contrasted with rats in which noradrenergic nerves were largely destroyed shortly after birth with the neurotoxin DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg sc × 2, P1 and P3); zimelidine (10 mg/kg sc, 30 min pretreatment, selective serotonin reuptake inhibitor). When rats attained 10 weeks of age, monoamine and their metabolite concentrations were determined in the frontal cortex, thalamus, and spinal cord by an HPLC/ED method. Antinociceptive effects after methanandamide (10 mg/kg ip) apply were evaluated by a battery of tests. In addition, immunohistochemistry and densitometric analysis of the cannabinoid CB(1) receptor in the rat brain was performed. DSP-4 lesioning was associated with a reduction in norepinephrine content of the frontal cortex (>90 %) and spinal cord (>80 %) with no changes in the thalamus. Neonatal DSP-4 treatment produced a significant reduction in the antinociceptive effect of methanandamide in the tail-immersion test, hot-plate test and writhing tests. In the paw pressure and formalin hind paw tests results were ambiguous. These findings indicate that the noradrenergic system exerts a prominent influence on analgesia acting via the cannabinoid system in brain, without directly altering CB(1) receptor density in the brain.

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

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2016-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1–based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs continue to become available, physicians will soon face the challenge of selecting the right option customized to their patient's needs. The following discussion, derived from an extensive literature search using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide, provides a comprehensive review of existing and upcoming molecules in the GLP-1 RA class in terms of their structure, pharmacological profiles, efficacy, safety, and convenience. Search Methodology: A literature search was conducted using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide. Relevant articles were those that discussed structural, pharmacokinetic and pharmacodynamic differences, classification, long-acting and short-acting GLP-1 RAs, phase 3 trials, and expert opinions. Additional targeted searches were conducted on diabetes treatment guidelines and reviews on safety, as well as the American Diabetes Association/European Society for Study of Diabetes (ADA/EASD statement on pancreatic safety.

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

    Science.gov (United States)

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

    2016-01-01

    Glucagon-like peptide-1 (GLP-1)-based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs) continue to become available, physicians will soon face the challenge of selecting the right option customized to their patient's needs. The following discussion, derived from an extensive literature search using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide, provides a comprehensive review of existing and upcoming molecules in the GLP-1 RA class in terms of their structure, pharmacological profiles, efficacy, safety, and convenience. Search Methodology: A literature search was conducted using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide. Relevant articles were those that discussed structural, pharmacokinetic and pharmacodynamic differences, classification, long-acting and short-acting GLP-1 RAs, phase 3 trials, and expert opinions. Additional targeted searches were conducted on diabetes treatment guidelines and reviews on safety, as well as the American Diabetes Association/European Society for Study of Diabetes (ADA/EASD) statement on pancreatic safety.

  2. Treatment with CB2 Agonist JWH-133 Reduces Histological Features Associated with Erectile Dysfunction in Hypercholesterolemic Mice

    Directory of Open Access Journals (Sweden)

    Rodrigo Araujo Fraga-Silva

    2013-01-01

    Full Text Available Hypercholesterolemia is one of the most important risk factors for erectile dysfunction, mostly due to the impairment of oxidative stress and endothelial function in the penis. The cannabinoid system might regulate peripheral mechanisms of sexual function; however, its role is still poorly understood. We investigated the effects of CB2 activation on oxidative stress and fibrosis within the corpus cavernosum of hypercholesterolemic mice. Apolipoprotein-E-knockout mice were fed with a western-type diet for 11 weeks and treated with JWH-133 (selective CB2 agonist or vehicle during the last 3 weeks. CB2 receptor expression, total collagen content, and reactive oxygen species (ROS production within the penis were assessed. In vitro corpus cavernosum strips preparation was performed to evaluate the nitric oxide (NO bioavailability. CB2 protein expression was shown in cavernosal endothelial and smooth muscle cells of wild type and hypercholesterolemic mice. Treatment with JWH-133 reduced ROS production and NADPH-oxidase expression in hypercholesterolemic mice penis. Furthermore, JWH-133 increased endothelial NO synthase expression in the corpus cavernosum and augmented NO bioavailability. The decrease in oxidative stress levels was accompanied with a reduction in corpus cavernosum collagen content. In summary, CB2 activation decreased histological features, which were associated with erectile dysfunction in hypercholesterolemic mice.

  3. Gonadotropin-secreting pituitary adenoma with concomitant hypersecretion of testosterone and elevated sperm count. Treatment with LRH agonist.

    Science.gov (United States)

    Zárate, A; Fonseca, M E; Mason, M; Tapia, R; Miranda, R; Kovacs, K; Schally, A V

    1986-09-01

    Hypersecretion of both FSH and LH was demonstrated in a man with pituitary macroadenoma, who also presented elevated levels of blood testosterone and an increased sperm count. The patient underwent transsphenoidal surgery followed immediately by cranial irradiation. Immunocytochemical analysis of the tumour revealed the presence of FSH, LH, TSH and the alpha-subunit. Gel chromatography of the serum on Sephadex G-100 revealed immunoactive FSH, LH and the alpha-subunit which coeluted with the labelled standards of corresponding hormones. Blood levels of both gonadotropins and testosterone remained persistently elevated up to one year following surgical decompression of the tumour and radiotherapy. It was decided to treat this patient with sc administration of 100 micrograms D-Trp6-LRH biweekly. After 20 weeks, LRH-analogue treatment resulted in the reduction of serum FSH and LH levels and a diminishing in tumour size as assessed by computed tomography scan of the pituitary. This report shows that in a patient with clinically and biochemically documented gonadotropin-secreting adenoma, inducing a state of persistent gonadal hyperfunction, pituitary surgery and cranial irradiation failed to normalize the biochemical abnormality; however, therapy with D-Trp6-LRH agonist induced clinical, biochemical and radiologic improvement.

  4. Screening for PPAR γ agonist from Myristica fragrans Houtt seeds for the treatment of Type 2 diabetes by in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Keri Lestari

    2012-10-01

    Full Text Available In general, a type two diabetes mellitus (T2DM patient suffers for hyperglycaemia and insulin resistance. Nowadays, there is an anti diabetes drug working as a PPAR/ agonist and has a significant effect to improve the hyperglycemia and insulin resistance condition. However, this drug gives a negative effect on lipid circulation parameters. In this investigation, nutmeg (Myristica fragrans extracts (NuSE was tested against PPARγ using cell-based GAL4/PPAR chimera transactivation and trancient transvection assay with three PPAR response element (PPREs containing reporters. The results demonstrate that the NuSE has significant PPARγ agonist activity, although their potency was less than the standard PPARγ full agonist. An investigation of antidiabetic activity of the NuSE has been carried out on rats. Rats were treated orally every day for six days with the ethanol of NuSE in several doses. The result of the experiment showed that each dose of NuSE gave hypoglycemic activity (p= 0.01 and p=0.05. The experiment also showed that an increase in dosage caused an increased in the hypoglycemic activity. Therefore, nutmeg (Myristica fragrans seeds might be potential against antidiabetic agent for the treatment of type two diabetes with a PPAR /. agonistic mechanism.

  5. Melatonin agonists and insomnia.

    Science.gov (United States)

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

    2010-02-01

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

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

    DEFF Research Database (Denmark)

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

    2007-01-01

    OBJECTIVE: To elucidate the association between treatment with ergot-derived dopamine agonists (EDDA) and valvular abnormalities amongst patients with idiopathic Parkinson's disease (IPD) and secondly, to analyse the yield of clinical screening for valvular heart disease. DESIGN: A cross....... Interventions. Patients were screened for valvular heart disease by clinical means and by examiner-blinded echocardiography. Main outcome measure was valvular regurgitation revealed by echocardiography. RESULTS: Severe aortic regurgitation (n = 4) or moderate aortic (n = 12), mitral (n = 3) or tricuspidal valve...

  7. Discovery of Isoxazole Analogs of Sazetidine-A as Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists for the Treatment of Depression

    OpenAIRE

    Liu, Jianhua; Yu, Li-Fang; Eaton, J. Brek; Caldarone, Barbara; Cavino, Katie; Ruiz, Christina; Terry, Matthew; Fedolak, Allison; Wang, DaGuang; Ghavami, Afshin; Lowe, David A; Brunner, Dani; Lukas, Ronald J; Kozikowski, Alan P.

    2011-01-01

    Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenalin are not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogs that interact with α4β2-nAChR as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selectiv...

  8. [Effect of combined treatment with dopamine receptor agonists and antagonists of aldosterone on the performance of daily blood pressure monitoring in patients with hypertension and concomitant obesity].

    Science.gov (United States)

    Lyzogub, V G; Sobol', V O; Dolynna, O V; Kuz'mins'ka, L A

    2012-01-01

    In hypertensive patients with concomitant obesity observed decrease in activity of dopaminergic system in conjunction with increased activity of the renin-angiotensin-aldosterone system. Identified changes point to the advisability of appointing this group of patients the dopamine receptor agonist - bromocriptine-KV and antagonist of aldosterone - veroshpiron. As a result of treatment was an increase in dopamine levels in the urine, a decrease of aldosterone in the blood, normalization of the daily blood pressure monitoring.

  9. Effects of a combined treatment with tamoxifen and estrogen receptor β agonists on human breast cancer cell lines.

    Science.gov (United States)

    Lattrich, Claus; Schüler, Susanne; Häring, Julia; Skrzypczak, Maciej; Ortmann, Olaf; Treeck, Oliver

    2014-01-01

    Coexpression of estrogen receptors (ER) α and β is present in about half of all breast cancer cases. Whereas ERα is a well-established target for endocrine therapy with the selective estrogen receptor modulator tamoxifen, the applicability of ERβ as target in breast cancer therapy is unclear. In this study, we examined the effects of two synthetic ERβ agonists alone and in combination with tamoxifen on ERα/β-positive breast cancer cells. We treated MCF-7 and T-47D breast cancer cells with the ERβ agonists ERB-041 and WAY-200070 and measured the effects on cell growth. In addition, transcriptome analyses were performed by means of Affymetrix GeneChip arrays. When given alone, ERβ agonists ERB-041 and WAY-200070 did not affect the growth of MCF-7 or T-47D cells. In contrast, addition of these drugs to tamoxifen increased its growth-inhibitory effect on both cell lines. This effect was more pronounced under serum-free conditions, but was also observed in the presence of serum in T-47D cells. Transcriptome analyses revealed a set of genes regulated after addition of ERβ agonists including S100A8 and CD177. The observed enhanced growth-inhibitory effects of a combination of tamoxifen and ERβ agonists in vitro encourage further studies to test its possible use in the clinical setting.

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

    Directory of Open Access Journals (Sweden)

    Zi-lin Li

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

  11. The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Casadesus, Gemma; Garrett, Matthew R; Webber, Kate M; Hartzler, Anthony W; Atwood, Craig S; Perry, George; Bowen, Richard L; Smith, Mark A

    2006-01-01

    Estrogen and other sex hormones have received a great deal of attention for their speculative role in Alzheimer's disease (AD), but at present a direct connection between estrogen and the pathogenesis of AD remains elusive and somewhat contradictory. For example, on one hand there is a large body of evidence suggesting that estrogen is neuroprotective and improves cognition, and that hormone replacement therapy (HRT) at the onset of menopause reduces the risk of developing AD decades later. However, on the other hand, studies such as the Women's Health Initiative demonstrate that HRT initiated in elderly women increases the risk of dementia. While estrogen continues to be investigated, the disparity of findings involving HRT has led many researchers to examine other hormones of the hypothalamic-pituitary-gonadal axis such as luteinising hormone (LH) and follicle-stimulating hormone. In this review, we propose that LH, rather than estrogen, is the paramount player in the pathogenesis of AD. Notably, both men and women experience a 3- to 4-fold increase in LH with aging, and LH receptors are found throughout the brain following a regional pattern remarkably similar to those neuron populations affected in AD. With respect to disease, serum LH level is increased in women with AD relative to non-diseased controls, and levels of LH in the brain are also elevated in AD. Mechanistically, we propose that elevated levels of LH may be a fundamental instigator responsible for the aberrant reactivation of the cell cycle that is seen in AD. Based on these aforementioned aspects, clinical trials underway with leuprolide acetate, a gonadotropin-releasing hormone agonist that ablates serum LH levels, hold great promise as a ready means of treatment in individuals afflicted with AD.

  12. [All signs of metabolic syndrome in the hypertensive ISIAH rats are associated with increased activity of transcription factors PPAR, LXR, PXR, and CAR in the liver].

    Science.gov (United States)

    Pivovarova, E N; Dushkin, M I; Perepechaeva, M L; Kobzev, V F; Trufakin, V A; Markel', A L

    2011-01-01

    It is known that the metabolic syndrome (MS), which includes hypertension, dislipidemia, glucose intolerance, and obesity leads to cardiovascular diseases. The MS risk is growing catastrophically. Molecular mechanisms allowing to understand the reason of integrated dysfunctions, taking place at MS cases, have remained almost unstudied. The chronical stress plays a crucial role in MS development; therefore in the present work a hypertensive rat strain with Inherited Stress-Induced Arterial Hypertension (ISIAH) was used as a model. It was shown that ISIAH rat strain as compared with the control WAG rat strain is characterized by increased content of triglyceride, VLDL and LDL cholesterols, a decreased content of HDL cholesterol, a high level of apolipoprotein B-100, and decreased level of apolipoprotein A-I. The ISIAH rats body weight was higher as compared with WAG rats; ISIAH rats blood glucose content was higher too. Thus, strain hypertension for ISIAH rat is accompanied by dislipidemia, increased glucose content, and increased body weight, representing a whole set of MS signs. Since at MS cases the systemic abnormalities in lipid and carbohydrate metabolism take place, the functional activity of transcription factors (TFs) participating in integral regulation of lipid and carbohydrate metabolism genes in liver was measured. PPAR, LXR, PXR, CAR DNA-binding activity was increased in ISIAH rats, suggesting involvement of these TFs in MS development. Integrated investigation of PPAR, LXR, PXR, CAR regulatory mechanisms, signal transduction and transcriptional targets will provide insights into the pathogenesis of MS and offer valuable information for designing of drugs for MS treatment.

  13. GPR119 agonists: a promising approach for T2DM treatment? A SWOT analysis of GPR119.

    Science.gov (United States)

    Kang, Sang-Uk

    2013-12-01

    Ever since its advent as a promising therapeutic target for type 2 diabetes mellitus (T2DM), G-protein-coupled receptor 119 (GPR119) has received much interest from the pharmaceutical industry. This interest peaked in June 2010, when Sanofi-Aventis agreed to pay Metabolex (Cymabay Therapeutics) US$375 million for MBX-2982, which was a representative orally active GPR119 agonist. However, Sanofi-Aventis opted to terminate the deal in May 2011 and another leading GPR119 agonist, GSK1292263, had a loss of efficacy during its clinical trial. In this review, I discuss the pros and cons of GPR119 through a strengths, weaknesses, opportunities, and threats (SWOT) analysis and propose development strategies for the eventual success of a GPR119 agonist development program.

  14. E17110 promotes reverse cholesterol transport with liver X receptor β agonist activity in vitro

    Directory of Open Access Journals (Sweden)

    Ni Li

    2016-05-01

    Full Text Available Liver X receptor (LXR plays an important role in reverse cholesterol transport (RCT, and activation of LXR could reduce atherosclerosis. In the present study we used a cell-based screening method to identify new potential LXRβ agonists. A novel benzofuran-2-carboxylate derivative was identified with LXRβ agonist activity: E17110 showed a significant activation effect on LXRβ with an EC50 value of 0.72 μmol/L. E17110 also increased the expression of ATP-binding cassette transporter A1 (ABCA1 and G1 (ABCG1 in RAW264.7 macrophages. Moreover, E17110 significantly reduced cellular lipid accumulation and promoted cholesterol efflux in RAW264.7 macrophages. Interestingly, we found that the key amino acids in the LXRβ ligand-binding domain had distinct interactions with E17110 as compared to TO901317. These results suggest that E17110 was identified as a novel compound with LXRβ agonist activity in vitro via screening, and could be developed as a potential anti-atherosclerotic lead compound.

  15. Apparent histological changes of adipocytes after treatment with CL 316,243, a ß-3-adrenergic receptor agonist

    Directory of Open Access Journals (Sweden)

    Ghorbani M

    2015-02-01

    Full Text Available Masoud Ghorbani,1,2,* Shahram Teimourian,3,* Reza Farzad,4 Nabiollah Namvar Asl4 1Research and Development Department, Pasteur Institute of Iran, Tehran, Iran; 2Department of Biochemistry, University of Ottawa, Ottawa, ON, Canada; 3Department of Medical Genetics, Iran University of Medical Sciences, Tehran, Iran; 4Department of Animal Science, Pasteur Institute of Iran, Research and Production Complex, Karaj, Iran*These authors contributed equally to this work Background and objectives: The objective of this experiment was to study the effect of CL 316,243 (CL (a highly selective ß3-adrenergic receptor agonist on cellular changes occurring in retroperitoneal white adipose tissue (RWAT of lean and obese rats. Methods: Ten-month-old lean and obese Zucker rats were implanted subcutaneously with osmotic mini-pumps, infusing either saline or CL (1 mg/kg body weight/day for 4 weeks. Results: There was no effect of CL on food intake. However, the resting metabolic rate in lean and obese rats increased by 55% and 96% per rat, respectively. Total RWAT weight decreased in both lean and obese rats under influence of CL treatment by 65% and 38%, respectively. Total body weight and body fat were lower in CL treated rats. Detection of uncoupling protein 1(UCP1 in RWAT was confirmed qualitatively by both immunohistochemistry and immunofluorescence using a rabbit anti rat UCP1 antibody which showed the appearance of a marked increase of this protein in the adipose tissue. Stained semi-thin sections (0.5 µm also demonstrated abundant nuclei in multilocular adipocytes, in endothelial cells associated with the vasculature, and in interstitial cells. In CL-treated obese rats, a clustering of several multilocular cells around the periphery of a white adipocyte was seen. Conclusion: These results indicate that treatment of both lean and obese Zucker rats with CL induces extensive remodeling of RWAT that includes shrinkage of white adipose tissue, appearance of

  16. We Need 2C but Not 2B: Developing Serotonin 2C (5-HT2C) Receptor Agonists for the Treatment of CNS Disorders.

    Science.gov (United States)

    Cheng, Jianjun; Kozikowski, Alan P

    2015-12-01

    The serotonin 2C (5-HT2C ) receptor has been identified as a potential drug target for the treatment of a variety of central nervous system (CNS) disorders, such as obesity, substance abuse, and schizophrenia. In this Viewpoint article, recent progress in developing selective 5-HT2C agonists for use in treating these disorders is summarized, including the work of our group. Challenges in this field and the possible future directions are described. Homology modeling as a method to predict the binding modes of 5-HT2C ligands to the receptor is also discussed. Compared to known ligands, the improved pharmacological profiles of the 2-phenylcyclopropylmethylamine-based 5-HT2C agonists make them preferred candidates for further studies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Serum inhibin A and inhibin B in central precocious puberty before and during treatment with GnRH agonists

    DEFF Research Database (Denmark)

    Sehested, A; Andersson, A M; Müller, J

    2000-01-01

    Serum levels of the gonadal hormones inhibin A and inhibin B are undetectable or low in prepubertal girls, and rise during puberty. In girls with central precocious puberty (CPP) the hypothalamic-pituitary-gonadal axis is prematurely activated, if the girl is thereafter treated with GnRH agonists...

  18. Final height in central precocious puberty after long term treatment with a slow release GnRH agonist

    NARCIS (Netherlands)

    Oostdijk, W; Rikken, B; Schreuder, S; Otten, B; Odink, R; Rouwe, C; Jansen, M; Gerver, WJ; Waelkens, J; Drop, S

    1996-01-01

    Objective-To study the resumption of puberty and the final height achieved in children with central precocious puberty (CPP) treated with the GnRH agonist triptorelin. Patients-31 girls and five boys with CPP who were treated with triptorelin 3.75 mg intramuscularly every four weeks. Girls were trea

  19. The newer Opioid Agonist Treatment with lower substitutive opiate doses is associated with better toxicology outcome than the older Harm Reduction Treatment.

    Science.gov (United States)

    Bizzarri, Jacopo V; Casetti, Valentina; Sanna, Livia; Maremmani, Angelo Giovanni Icro; Rovai, Luca; Bacciardi, Silvia; Piacentino, Daria; Conca, Andreas; Maremmani, Icro

    2016-01-01

    Charge-free heroin use disorder treatment in Italy follows two main approaches, i.e., harm reduction treatment (HRT) strategy in community low-threshold facilities for drug addiction and opioid agonist treatment (OAT) in high-threshold facilities for opioid addiction, focusing on pharmacological maintenance according to the Dole and Nyswander strategy. We aimed to compare the impact of HRT and OAT on patient outcome, as assessed through negativity for drugs on about 1-year urinalyses. We examined retrospectively the urinalyses of HRT and OAT patients for which at least four randomly sampled urinalyses per month were available for about 1 year, during which patients were undergoing methadone or buprenorphine maintenance; urinalyses focused on heroin, cocaine, cannabinoids, and their metabolites. Included were 189 HRT and 58 OAT patients. The latter were observed for a significantly longer period. There was a higher proportion of heroin- and cocaine-clean urinalyses in OAT patients, with cocaine-clean urinalyses discriminating best between the two groups. OAT patients were older, with longer dependence duration, more severe addiction history, and received lower methadone doses. Buprenorphine maintenance was more often associated with heroin-clean urinalyses. The higher the methadone doses, the lower were the percentage of heroin-clean urinalyses in HRT patients (negative correlation). The OAT approach was related to higher recovery and polyabuse abstinence rates compared to the HRT approach, despite greater severity of substance use, psychiatric and physical comorbidities. Our results are consistent with the possibility to use lower maintenance opiate doses (after induction and stabilization in methadone treatment according to Dole and Nyswander methodology) in treating heroin addiction. This seemed to be impossible adopting the currently accepted HRT model.

  20. Role of liver X receptors alpha agonist on expressions of LPS-induced inflammatory response associated factor IRAK-4 and NF-kappaB in Kupffer cells

    Institute of Scientific and Technical Information of China (English)

    Wang Ding; Miao Chunmu; Gong Jianping

    2008-01-01

    Objective: To explore the role of activated liver X receptor a (LXRa) on the expressions of interleukin-1 receptor associated kinase-4 (IRAK-4) and NF-kappaB (NF-κB) in the inflammatory response which induced by LPS in the Kupffer cells and to investigate the possible mechanisms of LXRα negative regulation of inflammatory response. Methods: The Kupffer cells were isolated from male Kunming mice by collagen perfusion in situ. And these cells were divided into 4 groups: normal control group, LPS treatment group, LXRα agonist T0901317 treatment group, LPS and T0901317 combined treatment group. The LPS treatment group were treated with a final concentration of 1 μg/ml LPS in RPMI 1640 and cultured for 6 h, the T0901317 treatment group were treated with a final concentration of 5 μg/ml in RPMI 1640 and cultured for 24 h, and the combined treatment group received pre-culture for 24 h with a final concentration of 1 μg/ml T0901317 in RPMI 1640 and then cultured for 6 h with a final concentration of 5 μg/ml LPS in RPMI 1640. All groups were cultured for 30 h. The expression of LXRα, IRAK-4 and NF-κB at mRNA and protein levels were detected by real-time PCR and Western blotting, and the TNF-α and IL-1β levels were detected by ELISA. Results: The levels of LXRα mRNA and protein were highest in T0901317 group, and lowest in LPS group (P0.05). Conclusion: These date suggest that the LXR agonists can effectively up-regulate the expressions of LXRa mRNA and protein and inhibit the inflammatory response. This may be via down-regulating the expressions of IRAK4 and NF-κB at mRNA and protein levels.

  1. Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys.

    Science.gov (United States)

    Banks, Matthew L

    2016-08-01

    Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. Behavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10mg/kg/day, intramuscular) treatment periods. Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights

  2. Bone mineral density and body composition in girls with idiopathic central precocious puberty before and after treatment with a gonadotropin-releasing hormone agonist

    Directory of Open Access Journals (Sweden)

    Sandra B. Alessandri

    2012-01-01

    Full Text Available OBJECTIVES: Idiopathic central precocious puberty and its postponement with a (gonadotropin-releasing hormone GnRH agonist are complex conditions, the final effects of which on bone mass are difficult to define. We evaluated bone mass, body composition, and bone remodeling in two groups of girls with idiopathic central precocious puberty, namely one group that was assessed at diagnosis and a second group that was assessed three years after GnRH agonist treatment. METHODS: The precocious puberty diagnosis and precocious puberty treatment groups consisted of 12 girls matched for age and weight to corresponding control groups of 12 (CD and 14 (CT girls, respectively. Bone mineral density and body composition were assessed by dual X-ray absorptiometry. Lumbar spine bone mineral density was estimated after correction for bone age and the mathematical calculation of volumetric bone mineral density. CONEP: CAAE-0311.0.004.000-06. RESULTS: Lumbar spine bone mineral density was slightly increased in individuals diagnosed with precocious puberty compared with controls; however, after correction for bone age, this tendency disappeared (CD = -0.74 + 0.9 vs. precocious puberty diagnosis = -1.73 + 1.2. The bone mineral density values of girls in the precocious puberty treatment group did not differ from those observed in the CT group. CONCLUSION: There is an increase in bone mineral density in girls diagnosed with idiopathic central precocious puberty. Our data indicate that the increase in bone mineral density in girls with idiopathic central precocious puberty is insufficient to compensate for the marked advancement in bone age observed at diagnosis. GnRH agonist treatment seems to have no detrimental effect on bone mineral density.

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

    OpenAIRE

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

    2016-01-01

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

  4. Activation of liver X receptors prevents statin-induced death of 3T3-L1 preadipocytes

    DEFF Research Database (Denmark)

    Madsen, Lise; Petersen, Rasmus K; Steffensen, Knut R;

    2008-01-01

    to differentiate by standard isobutylmethylxanthine/dexamethasone/insulin treatment in the presence of statins, they failed to differentiate and underwent massive apoptosis. The simultaneous addition of selective LXR agonists prevented the statin-induced apoptosis. By using mouse embryo fibroblasts from wild...... of LXRalpha, we demonstrate that the response to LXR agonists is LXR-dependent. Interestingly, LXR-mediated rescue of statin-induced apoptosis was not related to up-regulation of genes previously shown to be involved in the antiapoptotic action of LXR. Furthermore, forced expression of Bcl-2 did not prevent...... of IkappaBalpha prevented LXR agonist-dependent rescue of statin-induced apoptosis. Thus, the results presented in this paper provide novel insight into the action of statins on and LXR-dependent inhibition of apoptosis....

  5. EEPD1 Is a Novel LXR Target Gene in Macrophages Which Regulates ABCA1 Abundance and Cholesterol Efflux

    Science.gov (United States)

    Nelson, Jessica Kristine; Koenis, Duco Steven; Scheij, Saskia; Cook, Emma Clare Laura; Moeton, Martina; Santos, Ana; Lobaccaro, Jean-Marc Adolphe; Baron, Silvere

    2017-01-01

    Objective— The sterol-responsive nuclear receptors, liver X receptors α (LXRα, NR1H3) and β (LXRβ, NR1H2), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters ABCA1 and ABCG1 to promote efflux of excess cellular cholesterol. However, the full set of genes that contribute to LXR-stimulated cholesterol efflux is unknown, and their identification is the objective of this study. Approach and Results— We systematically compared the global transcriptional response of macrophages to distinct classes of LXR ligands. This allowed us to identify both common and ligand-specific transcriptional responses in macrophages. Among these, we identified endonuclease–exonuclease–phosphatase family domain containing 1 (EEPD1/KIAA1706) as a direct transcriptional target of LXRs in human and murine macrophages. EEPD1 specifically localizes to the plasma membrane owing to the presence of a myristoylation site in its N terminus. Accordingly, the first 10 amino acids of EEPD1 are sufficient to confer plasma membrane localization in the context of a chimeric protein with GFP. Functionally, we report that silencing expression of EEPD1 blunts maximal LXR-stimulated Apo AI-dependent efflux and demonstrate that this is the result of reduced abundance of ABCA1 protein in human and murine macrophages. Conclusions— In this study, we identify EEPD1 as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1. PMID:28082258

  6. EEPD1 Is a Novel LXR Target Gene in Macrophages Which Regulates ABCA1 Abundance and Cholesterol Efflux.

    Science.gov (United States)

    Nelson, Jessica Kristine; Koenis, Duco Steven; Scheij, Saskia; Cook, Emma Clare Laura; Moeton, Martina; Santos, Ana; Lobaccaro, Jean-Marc Adolphe; Baron, Silvere; Zelcer, Noam

    2017-03-01

    The sterol-responsive nuclear receptors, liver X receptors α (LXRα, NR1H3) and β (LXRβ, NR1H2), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters ABCA1 and ABCG1 to promote efflux of excess cellular cholesterol. However, the full set of genes that contribute to LXR-stimulated cholesterol efflux is unknown, and their identification is the objective of this study. We systematically compared the global transcriptional response of macrophages to distinct classes of LXR ligands. This allowed us to identify both common and ligand-specific transcriptional responses in macrophages. Among these, we identified endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1/KIAA1706) as a direct transcriptional target of LXRs in human and murine macrophages. EEPD1 specifically localizes to the plasma membrane owing to the presence of a myristoylation site in its N terminus. Accordingly, the first 10 amino acids of EEPD1 are sufficient to confer plasma membrane localization in the context of a chimeric protein with GFP. Functionally, we report that silencing expression of EEPD1 blunts maximal LXR-stimulated Apo AI-dependent efflux and demonstrate that this is the result of reduced abundance of ABCA1 protein in human and murine macrophages. In this study, we identify EEPD1 as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1. © 2017 The Authors.

  7. GLP-1 Receptor Agonists

    Science.gov (United States)

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

  8. Citrus ichangensis Peel Extract Exhibits Anti-Metabolic Disorder Effects by the Inhibition of PPARγ and LXR Signaling in High-Fat Diet-Induced C57BL/6 Mouse

    Directory of Open Access Journals (Sweden)

    Xiaobo Ding

    2012-01-01

    Full Text Available Obesity is a common nutritional disorder associated with type 2 diabetes, cardiovascular diseases, dyslipidemia, and certain cancers. In this study, we investigated the effects of Citrus ichangensis peel extract (CIE in high-fat (HF diet-induced obesity mice. Female C57BL/6 mice were fed a chow diet or an HF diet alone or supplemented with 1% w/w CIE for 8 weeks. We found that CIE treatment could lower blood glucose level and improve glucose tolerance. In the HF+CIE group, body weight gain, serum total cholesterol (TC and low-density lipoprotein cholesterol (LDL-c levels, and liver triglyceride (TG and TC concentrations were significantly (P<0.05 decreased relative to those in the HF group. To elucidate the mechanism of CIE on the metabolism of glucose and lipid, related genes expression in liver were examined. In liver tissue, CIE significantly decreased the mRNA expression levels of peroxisome proliferator-activated receptor γ (PPARγ and its target genes, such as fatty acid synthase (FAS and acyl-CoA oxidase (ACO. Moreover, CIE also decreased the expression of liver X receptor (LXR α and β which are involved in lipid and glucose metabolism. These results suggest that CIE administration could alleviate obesity and related metabolic disorders in HF diet-induced obesity mice through the inhibition of PPARγ and LXR signaling.

  9. Selective roles of the Nuclear Receptors LXR in the transcriptional control of classical and alternative macrophage activation = Efectos selectivos de los receptores nucleares LXR en el control transcripcional de la activación clásica y alternativa de macrófagos

    OpenAIRE

    León Moreno, Theresa Elizabeth

    2013-01-01

    [spa] El receptor nuclear LXR es un factor de transcripción dependiente de ligando. Los ligandos activadores de LXR son formas derivadas del colesterol. Esta tesis se ha elaborado en dos grandes bloques. En el primero, hemos caracterizado el papel antiinflamatorio que LXR ejerce en células espumosas, un tipo celular predominante en la placa aterosclérotica, activadas por la citoquina Interferon-gamma (IFN-γ) y por el componente bacteriano lipopolisacárido (LPS). Así mismo, hemos observado que...

  10. Effects of Chronic Dopamine D2R Agonist Treatment and Polysialic Acid Depletion on Dendritic Spine Density and Excitatory Neurotransmission in the mPFC of Adult Rats

    Directory of Open Access Journals (Sweden)

    Esther Castillo-Gómez

    2016-01-01

    Full Text Available Dopamine D2 receptors (D2R in the medial prefrontal cortex (mPFC are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM, a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal neurons, two additional features affected in schizophrenia. To evaluate these parameters, we have chronically treated adult rats with PPHT (a D2R agonist after enzymatic removal of PSA with Endo-N. Both treatments decreased spine density in apical dendrites of pyramidal neurons without affecting their inhibitory innervation. Endo-N also reduced the expression of vesicular glutamate transporter-1. These results indicate that D2R and PSA-NCAM are important players in the regulation of the structural plasticity of mPFC excitatory neurons. This is relevant to our understanding of the neurobiological basis of schizophrenia, in which structural alterations of pyramidal neurons and altered expression of D2R and PSA-NCAM have been found.

  11. Free fatty acid receptor agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II clinical development.

    Science.gov (United States)

    Li, Zheng; Qiu, Qianqian; Geng, Xinqian; Yang, Jianyong; Huang, Wenlong; Qian, Hai

    2016-08-01

    The alarming prevalence of type 2 diabetes mellitus (T2DM) stimulated the exploitation of new antidiabetic drugs with extended durability and enhanced safety. In this regard, the free fatty acid receptor 1 (FFA1) and FFA4 have emerged as attractive targets in the last decade. FFA1 has prominent advantages in promoting insulin and incretin secretion while FFA4 shows great potential in incretin secretion, insulin sensitization and anti-inflammatory effects. Herein, the authors focus specifically on FFA1 and FFA4 agonists in clinical trials and preclinical development. LY2922470, P11187 and SHR0534 are currently active in clinical trials while the CNX-011-67, SAR1, DS-1558 and BMS-986118 are in preclinical phase. The information for this review is retrieved from Integrity, Scifinder, Espacenet and clinicaltrials.gov databases. Current proof-of-concept in clinical trials suggests that FFA1 agonists have a significant improvement for T2DM without the risk of hypoglycemia. However, there are still several challenging problems including the mechanism of the receptor and the efficacy and safety of the ligands.

  12. Near-normalization of glycaemic control with glucagon-like peptide-1 receptor agonist treatment combined with exercise in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Mensberg, Pernille; Nyby, Signe; Jørgensen, Peter Godsk;

    2016-01-01

    .002)). Greater reductions in fasting plasma glucose (-3.4 ± 2.3 vs -0.3 ± 2.6 mM, p quality of life during......AIMS: Exercise as well as glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment improves glycaemic control in patients with type 2 diabetes. We investigated the effects of exercise in combination with a GLP-1RA (liraglutide) or placebo for the treatment of type 2 diabetes. METHODS: Thirty......-three overweight, dysregulated and sedentary patients with type 2 diabetes were randomly allocated to 16 weeks of exercise and liraglutide or exercise and placebo. Both groups had three supervised 60-minute training sessions per week including spinning and resistance training. RESULTS: HbA1c levels dropped by 2...

  13. Prostate specific antigen in boys with precocious puberty before and during gonadal suppression by GnRH agonist treatment

    DEFF Research Database (Denmark)

    Juul, A; Müller, J; Skakkebaek, N E

    1997-01-01

    In healthy boys, the pituitary-gonadal axis exhibits diurnal variation in early puberty. Serum testosterone levels are higher during the night and low or immeasurable during the day. These fluctuating levels of circulating androgens in early pubertal boys are difficult to monitor. Prostate specific...... antigen (PSA) is a marker of the androgen-dependent prostatic epithelial cell activity and it is used in the diagnosis and surveillance of adult patients with prostatic cancer. We have measured PSA concentrations in serum from boys with precocious puberty before and during gonadal suppression with Gn......RH agonists to evaluate the effect of normal and precocious puberty on PSA levels and to study the correlation between testosterone and PSA in boys....

  14. Nanoparticle-delivered multimeric soluble CD40L DNA combined with Toll-Like Receptor agonists as a treatment for melanoma.

    Directory of Open Access Journals (Sweden)

    Geoffrey W Stone

    Full Text Available Stimulation of CD40 or Toll-Like Receptors (TLR has potential for tumor immunotherapy. Combinations of CD40 and TLR stimulation can be synergistic, resulting in even stronger dendritic cell (DC and CD8+ T cell responses. To evaluate such combinations, established B16F10 melanoma tumors were injected every other day X 5 with plasmid DNA encoding a multimeric, soluble form of CD40L (pSP-D-CD40L either alone or combined with an agonist for TLR1/2 (Pam(3CSK(4 , TLR2/6 (FSL-1 and MALP2, TLR3 (polyinosinic-polycytidylic acid, poly(I:C, TLR4 ( monophosphoryl lipid A, MPL, TLR7 (imiquimod, or TLR9 (Class B CpG phosphorothioate oligodeoxynucleotide, CpG. When used by itself, pSP-D-CD40L slowed tumor growth and prolonged survival, but did not lead to cure. Of the TLR agonists, CpG and poly(I:C also slowed tumor growth, and the combination of these two TLR agonists was more effective than either agent alone. The triple combination of intratumoral pSP-D-CD40L + CpG + poly(I:C markedly slowed tumor growth and prolonged survival. This treatment was associated with a reduction in intratumoral CD11c+ dendritic cells and an influx of CD8+ T cells. Since intratumoral injection of plasmid DNA does not lead to efficient transgene expression, pSP-D-CD40L was also tested with cationic polymers that form DNA-containing nanoparticles which lead to enhanced intratumoral gene expression. Intratumoral injections of pSP-D-CD40L-containing nanoparticles formed from polyethylenimine (PEI or C32 (a novel biodegradable poly(B-amino esters polymer in combination with CpG + poly(I:C had dramatic antitumor effects and frequently cured mice of B16F10 tumors. These data confirm and extend previous reports that CD40 and TLR agonists are synergistic and demonstrate that this combination of immunostimulants can significantly suppress tumor growth in mice. In addition, the enhanced effectiveness of nanoparticle formulations of DNA encoding immunostimulatory molecules such as multimeric

  15. Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression.

    Science.gov (United States)

    Liu, Jianhua; Yu, Li-Fang; Eaton, J Brek; Caldarone, Barbara; Cavino, Katie; Ruiz, Christina; Terry, Matthew; Fedolak, Allison; Wang, Daguang; Ghavami, Afshin; Lowe, David A; Brunner, Dani; Lukas, Ronald J; Kozikowski, Alan P

    2011-10-27

    Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment, targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenaline, is not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogues that interact with α4β2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450-related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.

  16. Long-term treatment with the pan-PPAR agonist tetradecylthioacetic acid or fish oil is associated with increased cardiac content of n-3 fatty acids in rat

    Directory of Open Access Journals (Sweden)

    Strand Elin

    2012-06-01

    Full Text Available Abstract Background Excess peroxisome proliferator-activated receptor (PPAR stimulation has been associated with detrimental health effects including impaired myocardial function. Recently, supplementation with n-3 polyunsaturated fatty acids (PUFA has been associated with improved left ventricular function and functional capacity in patients with dilated cardiomyopathy. We investigated the long-term effects of the pan-PPAR agonist tetradecylthioacetic acid (TTA and/or high-dose fish oil (FO on cardiac fatty acid (FA composition and lipid metabolism. Male Wistar rats were given one out of four different 25% (w/v fat diets: control diet; TTA diet; FO diet; or diet containing both TTA and FO. Results After 50 weeks n-3 PUFA levels were increased by TTA and FO in the heart, whereas liver levels were reduced following TTA administration. TTA was associated with a decrease in arachidonic acid, increased activities of carnitine palmitoyltransferase II, fatty acyl-CoA oxidase, glycerol-3-phosphate acyltransferase, and fatty acid synthase in the heart. Furthermore, cardiac Ucp3 and Cact mRNA was upregulated. Conclusions Long-term treatment with the pan-PPAR agonist TTA or high-dose FO induced marked changes in PUFA composition and enzymatic activity involved in FA metabolism in the heart, different from liver. Changes included increased FA oxidation and a selective increase in cardiac n-3 PUFA.

  17. The Future of Opioid Agonist Therapies in Ukraine: A Qualitative Assessment of Multilevel Barriers and Ways Forward to Promote Retention in Treatment.

    Science.gov (United States)

    Bojko, Martha J; Mazhnaya, Alyona; Marcus, Ruthanne; Makarenko, Iuliia; Islam, Zahedul; Filippovych, Sergey; Dvoriak, Sergii; Altice, Frederick L

    2016-07-01

    Opioid agonist therapies (OAT) to treat opioid addiction in people who inject drugs (PWID) began in Ukraine in 2004. Scale-up of OAT, however, has been hampered by both low enrollment and high attrition. To better understand the factors influencing OAT retention among PWID in Ukraine, qualitative data from 199 PWIDs were collected during 25 focus groups conducted in five Ukrainian cities from February to April 2013. The experiences of PWID who were currently or previously on OAT or currently trying to access OAT were analyzed to identify entry and retention barriers encountered. Transcribed data were analyzed using a grounded theory approach. Individual beliefs about OAT, particularly misaligned treatment goals between clients and providers, influenced PWID's treatment seeking behaviors. Multiple programmatic and structural issues, including inconvenient hours and treatment site locations, complicated dosing regimens, inflexible medication dispensing guidelines, and mistreatment by clinic and medical staff also strongly influenced OAT retention. Findings suggest the need for both programmatic and policy-level structural changes such as revising legal regulations covering OAT dispensing, formalizing prescription dosing policies and making OAT more available through other sites, including primary care settings as a way to improve treatment retention. Quality improvement interventions that target treatment settings could also be deployed to overcome healthcare delivery barriers. Additional patient education and medical professional development around establishing realistic treatment goals as well as community awareness campaigns that address the myths and fears associated with OAT can be leveraged to overcome individual, family and community-level barriers.

  18. Molecular cloning, tissue expression and regulation of liver X receptor (LXR) transcription factors of Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss).

    Science.gov (United States)

    Cruz-Garcia, L; Minghetti, M; Navarro, I; Tocher, D R

    2009-05-01

    Fish are important sources of high quality protein, essential minerals such as iodine and selenium, vitamins including A, D and E, and omega-3 fatty acids in the human diet. With declining fisheries worldwide, farmed fish constitute an ever-increasing proportion of fish in the food basket. Sustainable development of aquaculture dictates that diets will have to contain increasing levels of plant products that are devoid of cholesterol, but contain phytosterols that are known to have physiological effects in mammals. Liver X receptors (LXR) are transcription factors whose activity is modulated by sterols, with activation inducing cholesterol catabolism and de novo fatty acid biosynthesis in liver. Transcriptomic analysis has shown that substitution of fish meal and oil with plant products induces genes of cholesterol and fatty acid metabolism in salmonids. Here we report the cloning of LXR cDNAs from two species of salmonid fish that are important in aquaculture. The full-length cDNA (mRNA) of LXR obtained from salmon was shown to be 3766 bp, which included a 5'-untranslated region (UTR) of 412 bp and a 3'-UTR of 1960 bp and an open reading frame (ORF) of 1394 bp, which specified a protein of 462 amino acids. The trout LXR full-length cDNA was 2056 bp, including 5'- and 3'-UTRs of 219 and 547 bp, respectively, and an ORF of 1290 bp, which specified a protein of 427 amino acids. The protein sequences included characteristic features of mammalian LXRs, including the DNA binding (DBD), containing P-box, ligand binding (LBD) and activation function-2 (AF-2) domains, D-box, D (hinge) region, and eight cysteines that belong to the two zinc fingers. Phylogenetic analysis clustered the salmonid LXRs together, more closely with zebrafish and more distantly from medaka and stickleback. A pair-wise comparison among vertebrate LXR sequences showed the amino acid sequence predicted by the salmon LXR ORF showed greatest identity to that of trout 97%, and 97%, 87% and 81% identity

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

    Science.gov (United States)

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

    2014-11-01

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

  20. Change in body mass index and insulin resistance after 1-year treatment with gonadotropin-releasing hormone agonists in girls with central precocious puberty.

    Science.gov (United States)

    Park, Jina; Kim, Jae Hyun

    2017-03-01

    Gonadotropin-releasing hormone agonist (GnRHa) is used as a therapeutic agent for central precocious puberty (CPP); however, increased obesity may subsequently occur. This study compared body mass index (BMI) and insulin resistance during the first year of GnRHa treatment for CPP. Patient group included 83 girls (aged 7.0-8.9 years) with developed breasts and a peak luteinizing hormone level of ≥5 IU/L after GnRH stimulation. Control group included 48 prepubertal girls. BMI and insulin resistance-related indices (homeostasis model assessment of insulin resistance [HOMA-IR] and quantitative insulin sensitivity check index [QUICKI]) were used to compare the groups before treatment, and among the patient group before and after GnRHa treatment. No statistical difference in BMI z-score was detected between the 2 groups before treatment. Fasting insulin and HOMA-IR were increased in the patient group; fasting glucose-to-insulin ratio and QUICKI were increased in the control group (all Presistance compared to the control group. During GnRHa treatment, normal-weight individuals showed increased BMI z-scores without increased insulin resistance; the overweight group demonstrated increased insulin resistance without significantly altered BMI z-scores. Long-term follow-up of BMI and insulin resistance changes in patients with CPP is required.

  1. Postoperative Levonorgestrel-Releasing Intrauterine System Insertion After Gonadotropin-Releasing Hormone Agonist Treatment for Preventing Endometriotic Cyst Recurrence: A Prospective Observational Study.

    Science.gov (United States)

    Kim, Min Kyoung; Chon, Seung Joo; Lee, Jae Hoon; Yun, Bo Hyon; Cho, SiHyun; Choi, Young Sik; Lee, Byung Seok; Seo, Seok Kyo

    2017-01-01

    The aim of this study was to evaluate the effectiveness of postoperative levonorgestrel-releasing intrauterine system (LNG-IUS) insertion after gonadotropin-releasing hormone agonist (GnRH-a) treatment for preventing endometriotic cyst recurrence. The LNG-IUS was applied to 28 women who had undergone surgery for endometriosis followed by 6 cycles of GnRH-a treatment. Clinical characteristics, endometriosis recurrence, and adverse effects were analyzed. Student t test was performed for analysis. Before surgery, 20 (71.4%) patients had dysmenorrhea, and the mean pain score (visual analog scale [VAS]) was 4.26. The numbers of women diagnosed with stage III endometriosis and stage IV endometriosis were 15 (53.6%) and 13 (46.4%), respectively, according to the revised American Fertility Society scoring system. The mean cancer antigen 125 levels and VAS scores were significantly lower after treatment than before treatment (11.61 vs 75.66 U/mL, P < .0001 and 0.50 vs 4.26 U/mL, P < .0001, respectively). Of the 28 patients, 13 (46.4%) simultaneously had adenomyosis, and 2 (7.1%) underwent LNG-IUS removal because of unresolved vaginal bleeding and dysmenorrhea. Recurrence was noted in 2 (7.1%) women. Postoperative LNG-IUS insertion after GnRH-a treatment is an effective approach for preventing endometriotic cyst recurrence, especially in women who do not desire to conceive.

  2. Assessment of stress levels in girls with central precocious puberty before and during long-acting gonadotropin-releasing hormone agonist treatment: a pilot study.

    Science.gov (United States)

    Menk, Tais A S; Inácio, Marlene; Macedo, Delanie B; Bessa, Danielle S; Latronico, Ana C; Mendonca, Berenice B; Brito, Vinicius Nahime

    2017-05-23

    The objective of the study was to determine the stress levels of girls with central precocious puberty (CPP) before and during treatment with a long-acting gonadotropin-releasing hormone agonist (GnRHa). The Child Stress Scale (CSS) was used for 10 unrelated girls with CPP before and after the first year of GnRHa treatment. The CSS is divided into four subscales (physical, psychological, psychological with depressive component and psychophysiological reactions). Through a quantitative analysis, it is possible to classify stress into four stages: alarm, resistance, near-exhaustion and exhaustion. At diagnosis, 90% of the girls showed stress levels scores at the alarm or resistance stage on at least one subscale, mostly in terms of physical and psychological reactions. The mean total stress score was significantly higher before when compared to after GnRHa treatment (43.4±15.6 vs. 28.9±9.7; pstress scores obtained in all subscales, except the one on psychophysiological reactions, were significantly higher before GnRHa treatment. Higher stress levels were a common finding in girls with CPP before treatment. The significant stress level reduction after pubertal suppression reinforces the idea that sexual precocity is a stressful condition in children. The CSS might be a useful tool for psychological assessment of patients with CPP.

  3. Intracellular β2-adrenergic receptor signaling specificity in mouse skeletal muscle in response to single-dose β2-agonist clenbuterol treatment and acute exercise.

    Science.gov (United States)

    Sato, Shogo; Shirato, Ken; Mitsuhashi, Ryosuke; Inoue, Daisuke; Kizaki, Takako; Ohno, Hideki; Tachiyashiki, Kaoru; Imaizumi, Kazuhiko

    2013-05-01

    The aim of this study was to clarify the intracellular β2-adrenergic receptor signaling specificity in mouse slow-twitch soleus and fast-twitch tibialis anterior (TA) muscles, resulting from single-dose β2-agonist clenbuterol treatment and acute exercise. At 1, 4, and 24 h after single-dose treatment with clenbuterol or after acute running exercise, the soleus and TA muscles were isolated and subjected to analysis. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) increased after single-dose clenbuterol treatment and acute exercise in the soleus muscle but not in the TA muscle. Although there was no change in the phosphorylation of Akt after acute exercise in either muscle, phosphorylation of Akt in the soleus muscle increased after single-dose clenbuterol treatment, whereas that in the TA muscle remained unchanged. These results suggest that p38 MAPK and Akt pathways play a functional role in the adaptation to clenbuterol treatment and exercise, particularly in slow-twitch muscles.

  4. Peroxisome proliferators-activated alpha agonist treatment ameliorates hepatic damage in rats with obstructive jaundice: an experimental study

    Directory of Open Access Journals (Sweden)

    Alper Murat

    2007-11-01

    Full Text Available Abstract Background Peroxisome proliferators-activated receptor alpha (PPARα activation modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of short-term administration of fenofibrate, a PPARα agonist, on proinflammatory cytokines, apoptosis, and hepatocellular damage in cholestasis. Methods Forty male Wistar rats were randomly divided into four groups: I = sham operated, II = bile duct ligation (BDL, III = BDL + vehicle (gum Arabic, IV = BDL + fenofibrate (100 mg/kg/day. All rats were sacrificed on 7th day after obtaining blood samples and liver tissue. Total bilirubin, aminotransferase (AST, alanine aminotransferase (ALT and alkaline phosphatase (ALP, gamma-glutamyl transferase, (GGT, tumor necrosis factor alpha (TNF-α, interleukin 1 beta (IL-1 β, and total bile acid (TBA in serum, and liver damage scores; portal inflammation, necrosis, bile duct number, in liver tissue were evaluated. Apoptosis in liver was also assessed by immunohistochemical staining. Results Fenofibrate administration significantly reduced serum total bilirubin, AST, ALT, ALP, and GGT, TNF-α, IL-1 β levels, and TBA (P P P P Conclusion Short-term administration of fenofibrate to the BDL rats exerts beneficial effects on hepatocellular damage and apoptosis.

  5. Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes.

    Science.gov (United States)

    Werner, Ulrich; Haschke, Guido; Herling, Andreas W; Kramer, Werner

    2010-09-24

    The glucagon-like peptide-1 (GLP-1) receptor represents an established therapeutic target in type 2 diabetes mellitus (T2DM). Agents that activate this receptor improve glucose tolerance alongside a low risk of hypoglycaemia, and have the potential to modify disease progression. Lixisenatide is a new potent and selective GLP-1 receptor agonist currently in development. The preclinical pharmacological profile of Lixisenatide suggests actions that are highly relevant to the long-term maintenance of glucose homeostasis. Lixisenatide protected Ins-1 cells (a rat-derived beta-cell line) from both lipid- and cytokine-induced apoptosis. More importantly, Lixisenatide also prevented lipotoxicity-induced insulin depletion in human islets and preserved insulin production, storage and pancreatic beta-cell function in vitro. Enhancement of insulin biosynthesis and pancreatic beta-cell volume could also be demonstrated in animal models of type 2 diabetes. The improvement of glucose-stimulated insulin secretion provided by Lixisenatide occurred in a strictly glucose-dependent manner. In animal models of diabetes, Lixisenatide improved basal blood glucose and HbA(1c) with a rapid onset and sustained duration of action, and prevented the deterioration of pancreatic responsiveness and glucose homeostasis. Lixisenatide also delayed gastric emptying and reduced food intake. The efficacy/safety profile of Lixisenatide is currently being studied further in an extensive ongoing Phase III clinical study programme. This article reviews the preclinical pharmacological profile of Lixisenatide.

  6. Treatment of chronic hepatitis B with pattern recognition receptor agonists: Current status and potential for a cure.

    Science.gov (United States)

    Chang, Jinhong; Guo, Ju-Tao

    2015-09-01

    Hepatitis B virus (HBV) has been considered to be a "stealth virus" that induces negligible innate immune responses during the early phase of infection. However, recent studies with newly developed experimental systems have revealed that virus infection can be recognized by pattern recognition receptors (PRR), eliciting a cytokine response that controls the replication of the virus. The molecular mechanisms by which interferons and other inflammatory cytokines suppress HBV replication and modulate HBV cccDNA metabolism and function are just beginning to be revealed. In agreement with the notion that the developmental and functional status of intrahepatic innate immunity determines the activation and maturation of the HBV-specific adaptive immune response and thus the outcome of HBV infection, pharmacological activation of intrahepatic innate immune responses with TLR7/8/9 or STING agonists efficiently controls HBV infection in preclinical studies and thus holds great promise for the cure of chronic hepatitis B. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."

  7. Pharmacogenetics of β2-Agonists

    Directory of Open Access Journals (Sweden)

    Nobuyuki Hizawa

    2011-01-01

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

  8. Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice

    Science.gov (United States)

    Rong, Shunxing; Cortés, Víctor A; Rashid, Shirya; Anderson, Norma N; McDonald, Jeffrey G; Liang, Guosheng; Moon, Young-Ah; Hammer, Robert E; Horton, Jay D

    2017-01-01

    The synthesis of cholesterol and fatty acids (FA) in the liver is independently regulated by SREBP-2 and SREBP-1c, respectively. Here, we genetically deleted Srebf-2 from hepatocytes and confirmed that SREBP-2 regulates all genes involved in cholesterol biosynthesis, the LDL receptor, and PCSK9; a secreted protein that degrades LDL receptors in the liver. Surprisingly, we found that elimination of Srebf-2 in hepatocytes of mice also markedly reduced SREBP-1c and the expression of all genes involved in FA and triglyceride synthesis that are normally regulated by SREBP-1c. The nuclear receptor LXR is necessary for Srebf-1c transcription. The deletion of Srebf-2 and subsequent lower sterol synthesis in hepatocytes eliminated the production of an endogenous sterol ligand required for LXR activity and SREBP-1c expression. These studies demonstrate that cholesterol and FA synthesis in hepatocytes are coupled and that flux through the cholesterol biosynthetic pathway is required for the maximal SREBP-1c expression and high rates of FA synthesis. DOI: http://dx.doi.org/10.7554/eLife.25015.001 PMID:28244871

  9. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists

    DEFF Research Database (Denmark)

    Holst, JJ; Kielgast, Urd; Holst, Jens J

    2009-01-01

    GLP-1 (glucagon-like peptide-1) is a peptide hormone secreted from endocrine cells in the intestinal mucosa in response to meals. The major effects of GLP-1 are to increase glucose-induced insulin secretion and reduce glucagon release, but GLP-1 also inhibits gastric emptying rate and reduces......, as well as the potential of GLP-1 as an adjuvant therapy in islet cell transplantation, will be reviewed. Suggestions for future studies of GLP-1 treatment in type 1 diabetes may include early treatment in order to preserve beta-cell mass and prolong the remission period, but should also take a potential...

  10. 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...

  11. Chronic Treatment with Opiate Agonists in Bulgaria - Assessing the Quality of Life Using SF 36 v. 2

    Directory of Open Access Journals (Sweden)

    Petrov Sava V.

    2016-06-01

    Full Text Available Introduction: Drug addictions to psychoactive substances are disorders with a complex bio-psycho-social genesis, which are characterized with chronic relapses. Substance addiction causes multifactorial damage to the normal functioning of individuals and requires a multicenter approach for the treatment process.

  12. Short-course TLR9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals with HIV infection

    DEFF Research Database (Denmark)

    Vibholm, Line; Schleimann, Mariane H; Højen, Jesper F

    2017-01-01

    characterized plasmacytoid dendritic cell, NK -and T cell activation using flow cytometry on baseline and after 4 weeks of treatment. HIV-1 transcription was quantified by measuring plasma HIV-1 RNA during MGN1703 administration. Results: In accordance with the cell-type specific expression of TLR9, MGN1703...

  13. Design, synthesis and pharmacology of 1,1-bistrifluoromethylcarbinol derivatives as liver X receptor β-selective agonists.

    Science.gov (United States)

    Koura, Minoru; Matsuda, Takayuki; Okuda, Ayumu; Watanabe, Yuichiro; Yamaguchi, Yuki; Kurobuchi, Sayaka; Matsumoto, Yuuki; Shibuya, Kimiyuki

    2015-07-01

    A novel series of 1,3-bistrifluoromethylcarbinol derivatives that act as liver X receptor (LXR) β-selective agonists was discovered. Structure-activity relationship studies led to the identification of molecule 62, which was more effective (Emax) and selective toward LXRβ than T0901317 and GW3965. Furthermore, 62 decreased LDL-C without elevating the plasma TG level and significantly suppressed the lipid-accumulation area in the aortic arch in a Bio F1B hamster fed a diet high in fat and cholesterol. We demonstrated that our LXRβ agonist would be potentially useful as a hypolipidemic and anti-atherosclerotic agent. In this manuscript, we report the design, synthesis and pharmacology of 1,3-bistrifluoromethylcarbinol derivatives. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Systemic treatment with a 5HT1a agonist induces anti-oxidant protection and preserves the retina from mitochondrial oxidative stress.

    Science.gov (United States)

    Biswal, Manas R; Ahmed, Chulbul M; Ildefonso, Cristhian J; Han, Pingyang; Li, Hong; Jivanji, Hiral; Mao, Haoyu; Lewin, Alfred S

    2015-11-01

    Chronic oxidative stress contributes to age related diseases including age related macular degeneration (AMD). Earlier work showed that the 5-hydroxy-tryptamine 1a (5HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) protects retinal pigment epithelium (RPE) cells from hydrogen peroxide treatment and mouse retinas from oxidative insults including light injury. In our current experiments, RPE derived cells subjected to mitochondrial oxidative stress were protected from cell death by the up-regulation of anti-oxidant enzymes and of the metal ion chaperone metallothionein. Differentiated RPE cells were resistant to oxidative stress, and the expression of genes for protective proteins was highly increased by oxidative stress plus drug treatment. In mice treated with 8-OH-DPAT, the same genes (MT1, HO1, NqO1, Cat, Sod1) were induced in the neural retina, but the drug did not affect the expression of Sod2, the gene for manganese superoxide dismutase. We used a mouse strain deleted for Sod2 in the RPE to accelerate age-related oxidative stress in the retina and to test the impact of 8-OH-DPAT on the photoreceptor and RPE degeneration developed in these mice. Treatment of mice with daily injections of the drug led to increased electroretinogram (ERG) amplitudes in dark-adapted mice and to a slight improvement in visual acuity. Most strikingly, in mice treated with a high dose of the drug (5 mg/kg) the structure of the RPE and Bruch's membrane and the normal architecture of photoreceptor outer segments were preserved. These results suggest that systemic treatment with this class of drugs may be useful in preventing geographic atrophy, the advanced form of dry AMD, which is characterized by RPE degeneration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Treatment intensification in patients with inadequate glycemic control on basal insulin: rationale and clinical evidence for the use of short‐acting and other glucagon‐like peptide‐1 receptor agonists

    Science.gov (United States)

    Bonadonna, Riccardo C.; Gentile, Sandro; Vettor, Roberto; Pozzilli, Paolo

    2016-01-01

    Summary A substantial proportion of patients with type 2 diabetes mellitus do not reach glycemic targets, despite treatment with oral anti‐diabetic drugs and basal insulin therapy. Several options exist for treatment intensification beyond basal insulin, and the treatment paradigm is complex. In this review, the options for treatment intensification will be explored, focusing on drug classes that act via the incretin system and paying particular attention to the short‐acting glucagon‐like peptide‐1 receptor agonists exenatide and lixisenatide. Current treatment guidelines will be summarized and discussed. © 2016 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd. PMID:26787264

  16. Characterization of dopamine D1 receptor agonists in vivo- Implications for the treatment of schizophrenia and Parkinson s disease

    OpenAIRE

    Isacson, Ruben

    2008-01-01

    Dopamine is fundamental in human behavior for movement, cognition and reward. A dysfunctional dopamine system is implicated in several neurological and psychiatric disorders such as Parkinson s disease and schizophrenia. Dopamine mediates its effects through five receptors. Dopamine D2 receptors are well studied and successful drug targets in the treatment of Parkinson s disease and schizophrenia. The functional role of dopamine D1 receptors is not fully understood and the c...

  17. [Side effects of treatment with the long-acting gonadorelin agonist triptorelin in a case of paraphilia].

    Science.gov (United States)

    Hoogeveen, J H; van der Veer, E

    2007-01-01

    A 35-year-old man with a paraphilia was treated with long-acting gonadorelin. The desired result was reduced preoccupation with sexuality, but there were various side effects including a serious amount of bone loss. We believe that more attention should be given to the adverse effects of long-term treatment with triptorelin. In our view the drug regimen needs to be revised.

  18. Cannabinoid receptor 1 antagonist treatment induces glucagon release and shows an additive therapeutic effect with GLP-1 agonist in diet-induced obese mice.

    Science.gov (United States)

    Patel, Kartikkumar Navinchandra; Joharapurkar, Amit Arvind; Patel, Vishal; Kshirsagar, Samadhan Govind; Bahekar, Rajesh; Srivastava, Brijesh Kumar; Jain, Mukul R

    2014-12-01

    Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

  19. Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive–Compulsive Disorder

    Directory of Open Access Journals (Sweden)

    Michelle M. Rodriguez

    2017-05-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are the only effective pharmacological treatments for obsessive–compulsive disorder (OCD. Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S-3-Methyl-1-[4-(trifluoromethyl-7-benzofuranyl]-piperazine (CPD 1 with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats and non-consummatory behaviors (marble-burying and nestlet-shredding in mice that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia. The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors

  20. Polymorphisms in NFkB, PXR, LXR and risk of colorectal cancer in a prospective study of Danes

    Directory of Open Access Journals (Sweden)

    Andersen Vibeke

    2010-09-01

    Full Text Available Abstract Background Transcription factors and nuclear receptors constitute a link between exposure to heterocyclic amines and polycyclic aromatic hydrocarbons from meat and tobacco smoke and colorectal cancer (CRC risk. The aim of this study was to investigate if polymorphisms in nuclear factor kappa-B, pregnane X receptor, and liver X receptor were associated with risk of CRC, and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use. Methods The polymorphisms nuclear factor kappa-B (NFkB, NFKB1 -94 insertion/deletion ATTG (rs28362491, pregnane X receptor (PXR, NR1I2 A-24381C (rs1523127, C8055T (rs2276707, A7635G (rs6785049, liver X receptor (LXR-β, NR1H3 C-rs1405655T, T-rs2695121C were assessed together with lifestyle factors in a nested case-cohort study of 378 CRC cases and 756 random participants from the Danish prospective Diet, Cancer and Health study of 57,053 persons. Results Carriers of NFkB -94deletion were at 1.45-fold higher risk of CRC than homozygous carriers of the insertion allele (incidence rate ratio (IRR = 1.45, 95% confidence interval (95% CI: 1.10-1.92. There was interaction between this polymorphism and intake of red and processed meat in relation to CRC risk. Carriers of NFkB -94deletion were at 3% increased risk pr 25 gram meat per day (95% CI: 0.98-1.09 whereas homozygous carriers of the insertion were not at increased risk (p for interaction = 0.03. PXR and LXR polymorphisms were not associated with CRC risk. There was no interaction between use of nonsteroid antiinflammatory drugs (NSAID or smoking status and NFkB, PXR or LXR polymorphisms. Conclusions A polymorphism in NFkB was associated with CRC risk and there was interaction between this polymorphism and meat intake in relation to CRC risk. This study suggests a role for NFkB in CRC aetiology.

  1. GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women

    DEFF Research Database (Denmark)

    Iepsen, Eva Pers Winning; Lundgren, Julie Rehné; Hartmann, Bolette

    2015-01-01

    bone mass reductions. DESIGN: Randomized control study. SETTING: Out-patient research hospital clinic. PARTICIPANTS: Thirty-seven healthy obese women. BMI 34±0.5 kg/m(2), age 46±2 years. INTERVENTION: After a low-calorie diet-induced 12% weight loss, participants were randomized to treatment...... with or without administration of the GLP-1 RA liraglutide (1.2mg/day) for 52 weeks. In case of weight gain, up to two meals per day could be substituted with a low-calorie diet product in order to maintain the weight loss. MAIN OUTCOME MEASURES: Total, pelvic and arm-leg bone mineral content (BMC) and bone......% and prevented bone loss after weight loss obtained through a low calorie-diet, supporting its role as a safe weight-lowering agent....

  2. Repeated morphine treatment-mediated hyperalgesia, allodynia and spinal glial activation are blocked by co-administration of a selective cannabinoid receptor type-2 agonist

    OpenAIRE

    Tumati, Suneeta; Largent-Milnes, Tally M.; Keresztes, Attila; Ren, Jiyang; Roeske, William R.; Vanderah, Todd W; Varga, Eva V.

    2012-01-01

    Spinal glial activation has been implicated in sustained morphine-mediated paradoxical pain sensitization. Since activation of glial CB2 cannabinoid receptors attenuates spinal glial activation in neuropathies, we hypothesized that CB2 agonists may also attenuate sustained morphine–mediated spinal glial activation and pain sensitization. Our data indicate that co-administration of a CB2-selective agonist (AM 1241) attenuates morphine (intraperitoneal; twice daily; 6 days)-mediated thermal hyp...

  3. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists

    DEFF Research Database (Denmark)

    Kielgast, Urd; Holst, Jens Juul; Madsbad, Sten

    2009-01-01

    for a beta-cell preserving effect. This review summarizes the present knowledge of GLP-1 and its analogues regarding its role as a possible treatment in patients with type 1 diabetes. The studies that address the effect of GLP-1 and GLP-1 analogues on beta-cell mass in both type 2 and type 1 diabetes...... appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence......GLP-1 (glucagon-like peptide-1) is a peptide hormone secreted from endocrine cells in the intestinal mucosa in response to meals. The major effects of GLP-1 are to increase glucose-induced insulin secretion and reduce glucagon release, but GLP-1 also inhibits gastric emptying rate and reduces...

  4. Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: A randomised double-blinded placebo-controlled clinical trial.

    Science.gov (United States)

    Jørgensen, Peter G; Jensen, Magnus T; Mensberg, Pernille; Storgaard, Heidi; Nyby, Signe; Jensen, Jan S; Knop, Filip K; Vilsbøll, Tina

    2017-02-11

    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 combined with supervised exercise in 33 dysregulated patients with type 2 diabetes on diet and/or metformin. Early diastolic myocardial tissue velocity was improved by exercise in the placebo group (-7.1 ± 1.6 cm/s (mean ± standard deviation) to -7.7 ± 1.8 cm/s, p = 0.01), but not in the liraglutide group (-7.1 ± 1.4 to -7.0 ± 1.4 cm/s, p = 0.60; between groups: p = 0.02). Similarly, the ratio of early and atrial mitral annular tissue velocities improved in the placebo group (1.0 ± 0.4 to 1.2 ± 0.4, p = 0.003), but not in the liraglutide group (1.0 ± 0.3 to 1.0 ± 0.3, p = 0.87; between groups: p = 0.03). We found no significant differences in heart rate, left ventricular structure or function within or between the groups. In conclusion, addition of liraglutide to exercise in sedentary patients with dysregulated type 2 diabetes may blunt the suggested beneficial effect of exercise on left ventricular diastolic function.

  5. Comparison of Three Doses of Gonadotrophin-releasing Hormone Agonist (GnRH-a) in IVF-ET Treatment Cycles

    Institute of Scientific and Technical Information of China (English)

    Xiao-ming ZHAO; Zhu-ping CHEN; Qi-de LIN

    2003-01-01

    Objective To investigate the optimal dose of GnRH-a, which is sufficient for down regulation of pituitary without over-suppression of ovarian function in IVF superovulation protocolsMethods Sixty patients undertook IVF-ET because of tube factor and /or endometriosis. Patients were divided into three groups randomly. Group A: 25 patients received a single dose of 1.88 mg Decapeptyl; Group B: 20 patients had a single dose of 2.50 mg Decapeptyl; Group C: 15 patients had a single dose of 3.75 mg Decapeptyl.Results The LH levels were 2.00±0.77 IU/L in Group A, 1.05±0.44 IU/L and 0.95±0.48 IU/L in Group B and C respectively on the day of starting gonadotropin injection; 1.97±0.76 IU/L in Group A, 0.96±0.42 IU/L and 0.77±0.49 IU/L in Group B and C respectively on the day of hCG administration. The LH levels in Group B and Group C were significantly lower than those in Group A (P<0.01). The mean number of gonadotropin ampoules was higher in Group B (38.05±6.08 ampoules) and Group C (40.0±10.62 ampoules) than in Group A (29.96±4.98 ampoules) (P<0.01). The duration of stimulation significantly increased in Group B (12.9±1.81 d) and Group C (13.6±2.63 d) as compared with that in Group A (11.24±1.36 d) (P<0.01). There were no differences among three groups in E2 levels on the day of hCG administration, the number of retrieved oocytes, fertilization rate, cleavage rate or pregnancy rate. There was no presence of LH peak in all groups.Conclusion The use of 1.88 mg Decapeptyl provides successful rate similar to 2.50 mg and 3.75 mg Decapeptyl, resulting in the reduced amount of gonadotropin, the duration of stimulation and the cost of treatment. The dose of 1.88 mg Decapeptyl is sufficient for pituitary down-regulation of IVF program for Chinese women.

  6. GnRH agonist triggering

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  7. Profiling the bronchodilator effects of the novel ultra-long-acting β2-agonist indacaterol against established treatments in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Vogelmeier, Claus; Magnussen, Helgo; LaForce, Craig; Owen, Roger; Kramer, Benjamin

    2011-10-01

    Indacaterol is a novel, inhaled, ultra-long-acting β(2)-agonist providing 24-h bronchodilation with once-daily (od) dosing for maintenance use in patients with chronic obstructive pulmonary disease (COPD). This article reviews the bronchodilator properties of indacaterol compared with other treatments used in COPD. Data from five published placebo-controlled studies were reviewed. Two 14-day crossover studies, the first comparing indacaterol 300 µg od with salmeterol 50 µg twice daily (bid), the second comparing indacaterol 150 µg and 300 µg od with tiotropium 18 µg od, assessed forced expiratory volume in 1 s (FEV(1)) at 24 h postdose (trough). Third, a 14-day crossover study evaluated trough FEV(1) following indacaterol 300 µg dosed morning or evening compared with salmeterol 50 µg bid. Fourth, a single-dose study of indacaterol 150 and 300 µg measured FEV(1) at 5 min postdose compared with salmeterol/fluticasone 50/500 µg and salbutamol 200 µg. Finally, data from a 1-year study with indacaterol 300 µg and formoterol 12 µg bid were examined to determine whether bronchodilation was maintained long term. In the first two studies, indacaterol increased trough FEV(1) after 14 days by a statistically significant and clinically relevant margin over placebo; indacaterol had a greater effect than salmeterol and a similar effect to tiotropium. In the third study, indacaterol had the same effect on trough FEV(1) whether dosed in the morning or evening. In the fourth study, the onset of the bronchodilator effect of indacaterol was similar to that of salbutamol. In the fifth study, the bronchodilator effect of indacaterol on trough FEV(1) was maintained at a significant and clinically relevant level over 52 weeks, whereas the bronchodilator effect of formoterol diminished over time. To conclude, indacaterol is a highly effective bronchodilator that is superior to or at least as effective as other available long-acting bronchodilators for COPD.

  8. Protein alterations induced by long-term agonist treatment of HEK293 cells expressing thyrotropin-releasing hormone receptor and G11alpha protein.

    Science.gov (United States)

    Drastichova, Zdenka; Bourova, Lenka; Hejnova, Lucie; Jedelsky, Petr; Svoboda, Petr; Novotny, Jiri

    2010-01-01

    This study aimed to determine whether sustained stimulation with thyrotropin-releasing hormone (TRH), a peptide with important physiological functions, can possibly affect expression of plasma membrane proteins in HEK293 cells expressing high levels of TRH receptor and G(11)alpha protein. Our previous experiments using silver-stained two-dimensional polyacrylamide gel electrophoretograms did not reveal any significant changes in an overall composition of membrane microdomain proteins after long-term treatment with TRH of these cells (Matousek et al. 2005 Cell Biochem Biophys 42: 21-40). Here we used a purified plasma membrane fraction prepared by Percoll gradient centrifugation and proteins resolved by 2D electrophoresis were stained with SYPRO Ruby gel stain. The high enrichment in plasma membrane proteins of this preparation was confirmed by a multifold increase in the number of TRH receptors and agonist stimulated G-protein activity, compared to postnuclear supernatant. By a combination of these approaches we were able to determine a number of clearly discernible protein changes in the plasma membrane-enriched fraction isolated from cells treated with TRH (1 x 10(-5) M, 16 h): 4 proteins disappeared, the level of 18 proteins decreased and the level of 39 proteins increased. Our concomitant immunochemical determinations also indicated a clear down-regulation of G(q/11)alpha proteins in preparations from hormone-treated cells. In parallel, we observed decrease in caspase 3 and alterations in some other apoptotic marker proteins, which were in line with the presumed antiapoptotic effect of TRH.

  9. Time course of altered sensitivity to inhibitory and excitatory agonist responses in the longitudinal muscle-myenteric plexus and analgesia in the guinea pig after chronic morphine treatment

    Directory of Open Access Journals (Sweden)

    Dane M Barrett

    2012-01-01

    Full Text Available Tolerance that develops after chronic morphine exposure has been proposed to be an adaptive response that develops and decays over a defined time course. The present study examined the development of tolerance to the acute hypothermic and analgesic effects of morphine and correlated the time course for the desensitization in vivo with the reduced responsiveness to DAMGO and 2-CADO and increased responsiveness to nicotine of the longitudinal muscle/myenteric plexus (LM/MP preparation in vitro. Assessment was performed at various times after morphine or placebo pellet implantation. Morphine produced a modest hypothermic response to which no tolerance developed. However, the development of tolerance to the analgesic effect of morphine, the inhibitory effect of DAMGO and CADO on neurogenic twitches of the LM/MP and hypersensitivity to the contractile response to nicotine was observed to occur in a time-dependent manner. The alterations in sensitivity to DAMGO, nicotine and responsiveness to morphine analgesia occurred between days 4 and 10 and returned to normal by day 14 post-implantation. In contrast, sensitivity of LM/MP preparations to 2-CADO displayed a similar time-dependent onset but the tolerance persisted beyond 14 days after implantation. These data suggest that the heterologous tolerance that develops after chronic morphine treatment is time-dependent and persistent but, ultimately returns to normal in the absence of any intervention. Furthermore, the data suggest that the basis of the adaptive phenomenon may involve multiple cellular mechanisms including the modulation of cell excitability and normal physiology but the consequences of the adaptation extend to all effects of the agonist.

  10. Human delta opioid receptor: functional studies on stably transfected Chinese hamster ovary cells after acute and chronic treatment with the selective nonpeptidic agonist SNC-80.

    Science.gov (United States)

    Malatynska, E; Wang, Y; Knapp, R J; Waite, S; Calderon, S; Rice, K; Hruby, V J; Yamamura, H I; Roeske, W R

    1996-09-01

    The SNC-80 series of nonpeptidic agonists for the delta-opioid receptor are being developed as potential analgesic drugs. It is important to understand their acute and chronic effects at human delta-opioid receptors. Thus, we measured the ability of SNC-80 and [D-Pen2,4'-Cl-Phe4,D-Pen5]enkephalin to inhibit forskolin-stimulated adenylyl cyclase activity in recombinant Chinese hamster ovary cells stably expressing the cloned human delta-opioid receptor. The calculated EC50 values for [D-Pen2,4'-Cl-Phe4,D-Pen5]enkephalin and SNC-80 were 0.6 +/- 0.1 nM and 6.3 +/- 0.1 nM, respectively. Pretreatment of these cells with SNC-80 (100 nM) for 24 hr produced 1) a time-dependent reduction of delta receptor density, as measured by radioligand binding studies with [3H]naltrindole; 2) a shift in the EC50 value of SNC-80 from 7.7 +/- 4.2 nM to 44.1 +/- 12 nM, as measured by the cyclic AMP assay; 3) a reduction in the maximum inhibition of adenylyl cyclase activity from 86% to 48%; 4) a marked increase in the forskolin stimulation of basal cyclic AMP accumulation by nearly 100% (from 442 pmol/mg of protein to 824 pmol/mg of protein); and 5) a 5-fold increase in forskolin-stimulated cyclic AMP accumulation after addition of naltrindole. These studies showed that SNC-80 produced desensitization and down-regulation of human delta-opioid receptors in recombinant Chinese hamster ovary cells after chronic treatment and that this effect was associated with an increase in adenylyl cyclase activity.

  11. ICAM-1-Targeted Liposomes Loaded with Liver X Receptor Agonists Suppress PDGF-Induced Proliferation of Vascular Smooth Muscle Cells

    Science.gov (United States)

    Huang, Xu; Xu, Meng-Qi; Zhang, Wei; Ma, Sai; Guo, Weisheng; Wang, Yabin; Zhang, Yan; Gou, Tiantian; Chen, Yundai; Liang, Xing-Jie; Cao, Feng

    2017-05-01

    The proliferation of vascular smooth muscle cells (VSMCs) is one of the key events during the progress of atherosclerosis. The activated liver X receptor (LXR) signalling pathway is demonstrated to inhibit platelet-derived growth factor BB (PDGF-BB)-induced VSMC proliferation. Notably, following PDGF-BB stimulation, the expression of intercellular adhesion molecule-1 (ICAM-1) by VSMCs increases significantly. In this study, anti-ICAM-1 antibody-conjugated liposomes were fabricated for targeted delivery of a water-insoluble LXR agonist (T0901317) to inhibit VSMC proliferation. The liposomes were prepared by filming-rehydration method with uniform size distribution and considerable drug entrapment efficiency. The targeting effect of the anti-ICAM-T0901317 liposomes was evaluated by confocal laser scanning microscope (CLSM) and flow cytometry. Anti-ICAM-T0901317 liposomes showed significantly higher inhibition effect of VSMC proliferation than free T0901317 by CCk8 proliferation assays and BrdU staining. Western blot assay further confirmed that anti-ICAM-T0901317 liposomes inhibited retinoblastoma (Rb) phosphorylation and MCM6 expression. In conclusion, this study identified anti-ICAM-T0901317 liposomes as a promising nanotherapeutic approach to overcome VSMC proliferation during atherosclerosis progression.

  12. Palmitic acid-induced apoptosis in pancreatic β-cells is increased by liver X receptor agonist and attenuated by eicosapentaenoate.

    Science.gov (United States)

    Liang, Huasheng; Zhong, Yuhua; Zhou, Shaobi; Li, Qingdi Quentin

    2011-01-01

    Saturated fatty acids are implicated in the development of diabetes via the impairment of pancreatic islet β-cell viability and function. Liver X receptors (LXRs) and eicosapentaenoate (EPA) are known regulators of fatty acid metabolism. However, their roles in the pathogenesis of diabetes remain incompletely understood. The aim of this study was to determine the effects of EPA and the LXR agonist T0901317 on saturated fatty acid (palmitic acid)-induced apoptosis in the insulinoma β-cell line INS-1, a model for insulin-secreting β-cells. T0901317 significantly promoted palmitic acid-induced apoptotic cell death in the INS-1 cells. Consistent with these results, caspase-3 activity and BAX and sterol regulatory element binding protein-1c (SREBP-1c) mRNA levels were markedly increased in INS-1 cells co-administered palmitic acid and T0901317. The production of reactive oxygen species was considerably higher in the cells cultured concurrently with T0901317 and palmitic acid than in the cells incubated with either agent alone. EPA treatment attenuated the cellular death promoted by palmitic acid and T0901317 in the INS-1 cells, disclosing a possible mediating mechanism involving the inhibition of SREBP-1c. Finally, T0901317 up-regulated the palmitic acid-induced expression of p27(KIP1), transforming growth factor beta 1, and SMAD3 proteins in INS-1 cells. These results demonstrate that palmitic acid-induced apoptosis in β-cells is enhanced by T0901317 via the activation of LXRs and is blocked by EPA via the inhibition of SREBP-1c, suggesting that the regulation of lipogenesis and lipotoxicity affecting pancreatic β-cell viability and insulin production may be a unique strategy for diabetes therapy.

  13. GnRH agonist for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI treatment cycles: Systematic review and meta-analysis.

    Science.gov (United States)

    Youssef, M A F; Abdelmoty, Hatem I; Ahmed, Mohamed A S; Elmohamady, Maged

    2015-05-01

    Final oocyte maturation in GnRH antagonist co-treated IVF/ICSI cycles can be triggered with HCG or a GnRH agonist. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of the final oocyte maturation trigger in GnRH antagonist co-treated cycles. Outcome measures were ongoing pregnancy rate (OPR) and ovarian hyperstimulation syndrome (OHSS) incidence. Searches: were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library, and databases of abstracts. There was a statistically significant difference against the GnRH agonist for OPR in fresh autologous cycles (n = 1024) with an odd ratio (OR) of 0.69 (95% CI: 0.52-0.93). In oocyte-donor cycles (n = 342) there was no evidence of a difference (OR: 0.91; 95% CI: 0.59-1.40). There was a statistically significant difference in favour of GnRH agonist regarding the incidence of OHSS in fresh autologous cycles (OR: 0.06; 95% CI: 0.01-0.33) and donor cycles respectively (OR: 0.06; 95% CI: 0.01-0.27). In conclusion GnRH agonist trigger for final oocyte maturation trigger in GnRH antagonist cycles is safer but less efficient than HCG.

  14. GnRH agonist for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI treatment cycles: Systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    M.A.F. Youssef

    2015-05-01

    Full Text Available Final oocyte maturation in GnRH antagonist co-treated IVF/ICSI cycles can be triggered with HCG or a GnRH agonist. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of the final oocyte maturation trigger in GnRH antagonist co-treated cycles. Outcome measures were ongoing pregnancy rate (OPR and ovarian hyperstimulation syndrome (OHSS incidence. Searches: were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library, and databases of abstracts. There was a statistically significant difference against the GnRH agonist for OPR in fresh autologous cycles (n = 1024 with an odd ratio (OR of 0.69 (95% CI: 0.52–0.93. In oocyte-donor cycles (n = 342 there was no evidence of a difference (OR: 0.91; 95% CI: 0.59–1.40. There was a statistically significant difference in favour of GnRH agonist regarding the incidence of OHSS in fresh autologous cycles (OR: 0.06; 95% CI: 0.01–0.33 and donor cycles respectively (OR: 0.06; 95% CI: 0.01–0.27. In conclusion GnRH agonist trigger for final oocyte maturation trigger in GnRH antagonist cycles is safer but less efficient than HCG.

  15. The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis.

    Science.gov (United States)

    Cheng, Huawei; Shang, Yuping; Jiang, Ling; Shi, Tian-lu; Wang, Lin

    2016-01-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-analysis was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by December 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calculated to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta-analysis. We found the effect of PPAR-γ agonists on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-analysis. There is insufficient evidence of statistically incognition of AD and mild-to-moderate AD patients have been improved who were treated with PPAR-γ agonists in our research. However, PPAR-γ agonists may be a promising therapeutic approach in future, especially pioglitazone, with large-scale randomized controlled trials to confirm.

  16. Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA1/GPR40), a Potential Target for the Treatment of Type II Diabetes

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Urban, Christian; Merten, Nicole;

    2008-01-01

    A series of 4-phenethynyldihydrocinnamic acid agonists of the free fatty acid receptor 1 (FFA 1) has been discovered and explored. The preferred compound 20 (TUG-424, EC 50 = 32 nM) significantly increased glucose-stimulated insulin secretion at 100 nM and may serve to explore the role of FFA 1 i...

  17. Association of blood eosinophils and plasma periostin with FEV1 response after 3-month inhaled corticosteroid and long-acting beta2-agonist treatment in stable COPD patients

    Directory of Open Access Journals (Sweden)

    Park HY

    2015-12-01

    with an improvement in forced expiratory volume in 1 second (FEV1 after 3-month treatment with ICS/long-acting beta2-agonist (LABA in stable COPD patients. Patients and methods: Blood eosinophils and plasma periostin levels were measured in 130 stable COPD subjects selected from the Korean Obstructive Lung Disease cohort. Subjects began a 3-month ICS/LABA treatment after washout period. Results: High blood eosinophils (>260/µL, adjusted odds ratio =3.52, P=0.009 and high plasma periostin (>23 ng/mL, adjusted odds ratio =3.52, P=0.013 were significantly associated with FEV1 responders (>12% and 200 mL increase in FEV1 from baseline after treatment. Moreover, the addition of high blood eosinophils to age, baseline positive bronchodilator response, and FEV1 <50% of the predicted value significantly increased the area under the curve for prediction of FEV1 responders (from 0.700 to 0.771; P=0.045. Conclusion: High blood eosinophils and high plasma periostin were associated with improved lung function after 3-month ICS/LABA treatment. In particular, high blood eosinophils, in combination with age and baseline lung function parameters, might be a possible biomarker for identification of COPD patients with favorable FEV1 improvement in response to ICS/LABA treatment. Keywords: eosinophils, periostin, COPD

  18. The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation[S

    Science.gov (United States)

    Sorrentino, Vincenzo; Nelson, Jessica K.; Maspero, Elena; Marques, André R. A.; Scheer, Lilith; Polo, Simona; Zelcer, Noam

    2013-01-01

    Low density lipoprotein (LDL) cholesterol is taken up into cells via clathrin-mediated endocytosis of the LDL receptor (LDLR). Following dissociation of the LDLR-LDL complex, LDL is directed to lysosomes whereas the LDLR recycles to the plasma membrane. Activation of the sterol-sensing nuclear receptors liver X receptors (LXRs) enhances degradation of the LDLR. This depends on the LXR target gene inducible degrader of the LDLR (IDOL), an E3-ubiquitin ligase that promotes ubiquitylation and lysosomal degradation of the LDLR. How ubiquitylation of the LDLR by IDOL controls its endocytic trafficking is currently unknown. Using genetic- and pharmacological-based approaches coupled to functional assessment of LDL uptake, we show that the LXR-IDOL axis targets a LDLR pool present in lipid rafts. IDOL-dependent internalization of the LDLR is independent of clathrin, caveolin, macroautophagy, and dynamin. Rather, it depends on the endocytic protein epsin. Consistent with LDLR ubiquitylation acting as a sorting signal, degradation of the receptor can be blocked by perturbing the endosomal sorting complex required for transport (ESCRT) or by USP8, a deubiquitylase implicated in sorting ubiquitylated cargo to multivesicular bodies. In summary, we provide evidence for the existence of an LXR-IDOL-mediated internalization pathway for the LDLR that is distinct from that used for lipoprotein uptake. PMID:23733886

  19. The content of PPAR, LXR, and RXR and the PPAR DNA-binding activity in macrophages over the course of inflammation in mice.

    Science.gov (United States)

    Dushkin, M I; Khoshchenko, O M; Chasovsky, M A; Pivovarova, E N

    2009-03-01

    The content of peroxisome proliferation activating proteins PPAR-alpha and PPAR-gamma, liver X receptors (LXR), and retinoid X receptors (RXR) and activity of PPAR-alpha, PPAR-gamma, and PPAR-delta binding to DNA response elements in C57Bl/6 mouse macrophages were studied during different phases of aseptic inflammation, induced by intraperitoneal injection of 50 mg/kg zymosan A. The DNA-binding activities of PPAR-alpha and PPAR-gamma and the levels of PPAR-alpha, PPAR-gamma, LXR, and RXR in peritoneal macrophages dropped on days 1 and 3 after zymosan injection. On days 7 and 14 the DNA-binding activity of PPAR-gamma and content of PPAR-gamma and LXR-beta protein increased in comparison with the control, while the DNA-binding activity and content of PPAR-alpha in the cells remained low. Recovery of RXR protein content in macrophages was observed only on day 14 after zymosan injection.

  20. Maternal Betaine Supplementation throughout Gestation and Lactation Modifies Hepatic Cholesterol Metabolic Genes in Weaning Piglets via AMPK/LXR-Mediated Pathway and Histone Modification

    Directory of Open Access Journals (Sweden)

    Demin Cai

    2016-10-01

    Full Text Available Betaine serves as an animal and human nutrient which has been heavily investigated in glucose and lipid metabolic regulation, yet the underlying mechanisms are still elusive. In this study, feeding sows with betaine-supplemented diets during pregnancy and lactation increased cholesterol content and low-density lipoprotein receptor (LDLR and scavenger receptor class B type I (SR-BI gene expression, but decreasing bile acids content and cholesterol-7a-hydroxylase (CYP7a1 expression in the liver of weaning piglets. This was associated with the significantly elevated serum betaine and methionine levels and hepatic S-adenosylmethionine (SAM and S-adenosylhomocysteine (SAH content. Concurrently, the hepatic nuclear transcription factor liver X receptor LXR was downregulated along with activated signal protein AMP-activated protein kinase (AMPK. Moreover, a chromatin immunoprecipitation assay showed lower LXR binding on CYP7a1 gene promoter and more enriched activation histone marker H3K4me3 on LDLR and SR-BI promoters. These results suggest that gestational and lactational betaine supplementation modulates hepatic gene expression involved in cholesterol metabolism via an AMPK/LXR pathway and histone modification in the weaning offspring.

  1. Maternal Betaine Supplementation throughout Gestation and Lactation Modifies Hepatic Cholesterol Metabolic Genes in Weaning Piglets via AMPK/LXR-Mediated Pathway and Histone Modification

    Science.gov (United States)

    Cai, Demin; Yuan, Mengjie; Liu, Haoyu; Pan, Shifeng; Ma, Wenqiang; Hong, Jian; Zhao, Ruqian

    2016-01-01

    Betaine serves as an animal and human nutrient which has been heavily investigated in glucose and lipid metabolic regulation, yet the underlying mechanisms are still elusive. In this study, feeding sows with betaine-supplemented diets during pregnancy and lactation increased cholesterol content and low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI) gene expression, but decreasing bile acids content and cholesterol-7a-hydroxylase (CYP7a1) expression in the liver of weaning piglets. This was associated with the significantly elevated serum betaine and methionine levels and hepatic S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content. Concurrently, the hepatic nuclear transcription factor liver X receptor LXR was downregulated along with activated signal protein AMP-activated protein kinase (AMPK). Moreover, a chromatin immunoprecipitation assay showed lower LXR binding on CYP7a1 gene promoter and more enriched activation histone marker H3K4me3 on LDLR and SR-BI promoters. These results suggest that gestational and lactational betaine supplementation modulates hepatic gene expression involved in cholesterol metabolism via an AMPK/LXR pathway and histone modification in the weaning offspring. PMID:27763549

  2. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

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

  3. Both radical prostatectomy following treatment with neoadjuvant LHRH agonist and estramustine and radiotherapy following treatment with neoadjuvant hormonal therapy achieved favorable oncological outcome in high-risk prostate cancer: a propensity-score matching analysis.

    Science.gov (United States)

    Koie, Takuya; Ohyama, Chikara; Yamamoto, Hayato; Imai, Atsushi; Hatakeyama, Shingo; Yoneyama, Takahiro; Hashimoto, Yasuhiro; Yoneyama, Tohru; Tobisawa, Yuki; Aoki, Masahiko; Takai, Yoshihiro

    2014-04-30

    To date, the different treatment modalities for high-risk prostate cancer (Pca) have not been compared in any sufficiently large-scale, prospective, randomized clinical trial. We used propensity-score matching analysis to compare the oncological outcomes of high-risk prostate cancer between patients treated with radical prostatectomy (RP) and those treated with radiation therapy (RT). We studied 216 patients who received neoadjuvant therapy followed by RP (RP cohort) and 81 patients who received neoadjuvant androgen-deprivation therapy (ADT) followed by RT (RT cohort). The RP cohort received a luteinizing hormone-releasing hormone agonist and estramustine phosphate (280 mg/day) for 6 months prior to RP. The RT cohort received ADT for at least 6 months prior to RT using a 3-dimensional conformal radiotherapy technique. The total radiation dose was 70 to 76 Gy administered at 2 Gy/fraction. Propensity-score matching identified 78 matched pairs of patients. The 3-year overall survival rates were 98.3% and 92.1% in the RP and RT groups, respectively (P=0.156). The 3-year biochemical recurrence-free survival rates were 86.4% and 89.4% in the RP and RT groups, respectively (P=0.878). Our study findings may suggest almost identical cancer control of RP and RT with appropriate neoadjuvant therapy in high-risk Pca. Therefore, issues of health-related quality of life may have an important impact on decision making in treatment of high-risk Pca.

  4. [Melatonin receptor agonist].

    Science.gov (United States)

    Uchiyama, Makoto

    2015-06-01

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

  5. GnRH agonist for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI treatment cycles: Systematic review and meta-analysis

    OpenAIRE

    Youssef, M.A.F.; Abdelmoty, Hatem I; Ahmed, Mohamed A.S.; Maged Elmohamady

    2015-01-01

    Final oocyte maturation in GnRH antagonist co-treated IVF/ICSI cycles can be triggered with HCG or a GnRH agonist. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of the final oocyte maturation trigger in GnRH antagonist co-treated cycles. Outcome measures were ongoing pregnancy rate (OPR) and ovarian hyperstimulation syndrome (OHSS) incidence. Searches: were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library, ...

  6. 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.

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

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

    1993-01-01

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

  8. Differential responses to acute administration of a new 5-HT7-R agonist as a function of adolescent pre-treatment: phMRI and immuno-histochemical study

    OpenAIRE

    Altabella, Luisa; Sbriccoli, Marco; Zoratto, Francesca; Poleggi, Anna; Vinci, Ramona; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Cardone, Franco; Canese, Rossella; Adriani, Walter

    2014-01-01

    LP-211 is a new, selective agonist of serotonin (5-hydroxytryptamine, 5-HT) receptor 7 (5-HT7-R), which is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive and sleep regulation. Adolescent subchronic LP-211 treatment produces some persisting changes in rats' forebrain structural and functional parameters. Here, using pharmacological MRI (phMRI), we investigated the effect of acute administration with LP-211 (10 mg/kg i.p.), or vehicle, to ad...

  9. Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages.

    Science.gov (United States)

    Ayaori, Makoto; Yakushiji, Emi; Ogura, Masatsune; Nakaya, Kazuhiro; Hisada, Tetsuya; Uto-Kondo, Harumi; Takiguchi, Shunichi; Terao, Yoshio; Sasaki, Makoto; Komatsu, Tomohiro; Iizuka, Maki; Yogo, Makiko; Uehara, Yoshinari; Kagechika, Hiroyuki; Nakanishi, Tsuyoshi; Ikewaki, Katsunori

    2012-04-01

    ABC transporter G1 (ABCG1) plays a pivotal role in HDL-mediated cholesterol efflux and atherogenesis. We investigated whether, and how, retinoic acid receptors (RARs) regulate ABCG1 expression in macrophages. All-trans retinoic acid (ATRA), an RAR ligand, increased ABCG1 protein levels and apoA-I/HDL-mediated cholesterol efflux from the macrophages. Both ATRA and other RAR agonists, TTNPB and Am580, increased major transcripts driven by promoter B upstream of exon 5, though minor transcripts driven by promoter A upstream of exon 1 were only increased by ATRA. The stimulatory effects of ATRA on ABCG1 expression were completely abolished in the presence of RAR/RXR antagonists but were only partially canceled in the presence of an LXR antagonist. Adenovirus with overexpressed oxysterol sulfotransferase abolished the LXR pathway, as previously reported, and ATRA-responsiveness in ABCA1/ABCG1 expressions were respectively attenuated by 38 and 22% compared to the control virus. Promoter assays revealed that ABCG1 levels were regulated more by promoter B than promoter A, and ATRA activated promoter B in a liver X receptor-responsive element (LXRE)-dependent manner. Further, LXRE-B in intron 7, but not LXRE-A in intron 5, enhanced ATRA responsiveness under overexpression of all RAR isoforms-RARα/β/γ. In contrast, the activation of promoter B by TTNPB depended on LXRE-B and RARα, but not on RARβ/γ. Finally, chromatin immunoprecipitation and gel-shift assays revealed a specific and direct repeat 4-dependent binding of RARα to LXRE-B. In conclusion, RAR ligands increase ABCA1/G1 expression and apoA-I/HDL-mediated cholesterol efflux from macrophages, and modulate ABCG1 promoter activity via LXRE-dependent mechanisms.

  10. GLP-1受体激动剂治疗2型糖尿病的 meta 分析%The Meta-analysis of GLP-1 Receptor Agonists on the Treatment of T2DM

    Institute of Scientific and Technical Information of China (English)

    2013-01-01

      目的比较 GLP-1受体激动剂与胰岛素治疗2型糖尿病的疗效及安全性。方法计算机检索 Springer、PubMed、Embase、CNKI 等数据库并手工检索相关文献。评价符合纳入标准的文献,对文献中的数据进行 meta 分析。结果GLP-1受体激动剂在控制 HbA1c 方面与胰岛素无明显差别,加权均数差=0.05,95%CI(-0.07,0.17);在减轻体重方面优于胰岛素,加权均数差=4.55,95%CI (3.97,5.14);在低血糖发生率方面优于胰岛素组,比值比=0.43295%CI (0.338,0.551)。结论 GLP-1受体激动剂是较胰岛素更有前景的治疗手段。%Objective To assess the efficacy and safety of GLP-1 receptor agonist on the treatment of T2DM. Methods:To search randomized controlled trials from Springer, Pubmed, Embase, CNKI and to evaluate the quality of RCTs which are included on the basis of criteria . Meta analysis was conducted by the software Stata 12.0. Results : Meta analysis indicated that :GLP-1 receptor agonist was not inferior than insulin in lowering hemoglobin A1C. It was more effective than insulin in lowering weight and reducing the risk of hypoglycemia. Conclusion: GLP-1 receptor agonist was an effective and safe treatment for T2DM.

  11. Effects of dose and duration of continuous GnRH-agonist treatment on induction of estrus in beagle dogs: competing and concurrent up-regulation and down-regulation of LH release.

    Science.gov (United States)

    Concannon, P W; Temple, M; Montanez, A; Newton, L

    2006-10-01

    Dose-response estrus-induction trials were conducted during anestrus in 93 treated and 6 control bitches, a continuous administration of the GnRH-agonist lutrelin with a potency 150 x GnRH, and at six different doses from 0.2 to 4.8 microg/kg/d for 7-14 days in 15 groups of six to eight dogs each in defined stages of natural or pharmacologically determined anestrus. Agonist treatment induced clinically and cytologically normal proestrus (in 89% of cases) within 4.8 +/- 0.2 x days, and resulted in behavioral estrus (71%), spontaneous late-proestrus LH (and FSH) surges, ovulation (59%) and pregnancy (44%) in a dose dependent manner. Outcomes of ovulation and pregnancy in most cases required that the dose be sufficiently large enough to routinely stimulate a large initial increase in LH and FSH (i.e., > or = 0.6 microg/kg/d), and of sufficient duration (i.e., > 7 days) to ensure that supra-basal gonadotropin levels persistedntil no longer needed for spontaneous continuation of an induced proestrus. Success additionally required that the GnRH dose be modest enough (i.e., induction results, including pregnancy rates of 100% in six bitches treated in natural-anestrus bitches, six bitches in which anestrus had been advanced by a luteolytic prostaglandin treatment and in six bitches in which anestrus had been extended by progesterone implants administered for 3 months. Although lutrelin is not commercially available, these results provide guidelines for the development of estrus-inducing protocols with other GnRH-agonists of known biopotencies.

  12. 过氧化物酶体增殖因子活化受体γ激动剂用于治疗皮肤病%Peroxisome proliferator-activated receptor-gamma agonists in the treatment of dermatoses

    Institute of Scientific and Technical Information of China (English)

    林熙然; 黄畋

    2008-01-01

    新近发现过氧化物酶体增殖因子活化受体γ在皮肤中调节多种重要的功能,包括细胞增殖与分化及免疫和炎症反应,因而可能成为治疗多种皮肤病的新靶标.临床上过氧化物酶体增殖因子活化受体γ激动剂已被试用于银屑病、银屑病性关节炎、特应性皮炎、黑素瘤、多毛症、血管肿瘤和脂肪营养不良等.过氧化物酶体增殖因子活化受体激动剂的研究可能提供皮肤病治疗的新手段.%Recent data have shown that peroxisome proliferator-activated receptor (PPAR)-gamma regulates many biological processes in skin, including cell proliferation and differentiation, immune response and inflammatory reactions. Thus, it may serve as a novel target for the treatment of various skin disorders. Clinically, PPARgamma agonists have been used to treat psoriasis, psoriatic arthritis, atopic dermatitis, melanoma, hirsutism, vascular tumors and lipodystrophy. Investigations into PPAR agonists may develop new approaches to the treatment of skin disorders.

  13. Role of prostaglandins and specific place in therapy of bimatoprost in the treatment of elevated intraocular pressure and ocular hypertension: A closer look at the agonist properties of bimatoprost and the prostamides

    Directory of Open Access Journals (Sweden)

    Scott D Smid

    2009-11-01

    Full Text Available Scott D SmidDiscipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, AustraliaAbstract: Bimatoprost is the only representative of a novel class of prostaglandin ethanolamide (prostamide compounds used therapeutically as an efficacious treatment for glaucoma. The pathways through which bimatoprost works to improve uveoscleral outflow to relieve elevated intraocular pressure are similar to those of the conventional prostaglandins used in glaucoma therapy, with some evidence of a preferential action at the trabecular meshwork. The pharmacology of bimatoprost is however, unclear. Pharmacological evidence supports a specific and distinct receptor-mediated agonist activity of bimatoprost at ‘prostamide’ receptors, which is selective to the prostamides as a class. However, other studies have reported either activity of bimatoprost at additional prostanoid and nonprostanoid receptors, or a conversion of bimatoprost to metabolites with agonist activity at prostaglandin FP receptors in the human eye. The formation of endogenous prostamides has been demonstrated in vivo, by a novel pathway involving the cyclooxygenase-2-mediated conversion of endogenous cannabinoid (endocannabinoid substrates. Irrespective of the pharmacology of bimatoprost and the prostamides in general, further studies are needed to determine the biological role and biochemical pathology of prostamides in the human eye, particularly in glaucoma. Such studies may improve our understanding of uveoscleral flow and may offer new treatments for controlling intraocular pressure.Keywords: bimatoprost, endocannabinoid, glaucoma, prostamides, trabecular meshwork

  14. [Expression of nuclear hormone receptors PPAR, LXR and RXR in the liver and lipid and glucose levels in blood in susceptible and resistant to hepatocarcinogenesis mice strains].

    Science.gov (United States)

    Pivovarova, E N; Baginskaia, N V; Perepechaeva, M L; Il'nitskaia, S I; Dushkin, M I

    2010-01-01

    Earlier it was shown that male mice of the DD/He strain were highly susceptible to ortho-aminoasotoluene (OAT) induced hepatocarcinogenesis, and resistant to spontaneous liver tumor development as compared to the CC57BR/Mv strain. In the present work we have made a comparative investigation of peroxisome proliferator-activated receptor (PPAR), liver X-receptor (LXR) and retinoic X-receptor (RXR) mRNA levels in liver as well as concentrations of corticosterone, glucose, lipids and insulin in blood of male DD/He and CC57BR/Mv mice. Using the multiplex RT-PCR method it was found that PPAR-alpha, PPAR-gamma, RXR-alpha and RXR-beta mRNA content was essentially decreased in the liver of DD mice as compared to mice of the CC57BR strain. No significant interstrain differences of LXR-alpha and LXR-beta mRNA content were found. In DD micetere was more then the 3-fold decrease of blood content of corticosterone, which is involved in PPAR and RXR regulation. DD mice demonstrated a significant decrease in blood serum glucose and insulin concentrations as well as higher reactivity to insulin as compared with CC57BR mice. Elevated blood total cholesterol and cholesterol HDL level were found in DD mice whereas triglyceride content was basically the same in both mouse strains. It is known that glucocorticoids, PPAR and RXR play crucial role in transcription regulation of inflammation response. Therefore our data allow to suggest that decreased corticosterone level in blood, PPAR and RXR mRNA content in liver of the DD strain may lead to induction of inflammation by OAT exposure, resulting in a high incidence of tumorigenesis in this strain.

  15. Ovariectomy and subsequent treatment with estrogen receptor agonists tune the innate immune system of the hippocampus in middle-aged female rats.

    Science.gov (United States)

    Sárvári, Miklós; Kalló, Imre; Hrabovszky, Erik; Solymosi, Norbert; Liposits, Zsolt

    2014-01-01

    The innate immune system including microglia has a major contribution to maintenance of the physiological functions of the hippocampus by permanent monitoring of the neural milieu and elimination of tissue-damaging threats. The hippocampus is vulnerable to age-related changes ranging from gene expression to network connectivity. The risk of hippocampal deterioration increases with the decline of gonadal hormone supply. To explore the impact of hormone milieu on the function of the innate immune system in middle-aged female rats, we compared mRNA expression in the hippocampus after gonadal hormone withdrawal, with or without subsequent estrogen replacement using estradiol and isotype-selective estrogen receptor (ER) agonists. Targeted profiling assessed the status of the innate immune system (macrophage-associated receptors, complement, inhibitory neuronal ligands), local estradiol synthesis (P450 aromatase) and estrogen reception (ER). Results established upregulation of macrophage-associated (Cd45, Iba1, Cd68, Cd11b, Cd18, Fcgr1a, Fcgr2b) and complement (C3, factor B, properdin) genes in response to ovariectomy. Ovariectomy upregulated Cd22 and downregulated semaphorin3A (Sema3a) expression, indicating altered neuronal regulation of microglia. Ovariectomy also led to downregulation of aromatase and upregulation of ERα gene. Of note, analogous changes were observed in the hippocampus of postmenopausal women. In ovariectomized rats, estradiol replacement attenuated Iba1, Cd11b, Fcgr1a, C3, increased mannose receptor Mrc1, Cd163 and reversed Sema3a expression. In contrast, reduced expression of aromatase was not reversed by estradiol. While the effects of ERα agonist closely resembled those of estradiol, ERβ agonist was also capable of attenuating the expression of several macrophage-associated and complement genes. These data together indicate that the innate immune system of the aging hippocampus is highly responsive to the gonadal hormone milieu. In

  16. Ovariectomy and subsequent treatment with estrogen receptor agonists tune the innate immune system of the hippocampus in middle-aged female rats.

    Directory of Open Access Journals (Sweden)

    Miklós Sárvári

    Full Text Available The innate immune system including microglia has a major contribution to maintenance of the physiological functions of the hippocampus by permanent monitoring of the neural milieu and elimination of tissue-damaging threats. The hippocampus is vulnerable to age-related changes ranging from gene expression to network connectivity. The risk of hippocampal deterioration increases with the decline of gonadal hormone supply. To explore the impact of hormone milieu on the function of the innate immune system in middle-aged female rats, we compared mRNA expression in the hippocampus after gonadal hormone withdrawal, with or without subsequent estrogen replacement using estradiol and isotype-selective estrogen receptor (ER agonists. Targeted profiling assessed the status of the innate immune system (macrophage-associated receptors, complement, inhibitory neuronal ligands, local estradiol synthesis (P450 aromatase and estrogen reception (ER. Results established upregulation of macrophage-associated (Cd45, Iba1, Cd68, Cd11b, Cd18, Fcgr1a, Fcgr2b and complement (C3, factor B, properdin genes in response to ovariectomy. Ovariectomy upregulated Cd22 and downregulated semaphorin3A (Sema3a expression, indicating altered neuronal regulation of microglia. Ovariectomy also led to downregulation of aromatase and upregulation of ERα gene. Of note, analogous changes were observed in the hippocampus of postmenopausal women. In ovariectomized rats, estradiol replacement attenuated Iba1, Cd11b, Fcgr1a, C3, increased mannose receptor Mrc1, Cd163 and reversed Sema3a expression. In contrast, reduced expression of aromatase was not reversed by estradiol. While the effects of ERα agonist closely resembled those of estradiol, ERβ agonist was also capable of attenuating the expression of several macrophage-associated and complement genes. These data together indicate that the innate immune system of the aging hippocampus is highly responsive to the gonadal hormone milieu

  17. Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain.

    Science.gov (United States)

    Giri, Aswini Kumar; Apostol, Christopher R; Wang, Yue; Forte, Brittany L; Largent-Milnes, Tally M; Davis, Peg; Rankin, David; Molnar, Gabriella; Olson, Keith M; Porreca, Frank; Vanderah, Todd W; Hruby, Victor J

    2015-11-12

    Multifunctional ligands with agonist bioactivities at μ/δ opioid receptors (MOR/DOR) and antagonist bioactivity at the neurokinin-1 receptor (NK1R) have been designed and synthesized. These peptide-based ligands are anticipated to produce better biological profiles (e.g., higher analgesic effect with significantly less adverse side effects) compared to those of existing drugs and to deliver better synergistic effects than coadministration of a mixture of multiple drugs. A systematic structure-activity relationship (SAR) study has been conducted to find multifunctional ligands with desired activities at three receptors. It has been found that introduction of Dmt (2,6-dimethyl-tyrosine) at the first position and NMePhe at the fourth position (ligand 3: H-Dmt-d-Ala-Gly-NMePhe-Pro-Leu-Trp-NH-Bn(3',5'-(CF3)2)) displays binding as well as functional selectivity for MOR over DOR while maintaining efficacy, potency, and antagonist activity at the NK1R. Dmt at the first position with Phe(4-F) at the fourth position (ligand 5: H-Dmt-d-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3',5'-(CF3)2)) exhibits balanced binding affinities at MOR and DOR though it has higher agonist activity at DOR over MOR. This study has led to the discovery of several novel ligands including 3 and 5 with excellent in vitro biological activity profiles. Metabolic stability studies in rat plasma with ligands 3, 5, and 7 (H-Tyr-d-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3',5'-(CF3)2)) showed that their stability depends on modifications at the first and fourth positions (3: T1/2 > 24 h; 5: T1/2 ≈ 6 h; 7: T1/2 > 2 h). Preliminary in vivo studies with these two ligands have shown promising antinociceptive activity.

  18. Spirocyclic delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl) benzamide (ADL5747).

    Science.gov (United States)

    Le Bourdonnec, Bertrand; Windh, Rolf T; Leister, Lara K; Zhou, Q Jean; Ajello, Christopher W; Gu, Minghua; Chu, Guo-Hua; Tuthill, Paul A; Barker, William M; Koblish, Michael; Wiant, Daniel D; Graczyk, Thomas M; Belanger, Serge; Cassel, Joel A; Feschenko, Marina S; Brogdon, Bernice L; Smith, Steven A; Derelanko, Michael J; Kutz, Steve; Little, Patrick J; DeHaven, Robert N; DeHaven-Hudkins, Diane L; Dolle, Roland E

    2009-09-24

    Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.

  19. Effect of AVE 0991 angiotensin-(1-7) receptor agonist treatment on elemental and biomolecular content and distribution in atherosclerotic plaques of apoE-knockout mice

    Science.gov (United States)

    Kowalska, J.; Gajda, M.; Jawień, J.; Kwiatek, W. M.; Appel, K.; Dumas, P.

    2013-12-01

    Gene-targeted apolipoprotein E-knockout (apoE-KO) mice display early and highly progressive vascular lesions containing lipid deposits and they became a reliable animal model to study atherosclerosis. The aim of the present study was to investigate the effect of AVE 0991 angiotensin-(1-7) receptor agonist on the distribution of selected pro- and anti- inflammatory elements as well as biomolecules in atherosclerotic plaques of apoE-knockout mice. Synchrotron radiation-based X-ray fluorescence (micro-XRF) and Fourier Transform Infrared (micro-FTIR) microspectroscopies were applied. Two-month-old apoE-KO mice were fed for following four months diet supplemented with AVE 0991 (0.58 μmol/kg b.w. per day). Histological sections of ascending aortas were analyzed spectroscopically. The distribution of P, Ca, Fe and Zn were found to correspond with histological structure of the lesion. Significantly lower contents of P, Ca, Zn and significantly higher content of Fe were observed in animals treated with AVE 0991. Biomolecular analysis showed lower lipids saturation level and lower lipid to protein ratio in AVE 0991 treated group. Protein secondary structure was studied according to the composition of amide I band (1660 cm-1) and it demonstrated higher proportion of β-sheet structure as compared to α-helix in both studied groups.

  20. 多巴胺受体激动剂在延缓和治疗帕金森病相关运动并发症中的临床应用%Clinical application of dopamine agonists in the postponement and treatment of Parkinson’s disease-related motor complications

    Institute of Scientific and Technical Information of China (English)

    高佳佳; 赵延欣

    2015-01-01

    本文从多巴胺受体激动剂的分类、作用机制和临床应用等方面综述多巴胺受体激动剂在延缓和治疗帕金森病相关运动并发症中的价值。%The value of dopamine agonists in the postponement and treatment of Parkinson’s disease-related motor complications is reviewed by referring to recent literature, and the classiifcation of dopamine agonists and their mechanism of action and clinical application in the treatment of Parkinson’s disease are summarized, which indicates that dopamine agonists can delay the development of motor complications in Parkinson’s disease.

  1. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon

    2011-01-01

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

  2. Does prolonged pituitary down-regulation with gonadotropin-releasing hormone agonist improve the live-birth rate in in vitro fertilization treatment?

    Science.gov (United States)

    Ren, Jianzhi; Sha, Aiguo; Han, Dongmei; Li, Ping; Geng, Jie; Ma, Chaihui

    2014-07-01

    To evaluate the effects of a prolonged duration of gonadotropin-releasing hormone agonist (GnRH-a) in pituitary down-regulation for controlled ovarian hyperstimulation (COH) on the live-birth rate in nonendometriotic women undergoing in vitro fertilization and embryo transfer (IVF-ET). Retrospective cohort study. University-affiliated hospital. Normogonadotropic women undergoing IVF. Three hundred seventy-eight patients receiving a prolonged pituitary down-regulation with GnRH-a before ovarian stimulation and 422 patients receiving a GnRH-a long protocol. Live-birth rate per fresh ET. In comparison with the long protocol, the prolonged down-regulation protocol required a higher total dose of gonadotropins. A lower serum luteinizing hormone (LH) level on the starting day of gonadotropin and the day of human chorionic gonadotropin (hCG) and a fewer number of oocytes and embryos were observed in the prolonged down-regulation protocol. However, the duration of stimulation and number of high-quality embryos were comparable between the two groups. A statistically significantly higher implantation rate (50.27% vs. 39.69%), clinical pregnancy rate (64.02% vs. 56.87%) and live-birth rate per fresh transfer cycle (55.56% vs. 45.73%) were observed in the prolonged protocol. Prolonged down-regulation in a GnRH-a protocol might increase the live-birth rates in normogonadotropic women. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  3. Intermittent treatment with parathyroid hormone (PTH) as well as a non-peptide small molecule agonist of the PTH1 receptor inhibits adipocyte differentiation in human bone marrow stromal cells.

    Science.gov (United States)

    Rickard, David J; Wang, Fei-Lan; Rodriguez-Rojas, Ana-Maria; Wu, Zining; Trice, Wen J; Hoffman, Sandra J; Votta, Bartholomew; Stroup, George B; Kumar, Sanjay; Nuttall, Mark E

    2006-12-01

    Whereas continuous PTH infusion increases bone resorption and bone loss, intermittent PTH treatment stimulates bone formation, in part, via reactivation of quiescent bone surfaces and reducing osteoblast apoptosis. We investigated the possibility that intermittent and continuous PTH treatment also differentially regulates osteogenic and adipocytic lineage commitment of bone marrow stromal progenitor/mesenchymal stem cells (MSC). The MSC were cultured under mildly adipogenic conditions in medium supplemented with dexamethasone, insulin, isobutyl-methylxanthine and troglitazone (DIIT), and treated with 50 nM human PTH(1-34) for either 1 h/day or continuously (PTH replenished every 48 h). After 6 days, cells treated with PTH for 1 h/day retained their normal fibroblastic appearance whereas those treated continuously adopted a polygonal, irregular morphology. After 12-18 days numerous lipid vacuole and oil red O-positive adipocytes had developed in cultures treated with DIIT alone, or with DIIT and continuous PTH. In contrast, adipocyte number was reduced and alkaline phosphatase staining increased in the cultures treated with DIIT and 1 h/day PTH, indicating suppression of adipogenesis and possible promotion of early osteoblastic differentiation. Furthermore, intermittent but not continuous PTH treatment suppressed markers of differentiated adipocytes such as mRNA expression of lipoprotein lipase and PPARgamma as well as glycerol 3-phosphate dehydrogenase activity. All of these effects of intermittent PTH were also produced by a 1 h/day treatment with AH3960 (30 microM), a small molecule, non-peptide agonist of the PTH1 receptor. AH3960, like PTH, activates both the cAMP and calcium signaling pathways. Treatment with the adenylyl cyclase activator forskolin for 1 h/day, mimicked the anti-adipogenic effect of intermittent PTH, whereas pretreatment with the protein kinase-A inhibitor H89 prior to intermittent PTH resulted in almost complete conversion to adipocytes. In

  4. Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta-analysis.

    NARCIS (Netherlands)

    Dekkers, O.M.; Lagro, J.; Burman, P.; Jorgensen, J.O.; Romijn, J.A.; Pereira, A.M.

    2010-01-01

    CONTEXT: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details. OBJECTIVE: The aim of the study was to assess the effect of dopamine agonist withdrawal

  5. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients.

    Science.gov (United States)

    Abd El Aziz, Mirna S; Kahle, Melanie; Meier, Juris J; Nauck, Michael A

    2017-02-01

    To study differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose-lowering medications (OGLM). Prospective, randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared. Of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively (Δ -.12%, P heartrate was higher with GLP-1 RAs ( P < .0001). Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better than short-acting GLP-1 RAs in reducing HbA1c and fasting glucose, but were similar regarding bodyweight. Slightly better glycaemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP-1 RAs. © 2016 John Wiley & Sons Ltd.

  6. [A new LH-RH agonist for treatment of prostate cancer, 3-month controlled-release formulation of goserelin acetate (Zoladex LA 10.8 mg depot)--outline of pre-clinical and clinical studies].

    Science.gov (United States)

    Tsukagoshi, Shigeru

    2002-09-01

    Goserelin acetate is a LH-RH agonist developed by AstraZeneca (formerly ICI, UK), and has been used clinically for the treatment of prostate cancer as a 4-week controlled-release formulation (Zoladex 3.6 mg depot). Recently, a new drug (Zoladex LA 10.8 mg depot) with 3-month controlled-release formulation was developed and became commercially available in Japan. In the randomized comparative phase III studies carried out with global bases, single administration of the new drug yielded almost equivalent anti-testosterone effect and the same serum level of the previous 3.6 mg depot formulation in 3-times continuous administration. In these studies, adverse drug reactions, which were mainly due to pharmacological effects of the new drug and minimal, were found in 52.6% (41/78) compared with 54.8% (46/84) with the previous 3.6 mg depot formulation. In the phase III studies, there were no significant differences in average serum testosterone levels between the two formulations at 12 and 13 weeks after administration. In the Japanese late phase II study with untreated patients, castration effect was observed in all 20 cases entered in the trial. In 20 cases in which treatment was switched from 3.6 mg depot to the new formulation, there were no significant changes in serum testosterone levels at castration level of the untreated patients, 90% (18/20) responded to the treatment, and normalization of PSA level was found in 75.0% (15/20). The adverse drug reactions were mainly increased triglyceride level and hot flushes. In the retrospective evaluation of untreated patients in this trial and the post-marketing clinical trial data for 3.6 mg depot, it was concluded that the new drug had almost the same efficacy and safety profile as 3.6 mg depot in Japanese people. These results indicate that Zoladex LA 10.8 mg depot has the same efficacy and safety as 3.6 mg depot with administration every three months, the burden of injection of LH-RH agonist can be reduced. This new

  7. Dihydrocodeine / Agonists for Alcohol Dependents

    Directory of Open Access Journals (Sweden)

    Albrecht eUlmer

    2012-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Malcolm R Sears

    2001-01-01

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

  9. 偏头痛治疗曙光初现5-HT1B/1D受体激动剂的临床应用%Clinical application of 5-HT1B/1D receptor agonist(triptan) to the treatment of migraine--a ray of sunlight

    Institute of Scientific and Technical Information of China (English)

    张石革; 马国辉

    2004-01-01

    OBJECTIVE:Migraine is a common and frequently-occurring disease in neuromedicine.with understading of mechanism of migraine,new anti-migraine drugs have been found constantly to summarize the aspect of clinical application and progress on 5-HT1B/1D receptor agonist(Triptan).METHODS: To collecte medical literatures in recent years at home and abroad.CONCLUSION:Advance in 5-HT1B/1D receptor agonist has been swiftly in recent years, it has higher selectivity to 5-HT1B/1D receptor, contraction of cerebral vessel and arteriae temporalis, efficacy being related to dosage, promoting distribution of blood flow,so 5-HT1B/1D receptor agonist(triptan) plays an important roles in treatment of migraine.

  10. ChIP-seq profiling of the active chromatin marker H3K4me3 and PPARγ, CEBPα and LXR target genes in human SGBS adipocytes

    Science.gov (United States)

    Galhardo, Mafalda; Sinkkonen, Lasse; Berninger, Philipp; Lin, Jake; Sauter, Thomas; Heinäniemi, Merja

    2014-01-01

    Transcription factors (TFs) represent key factors to establish a cellular phenotype. It is known that several TFs could play a role in disease, yet less is known so far how their targets overlap. We focused here on identifying the most highly induced TFs and their putative targets during human adipogenesis. Applying chromatin immunoprecipitation coupled with deep sequencing (ChIP-Seq) in the human SGBS pre-adipocyte cell line, we identified genes with binding sites in their vicinity for the three TFs studied, PPARγ, CEBPα and LXR. Here we describe the experimental design and quality controls in detail for the deep sequencing data and related results published by Galhardo et al. in Nucleic Acids Research 2014 [1] associated with the data uploaded to NCBI Gene Expression Omnibus (GSE41578). PMID:26484099

  11. ChIP-seq profiling of the active chromatin marker H3K4me3 and PPARγ, CEBPα and LXR target genes in human SGBS adipocytes

    Directory of Open Access Journals (Sweden)

    Mafalda Galhardo

    2014-12-01

    Full Text Available Transcription factors (TFs represent key factors to establish a cellular phenotype. It is known that several TFs could play a role in disease, yet less is known so far how their targets overlap. We focused here on identifying the most highly induced TFs and their putative targets during human adipogenesis. Applying chromatin immunoprecipitation coupled with deep sequencing (ChIP-Seq in the human SGBS pre-adipocyte cell line, we identified genes with binding sites in their vicinity for the three TFs studied, PPARγ, CEBPα and LXR. Here we describe the experimental design and quality controls in detail for the deep sequencing data and related results published by Galhardo et al. in Nucleic Acids Research 2014 [1] associated with the data uploaded to NCBI Gene Expression Omnibus (GSE41578.

  12. Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-α agonist treatment.

    Science.gov (United States)

    Mráz, M; Lacinová, Z; Kaválková, P; Haluzíková, D; Trachta, P; Drápalová, J; Hanušová, V; Haluzík, M

    2011-01-01

    The aim of our study was to measure serum concentrations of fibroblast growth factor 19 (FGF-19) in patients with obesity (OB), obesity and type 2 diabetes mellitus (T2DM) and healthy subjects (C) at baseline and after selected interventions. We measured serum FGF-19 levels and other biochemical and hormonal parameters in 29 OB and 19 T2DM females and 30 sex- and age-matched control subjects. The interventions were acute hyperinsulinemia during isoglycemic-hyperinsulinemic clamp (n=11 for T2DM and 10 for C), very-low calorie diet (VLCD, n=12 for OB) and 3 months treatment with PPAR-alpha agonist fenofibrate (n=11 for T2DM). Baseline serum FGF-19 levels were significantly lower in OB relative to C group (132.1+/-12.7 vs. 202.2+/-16.7 pg/ml, pmonths of fenofibrate treatment markedly reduced FGF-19 levels in T2DM patients (194.58+/-26.2 vs. 107.47+/-25.0 pg/ml, pnutritional status, but were not related to parameters of glucose metabolism or insulin sensitivity.

  13. Near-normalization of glycaemic control with glucagon-like peptide-1 receptor agonist treatment combined with exercise in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Mensberg, Pernille; Nyby, Signe; Jørgensen, Peter Godsk

    2017-01-01

    .002)). Greater reductions in fasting plasma glucose (-3.4 ± 2.3 vs -0.3 ± 2.6 mM, p quality of life during...... the intervention. CONCLUSIONS: In obese patients with type 2 diabetes, exercise combined with GLP-1RA treatment near-normalised HbA1c levels and caused a robust weight loss when compared to placebo. These results suggest that a combination of exercise and GLP-1RA treatment is effective in type 2 diabetes....

  14. Immunomodulatory Agents with Antivascular Activity in the Treatment of Non-Small Cell Lung Cancer: Focus on TLR9 Agonists, IMiDs and NGR-TNF

    Directory of Open Access Journals (Sweden)

    Angelo Corti

    2010-01-01

    Full Text Available Standard treatments for nonsmall cell lung cancer (NSCLC, such as surgery, chemotherapy, and radiotherapy, often lead to disappointing results. Unfortunately, also the various immunotherapeutic approaches so far tested have not produced satisfactory results to be widely applied in the clinical practice. However, the recent development of new immunomodulatory agents may open promising therapeutic options. This paper focuses on PF3512676, lenalidomide, and NGR-TNF, that is, drugs belonging to three different classes of immunomodulatory agents, that are also capable to affect tumor blood vessels with different mechanisms, and discusses the potential role of such agents in NSCLC treatment strategy.

  15. Differential effects of repeated low dose treatment with the cannabinoid agonist WIN 55,212-2 in experimental models of bone cancer pain and neuropathic pain

    DEFF Research Database (Denmark)

    Hald, Andreas; Ding, Ming; Egerod, Kristoffer Lihme;

    2008-01-01

    . Furthermore, this treatment strategy was not found to induce measurable CNS related side effects or tolerance. Cancer cell viability assays and bone volume fraction assessed by micro computed tomography (microCT) demonstrated that these effects were not due to changes in cancer progression. The difference...

  16. Differential responses to acute administration of a new 5-HT7-R agonist as a function of adolescent pre-treatment: phMRI and immuno-histochemical study.

    Science.gov (United States)

    Altabella, Luisa; Sbriccoli, Marco; Zoratto, Francesca; Poleggi, Anna; Vinci, Ramona; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Cardone, Franco; Canese, Rossella; Adriani, Walter

    2014-01-01

    LP-211 is a new, selective agonist of serotonin (5-hydroxytryptamine, 5-HT) receptor 7 (5-HT7-R), which is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive and sleep regulation. Adolescent subchronic LP-211 treatment produces some persisting changes in rats' forebrain structural and functional parameters. Here, using pharmacological MRI (phMRI), we investigated the effect of acute administration with LP-211 (10 mg/kg i.p.), or vehicle, to adult rats previously exposed to the same drug (0.25 mg/kg/day for 5 days), or vehicle, during adolescence (44-48 post-natal days); histology and immuno-histochemistry were performed ex vivo to evaluate neuro-anatomical and physiological long-term adaptation to pharmacological pre-treatment. The phMRI signal reveals forebrain areas (i.e., hippocampus, orbital prefrontal cortex), activated in response to LP-211 challenge independently of adolescent pre-treatment. In septum and nucleus accumbens, sensitized activation was found in adolescent pre-treated rats but not in vehicle-exposed controls. Immuno-histochemical analyses showed marked differences in septum as long-term consequence of the adolescent pre-treatment: increased level of 5-HT7-R, increased number of 5-HT7-R positive cells, and enhanced astrocyte activation. For nucleus accumbens, immuno-histochemical analyses did not reveal any difference between adolescent pre-treated rats and vehicle-exposed controls. In conclusion, subchronic LP-211 administration during adolescence is able to induce persistent physiological changes in the septal 5-HT7-R expression and astrocyte response that can still be observed in adulthood. Data shed new insights into roles of 5-HT7-R for normal and pathologic behavioral regulations.

  17. Differential responses to acute administration of a new 5-HT7-R agonist as a function of adolescent pre-treatment: phMRI and immuno-histochemical study

    Directory of Open Access Journals (Sweden)

    Luisa eAltabella

    2014-12-01

    Full Text Available LP-211 is a new, selective agonist of serotonin (5-hydroxytryptamine, 5-HT receptor 7 (5-HT7-R, which is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive or sleep regulation. Adolescent subchronic LP-211 treatment produces some persisting changes in rats’ forebrain structural and functional parameters. Here, using pharmacological MRI (phMRI, we investigated the effect of acute administration with LP-211 (10 mg/kg i.p., or vehicle, to adult rats previously exposed to the same drug (0.25 mg/kg/day for 5 days, or vehicle, during adolescence (44 to 48 post-natal days; histology and immuno-histochemistry were performed ex vivo to evaluate neuro-anatomical and physiological long-term adaptation to pharmacological pre-treatment. The phMRI signal reveals forebrain areas (i.e. hippocampus, orbital prefrontal cortex, activated in response to LP-211 challenge independently of adolescent pre-treatment. In septum and nucleus accumbens, sensitized activation was found in adolescent pre-treated rats but not in vehicle-exposed controls. Immuno-histochemical analyses showed marked differences in septum as long-term consequence of the adolescent pre-treatment: increased level of 5-HT7-R, increased number of 5-HT7-R positive cells, and enhanced astrocyte activation. For nucleus accumbens, immuno-histochemical analyses did not reveal any difference between adolescent pre-treated rats and vehicle-exposed controls. In conclusion, subchronic LP-211 administration during adolescence is able to induce persistent physiological changes in the septal 5-HT7-R expression and astrocyte response that can still be observed in adulthood. Data shed new insights into roles of 5-HT7-R for normal and pathologic behavioral regulations.

  18. Transdermal delivery of dopamine receptor agonists.

    Science.gov (United States)

    Reichmann, Heinz

    2009-12-01

    Conceptually, continuous dopaminergic stimulation is universally accepted to be the preferred therapeutic strategy to prevent or postpone dyskinesia in Parkinson's disease (PD). L-dopa has a short half-life of 2 hours and causes dyskinesia, whereas dopamine receptor agonists usually have a much longer half-life. Of the latter agents, cabergoline has the longest half-life of 68 hours and is ideal for the prevention of dyskinesia; but this is also true for other dopamine receptor agonists such as ropinirole or pramipexole, which have a shorter half-life of about 6-8 hours. Due to the possible development of valvular fibrosis, cabergoline is, however, only approved as a second-line treatment in PD, and patch technology has therefore gained major interest. So far, rotigotine is the only dopamine receptor agonist available as a patch. There is good evidence that once-daily patch usage provides patients with constant dopaminergic stimulation, and that patches are of equal potency to other oral non-ergot derivatives such as ropinirole and pramipexole. The disadvantages of patches are skin irritation and crystallization of the drug if not kept in the refrigerator. Copyright 2009 Elsevier Ltd. All rights reserved.

  19. 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....

  20. Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice

    DEFF Research Database (Denmark)

    Yu, Mikyung; Amengual, Jaume; Menon, Arjun

    2017-01-01

    The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating...... are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice...

  1. Effects of chronic treatment with the new ultra-long-acting β2 -adrenoceptor agonist indacaterol alone or in combination with the β1 -adrenoceptor blocker metoprolol on cardiac remodelling.

    Science.gov (United States)

    Rinaldi, Barbara; Donniacuo, Maria; Sodano, Loredana; Gritti, Giulia; Martuscelli, Eugenio; Orlandi, Augusto; Rafaniello, Concetta; Rossi, Francesco; Calzetta, Luigino; Capuano, Annalisa; Matera, Maria Gabriella

    2015-07-01

    The ability of a chronic treatment with indacaterol, a new ultra-long-acting β2 -adrenoceptor agonist, to reverse cardiac remodelling and its effects in combination with metoprolol, a selective β1 -adrenoceptor antagonist, were investigated on myocardial infarction in a rat model of heart failure (HF). We investigated the effects of indacaterol and metoprolol, administered alone or in combination, on myocardial histology, β-adrenoceptor-mediated pathways, markers of remodelling and haemodynamic parameters in a rat model of HF. Five groups of rats were assessed: sham-operated rats; HF rats; HF + indacaterol 0.3 mg·kg(-1) ·day(-1) ; HF + metoprolol 100 mg·kg(-1) ·day(-1) ; HF + metoprolol + indacaterol. All pharmacological treatments continued for 15 weeks. Treatment with either indacaterol or metoprolol significantly reduced the infarct size in HF rats. However, the combination of indacaterol and metoprolol reduced the infarct size even further, reduced both BP and heart rate, reversed the decrease in ejection fraction, normalized left ventricular systolic and diastolic internal diameters, normalized the decreased β1 adrenoceptor mRNA expression as well as cardiac cAMP levels and reduced cardiac GPCR kinase 2 expression, compared with the untreated HF group. The results of our study demonstrated an additive interaction between indacaterol and metoprolol in normalizing and reversing cardiac remodelling in our experimental model of HF. The translation of these findings to clinical practice might be of interest, as this combination of drugs could be safer and more effective in patients suffering from HF and COPD. © 2015 The British Pharmacological Society.

  2. Induction of hepatic carbonyl reductase/20{beta}-hydroxysteroid dehydrogenase mRNA in rainbow trout downstream from sewage treatment works-Possible roles of aryl hydrocarbon receptor agonists and oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Albertsson, E., E-mail: eva.albertsson@zool.gu.se [Department of Zoology, University of Gothenburg, Box 463, SE-405 30 Goeteborg (Sweden); Larsson, D.G.J. [Department of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Box 434, SE-405 30 Goeteborg (Sweden); Foerlin, L. [Department of Zoology, University of Gothenburg, Box 463, SE-405 30 Goeteborg (Sweden)

    2010-05-05

    Carbonyl reductase/20{beta}-hydroxysteroid dehydrogenase (CR/20{beta}-HSD) serves both as a key enzyme in the gonadal synthesis of maturing-inducing hormone in salmonids, and as an enzyme protecting against certain reactive oxygen species. We have previously shown that mRNA of the hepatic CR/20{beta}-HSD B isoform is increased in rainbow trout caged downstream from a Swedish sewage treatment plant. Here, we report an increase of both the A as well as B form in fish kept downstream from a second sewage treatment plant. The two mRNAs were also induced in fish hepatoma cells in vitro after exposure to effluent extract. This indicates that the effects observed in vivo could be a direct effect on the liver, i.e. the mRNA induction does not require a signal from any other organ. When fish were exposed in vivo to several effluents treated with more advanced methods (ozone, moving bed biofilm reactor or membrane bioreactor) the expression of hepatic mRNA CR/20{beta}-HSD A and B was significantly reduced. Their abundance did not parallel the reduction of estrogen-responsive transcripts, in agreement with our previous observations that ethinylestradiol is not a potent inducer. Treatment with norethisterone, methyltestosterone or hydrocortisone in vivo did not induce the hepatic CR/20{beta}-HSD A and B mRNA expression. In contrast, both isoforms were markedly induced by the aryl hydrocarbon receptor agonist {beta}-naphthoflavone as well as by the pro-oxidant herbicide paraquat. We hypothesize that the induction of CR/20{beta}-HSD A and B by sewage effluents could be due to anthropogenic contaminants stimulating the aryl hydrocarbon receptor and/or causing oxidative stress.

  3. Patient perspectives on buprenorphine/naloxone: a qualitative study of retention during the starting treatment with agonist replacement therapies (START) study.

    Science.gov (United States)

    Teruya, Cheryl; Schwartz, Robert P; Mitchell, Shannon Gwin; Hasson, Albert L; Thomas, Christie; Buoncristiani, Samantha H; Hser, Yih-Ing; Wiest, Katharina; Cohen, Allan J; Glick, Naomi; Jacobs, Petra; McLaughlin, Paul; Ling, Walter

    2014-01-01

    This study examines the barriers and facilitators of retention among patients receiving buprenorphine/naloxone at eight community-based opioid treatment programs across the United States. Participants (n = 105) were recruited up to three and a half years after having participated in a randomized clinical trial comparing the effect of buprenorphine/naloxone and methadone on liver function. Semi-structured interviews were conducted with 67 patients provided with buprenorphine/naloxone who had terminated early and 38 patients who had completed at least 24 weeks of the trial. Qualitative data were analyzed using the constant comparison method. Barriers to buprenorphine/naloxone retention that emerged included factors associated with: (1) the design of the clinical trial; (2) negative medication or treatment experience; and (3) personal circumstances. The facilitators comprised: (1) positive experience with the medication; (2) personal determination and commitment to complete; and (3) staff encouragement and support. The themes drawn from interviews highlight the importance of considering patients' prior experience with buprenorphine/naloxone and methadone, medication preference, personal circumstances, and motivation to abstain from illicit use or misuse of opioids, as these may influence retention. Ongoing education of patients and staff regarding buprenorphine/naloxone, especially in comparison to methadone, and support from staff and peers are essential.

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

    Science.gov (United States)

    Ito, Chihiro

    2009-06-01

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

  5. Modulation of P2 receptors on pancreatic β-cells by agonists and antagonists: a molecular target for type 2 diabetes treatment.

    Science.gov (United States)

    Pacheco, Paulo Anastácio Furtado; Ferreira, Leonardo Gomes Braga; Alves, Luiz Anastacio; Faria, Robson Xavier

    2013-05-01

    Morbidity and mortality from diabetes mellitus (DM) are serious worldwide concerns. By the year 2030, the estimated number of diabetic patients will reach a staggering 439 million worldwide. Diabetes mellitus type 2 (DM2), which involves disturbances in both insulin secretion and resistance, is the most common form of diabetes and affects approximately 5 to 7% of the world's population. When a patient with DM2 cannot regulate his or her blood glucose levels through diet, weight loss, or exercise, oral medications, such as hypoglycemic agents (i.e., sulphonylureas, biguanides, alpha glucosidase inhibitors and thiazolidinediones), are crucial. Here, we discuss some physiological aspects of P2 receptors on pancreatic β-cells, which express a variety of P2 receptor isoforms. These receptors enhance glucose-dependent insulin release. In addition, we speculate on the potential of purinergic compounds as novel or additional treatments for Type 2 Diabetes mellitus.

  6. Critical appraisal and update on the clinical utility of agomelatine, a melatonergic agonist, for the treatment of major depressive disease in adults

    Directory of Open Access Journals (Sweden)

    Robert H Howland

    2009-11-01

    Full Text Available Robert H HowlandUniversity of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh PA, USAAbstract: This article describes the pharmacology of the novel atypical antidepressant drug agomelatine, critically reviews and evaluates its clinical use for the treatment of major depression, and suggests areas for further research. Agomelatine is a synthetic analog of the hormone melatonin. It stimulates the activity of melatonin MT1 and MT2 receptors and inhibits the activity of serotonin 5HT-2C receptor subtypes. Three acute trials demonstrated clinically modest, but statistically significant benefits over placebo. Three acute trials did not find agomelatine more effective than placebo. A meta-analysis of these six trials demonstrated a small, statistically significant, marginally clinically relevant difference between agomelatine and placebo. The only placebo-controlled study in elderly patients did not demonstrate a significant benefit for agomelatine. It was more effective than placebo in only one of two relapse prevention studies. Agomelatine was generally well tolerated compared to placebo. Its side-effect profile is different than and compares favorably to other antidepressant drugs. The overall tolerability of agomelatine in head-to-head comparisons was not substantially better than active drug comparators. Agomelatine is contraindicated in patients with impaired liver function and in patients taking drugs that potently inhibit CYP-1A2 metabolic enzymes. Because elevated liver enzymes are common, and there is a rare risk of more serious liver reactions, routine laboratory monitoring of liver function is recommended periodically throughout treatment. Agomelatine does not have clinically significant advantages compared to other antidepressant drugs, and it has certain limitations and disadvantages. Because of its unique pharmacology and relatively benign tolerability profile

  7. [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.

  8. Preventive and treatment value of dopamine receptor agonists in ovarian hyperstimulation syndrome%多巴胺受体激动剂在卵巢过度刺激综合征的防治价值

    Institute of Scientific and Technical Information of China (English)

    杨蕊; 马彩虹

    2012-01-01

    The vascular endothelial growth factor (VEGF) is a crucial element for increased vascular permeability which determines ovarian hyperstimulation syndrome (OHSS). Dopamine receptor agonists can selectively inhibit VEGF-induced vascular permeability without interfering with angiogenesis. Vascular endothelial growth factor receptor-2 (VEGFR-2) phosphorylation reduction seems to he associated with this effect. The preventive use of dopamine receptor agonists reduces the risk of OHSS in women after ovarian stimulation for in vitro fertilization (IVF). Statistically, evidence of their preventive effect on the severe OHSS is not as clear as on the moderate OHSS. The use of dopamine receptor agonists does not influence the outcome of IVF cycles. The occurrence of obstetric or neonatal complications is similar with that in control groups. The oral administration of cahergoline is the best studied dopamine receptor agonists regimen in the prevention of OHSS. High-dose quinagolide is rarely applied due to its intolerable side effects. Oral bromocriptine can also be occasionally associated with severe gastric discomfort, although less frequently than with quinagoline. Rectal bromocriptine is used with more and more frequency because of its safety, but it still requires further study. Although published data suggest that dopamine agonists also improve the clinical evolution of established OHSS, no randomized controlled trials have been reported to confirm their effectiveness. The use of dopamine receptor agonists may be combined with with other strategies to prevent or control OHSS, such as GnRH antagonists, in order to improve its efficacy.

  9. Testicular germ cell sensitivity to TRAIL-induced apoptosis is dependent upon p53 expression and is synergistically enhanced by DR5 agonistic antibody treatment.

    Science.gov (United States)

    McKee, Chad M; Ye, Yang; Richburg, John H

    2006-12-01

    The ability of the TRAIL/DR5 signaling pathway to induce apoptosis has generally been limited to tumor cells. Here we report that in primary testis explants, addition of TRAIL (0.5 mug/ml) caused a three-fold increase in germ cell apoptosis. Furthermore, exposure of C57BL/6 mice to the testicular toxicant, mono-(2-ethylhexyl) phthalate (MEHP), caused an increased p53 stability and elevated DR5 mRNA levels coincident with increases in the levels of apoptosis in spermatocytes. To further assess the mechanisms responsible for the sensitivity of germ cells to undergo TRAIL/DR5-mediated apoptosis, we used the germ cell lines GC-1spg and GC-2spd(ts) (a temperature sensitive spermatocyte-like cell line that allows for p53 nuclear localization at 32 degrees C but not 37 degrees C). Addition of TRAIL and the anti-DR5 monoclonal antibody, MD5-1, triggered a robust synergistic increase of apoptosis in p53 permissive GC-2 cells (32 degrees C) but not in GC-1 cells. In addition, DR5 levels on the plasma membrane of permissive cells were considerably enhanced concomitant with p53 expression and after MD5-1 treatment. These data represent the first indication that testicular germ cells, specifically spermatocytes, can undergo TRAIL-mediated apoptosis and the clinically relevant observation that pretreatment with a DR5 monoclonal antibody can greatly sensitize their apoptotic response to TRAIL.

  10. GLP-1受体激动剂治疗非酒精性脂肪肝的新进展%Update study of GLP-1 receptor agonist in the treatment of non-alcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    李春君; 于德民

    2015-01-01

    非酒精性脂肪性肝病(NAFLD)是在世界范围内最常见的一种肝脏疾病,然而目前尚无特异性的治疗药物。胰升糖素样肽-1受体激动剂(GLP-1Ra)是基于肠促胰素为靶点治疗2型糖尿病的一类新药物。近期,动物和临床研究证实GLP-1Ra类药物能够有效减少肝脏脂肪沉积,减轻脂肪变性,是治疗NAFLD的一类最有希望的药物。本文将GLP-1Ra类药物改善NAFLD基础和临床研究证据及作用机制综述如下。%Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases across the world, but there is still no specific treatment for NAFLD. Glucogon-like peptide 1 receptor agonist (GLP-1Ra) is a novel drug for the treatment of type 2 diabetes, based on incretin hormone target. Animal and clinical studies have demonstrated that GLP-1Ra can effec⁃tively reduce fat deposit in liver and attenuate hepatic steatosis. Therefore, GLP-1Ra is a promising therapeutic approachagainst NAFLD. In this review, we provided an overview of the clinical and basic research evidences and mechanisms in re⁃lieving NAFLD.

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Henrik H Hansen

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

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

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    乐卫东; Jank.J

    2002-01-01

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

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

    Science.gov (United States)

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

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.

  16. 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

  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...

  18. Synthesis of urea acetates as potential PPARα/γ,dual agonists

    Institute of Scientific and Technical Information of China (English)

    Chang Yan Zhao; Chang Qing Shi; Yuan Wei Chen

    2008-01-01

    In the quest for novel PPARα/γ dual agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia,we designed and synthesized a series of urea acetates as potential PPARα/γ dual agonists.The structure of the target compounds,intermediates were characterized by 1H NMR,HRMS.

  19. Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88.

    Science.gov (United States)

    Dzierba, Carolyn D; Bi, Yingzhi; Dasgupta, Bireshwar; Hartz, Richard A; Ahuja, Vijay; Cianchetta, Giovanni; Kumi, Godwin; Dong, Li; Aleem, Saadat; Fink, Cynthia; Garcia, Yudith; Green, Michael; Han, Jianxin; Kwon, Soojin; Qiao, Ying; Wang, Jiancheng; Zhang, Yulian; Liu, Ying; Zipp, Greg; Liang, Zhi; Burford, Neil; Ferrante, Meredith; Bertekap, Robert; Lewis, Martin; Cacace, Angela; Grace, James; Wilson, Alan; Nouraldeen, Amr; Westphal, Ryan; Kimball, David; Carson, Kenneth; Bronson, Joanne J; Macor, John E

    2015-04-01

    Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. 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...

  1. An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.

    Science.gov (United States)

    Becker, Oren M; Dhanoa, Dale S; Marantz, Yael; Chen, Dongli; Shacham, Sharon; Cheruku, Srinivasa; Heifetz, Alexander; Mohanty, Pradyumna; Fichman, Merav; Sharadendu, Anurag; Nudelman, Raphael; Kauffman, Michael; Noiman, Silvia

    2006-06-01

    We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.

  2. Gonadotropin-Releasing Hormone Agonist Combined With a Levonorgestrel-Releasing Intrauterine System or Letrozole for Fertility-Preserving Treatment of Endometrial Carcinoma and Complex Atypical Hyperplasia in Young Women.

    Science.gov (United States)

    Zhou, Huimei; Cao, Dongyan; Yang, Jiaxin; Shen, Keng; Lang, Jinghe

    2017-07-01

    The aim of this study was to evaluate the efficacy and safety with gonadotropin-releasing hormone agonist (GnRHa) combined with a levonorgestrel-releasing intrauterine system or an aromatase inhibitor (letrozole) in young women with well-differentiated early endometrial carcinoma (EC) and complex atypical hyperplasia (CAH). We performed a retrospective analysis including the clinical characteristics of 29 patients younger than 45 years with early well-differentiated endometrioid adenocarcinoma of the uterus (EC) or CAH who were treated at the Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, from January 2012 to April 2016. Eighteen patients were treated with the combination of intramuscular injections of GnRHa every 4 weeks with the levonorgestrel intrauterine hormonal system (Mirena® Bayer Health Care Pharmaceutical Inc, Wayne, NY) was inserted. Eleven patients were treated with the combination of intramuscular injections of GnRHa every 4 weeks with oral letrozole 2.5 mg daily. The patients underwent follow-up with endometrial sampling by hysteroscopy and curettage for endometrial response every 3 months. After a median follow-up of 18.7 months (range, 5.6-54.9 months), 15 women (88.2%) in the EC group and 12 women (100%) in the CAH group had complete response (CR) after GnRHa combination treatment. Among the women who achieved CR, 1 woman (8.3%) with CAH and 1 woman (5.9%) with EC had recurrence after CR, and they finally underwent a hysterectomy. Time to CR was similar in the 2 groups (4.5 ± 1.9 months in the CAH group vs 5.0 ± 2.9 months in the EC group). Ten women (34.5%) had CR after the first 3 months, 8 women (27.6%) had CR after 6 months, and 9 women (31.0%) had CR after 9 months. Both GnRHa with the levonorgestrel-releasing intrauterine system and GnRHa with letrozole are alternative treatments for women with CAH and EC who desire fertility preservation. A larger multicenter trial of the fertility-preserving treatment is

  3. Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): Role of ICS.

    Science.gov (United States)

    Latorre, M; Novelli, F; Vagaggini, B; Braido, F; Papi, A; Sanduzzi, A; Santus, P; Scichilone, N; Paggiaro, P

    2015-02-01

    Inhaled corticosteroids (ICS) are frequently recommended for the treatment of asthma and COPD, often in combination with long-acting beta2-agonists (LABA), depending on the severity of the disease and/or on the specific phenotype. Several ICS/LABA combinations are currently available that differ in their pharmacokinetic characteristics and dose of both components. Thus, this review assesses differences in the efficacy and the safety profiles of the ICS components in the two more frequently used ICS/LABA combinations (budesonide/formoterol and fluticasone/salmeterol) for the management of COPD. Whereas the basic mechanism of action is similar for all ICS (binding with the intracellular glucocorticoid receptor, which mediates both genomic and non genomic effects), the pharmacokinetic and characteristics of ICS are quite different in terms of receptor affinity, bioavailability, lipophilicity and drug persistence in the airways. Fluticasone persists longer in airway mucus and requires more time to dissolve in the lining fluid and then enter the airway wall, whereas budesonide is cleared more quickly from the airways. Comparative efficacy of the two major ICS/LABA combinations recommended for the treatment of COPD show similar efficacy in terms of reduction of exacerbations, improvement in forced expiratory volume in the first second (FEV1) and quality of life. One retrospective cohort study suggested a greater efficacy for the budesonide/formoterol combination on hospital or emergency department admissions, oral corticosteroid courses, and addition of tiotropium, and an observational real-life study reported a greater reduction of COPD exacerbations with budesonide/formoterol than with fluticasom/salmeterol combination. Among the potential side effects of chronic ICS treatment in patients with COPD, recently the use of fluticasone or fluticasone/salmeterol combination has been associated with a higher prevalence of pneumonia in the major long-term studies. On the other

  4. Reproductive pharmacology of LHRH and agonists in females and males.

    Science.gov (United States)

    Corbin, A; Bex, F J

    1980-06-01

    This report reviews research supporting the anti-reproductive pharmacologic characteristics of LHRH (luteinizing hormone releasing hormone) and its agonist analogues, and their relevance to fertility regulation in the clinic. Approximately 1000 derivatives of LHRH have been synthesized since 1971. LHRH and agonistic derivatives have the ability to induce the release of pituitary LH and FSH (follicle stimulating hormone), and ovulation in a variety of animal models. These agents have been shown to produce predictable postcoital contraceptive effects, such activity and potency having been related to its basic agonist properties. This class of peptides also have the ability to 1) retard puberty; 2) disrupt the estrous cycle (delay onset of estrus and mating); 3) induce premature ovulation; 4) induce luteolysis; 5) cause ovarian and uterine regression; 6) reduce fecundity in inseminated animals; and 7) inhibit ovarian/uterine stimulation which occurs with human chorionic gonadotropin. These effects are reversible because once treatment is withdrawn, normal breeding processes resume quickly. Several LHRH agonists are also being tapped for use as a potential luteal phase-inhibiting/menses-inducing approach to contraception. In the male, however, the agonists cannot function as contraceptives due to the inappropriate dissociation between testosterone production and spermatogenesis. The antireproductive mechanisms of LHRH agonists can be traced to the 1) hypersecretion of LH; 2) dysphasic FSH and distorted prolactin secretion; 3) decrease in gonadal LH, FSH and prolactin receptors; and 4) inhibition of steroidogenesis and eventual disruption of the reproductive continuum. They may also be useful as anti-tumor agents in steroid-dependent mammary gland and prostatic neoplasms. Toxicologic, pathologic and ancillary pharmacologic studies involving varied dosing regimens show encouraging potential of selected agonists as contraceptive agents with no related side effects.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

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

    Science.gov (United States)

    Nirenberg, Melissa J; Waters, Cheryl

    2006-04-01

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

  7. Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection.

    Science.gov (United States)

    Ramezani, Ali; Dubrovsky, Larisa; Pushkarsky, Tatiana; Sviridov, Dmitri; Karandish, Sara; Raj, Dominic S; Fitzgerald, Michael L; Bukrinsky, Michael

    2015-09-01

    Previous studies demonstrated that liver X receptor (LXR) agonists inhibit human immunodeficiency virus (HIV) replication by upregulating cholesterol transporter ATP-binding cassette A1 (ABCA1), suppressing HIV production, and reducing infectivity of produced virions. In this study, we extended these observations by analyzing the effect of the LXR agonist T0901317 [N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide] on the ongoing HIV infection and investigating the possibility of using LXR agonist for pre-exposure prophylaxis of HIV infection in a humanized mouse model. Pre-exposure of monocyte-derived macrophages to T0901317 reduced susceptibility of these cells to HIV infection in vitro. This protective effect lasted for up to 4 days after treatment termination and correlated with upregulated expression of ABCA1, reduced abundance of lipid rafts, and reduced fusion of the cells with HIV. Pre-exposure of peripheral blood leukocytes to T0901317 provided only a short-term protection against HIV infection. Treatment of HIV-exposed humanized mice with LXR agonist starting 2 weeks postinfection substantially reduced viral load. When eight humanized mice were pretreated with LXR agonist prior to HIV infection, five animals were protected from infection, two had viral load at the limit of detection, and one had viral load significantly reduced relative to mock-treated controls. T0901317 pretreatment also reduced HIV-induced dyslipidemia in infected mice. In conclusion, these results reveal a novel link between LXR stimulation and cell resistance to HIV infection and suggest that LXR agonists may be good candidates for development as anti-HIV agents, in particular for pre-exposure prophylaxis of HIV infection.

  8. Beta-2-agonists of third generation.

    Science.gov (United States)

    Palma-Carlos, A G; Palma-Carlos, G S

    1986-04-01

    Beta-adrenergic agents have been used for a long time in the treatment of asthma. For the purpose of bronchodilation the better results would be attained with the increase in Beta-2-selectivity. From the newer Beta-agonists the mot currently used are TERBUTALINE, FENOTEROL, SALBUTAMOL, CLEMBUTEROL, TOLBUTEROL, CARBUTEROL, PROCATEROL, RIMITEROL and REPROTEROL, this last combining in its molecule the structure of a beta-agonist with a Xanthine group. These agents could be used in different ways, by mouth, injection and inhalation (with a exception of Clembuterol which is effective only by oral route). The authors have, some years ago, comparatively studied the bronchodilating effect of Salbutamol and Fenoterol including 18 patients. The main increase of PFR was slightly higher after FENOTEROL but this difference was not significant. The authors have studied REPROTEROL by inhalation and oral routes in 11 asthmatic patients. After inhalation of 400 mcg of REPROTEROL the bronchodilator effect was comparable to others inhaled bronchodilators. However they could not confirm that REPROTEROL acts also as a Xanthine and only traces of Theophylline have been detected in blood of subjects taking it. These data seem to indicate that REPROTEROL do not release Theophylline in the body or only release a Xanthine like compound not detected by "EMIT" of high pressure liquid chromatography.

  9. Novel diazabicycloalkane delta opioid agonists.

    Science.gov (United States)

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80. Published by Elsevier Ltd.

  10. Liver X receptor regulation of thyrotropin-releasing hormone transcription in mouse hypothalamus is dependent on thyroid status.

    Directory of Open Access Journals (Sweden)

    Rym Ghaddab-Zroud

    Full Text Available Reversing the escalating rate of obesity requires increased knowledge of the molecular mechanisms controlling energy balance. Liver X receptors (LXRs and thyroid hormone receptors (TRs are key physiological regulators of energetic metabolism. Analysing interactions between these receptors in the periphery has led to a better understanding of the mechanisms involved in metabolic diseases. However, no data is available on such interactions in the brain. We tested the hypothesis that hypothalamic LXR/TR interactions could co-regulate signalling pathways involved in the central regulation of metabolism. Using in vivo gene transfer we show that LXR activation by its synthetic agonist GW3965 represses the transcriptional activity of two key metabolic genes, Thyrotropin-releasing hormone (Trh and Melanocortin receptor type 4 (Mc4r in the hypothalamus of euthyroid mice. Interestingly, this repression did not occur in hypothyroid mice but was restored in the case of Trh by thyroid hormone (TH treatment, highlighting the role of the triiodothyronine (T3 and TRs in this dialogue. Using shLXR to knock-down LXRs in vivo in euthyroid newborn mice, not only abrogated Trh repression but actually increased Trh transcription, revealing a potential inhibitory effect of LXR on the Hypothalamic-Pituitary-Thyroid axis. In vivo chromatin immunoprecipitation (ChIP revealed LXR to be present on the Trh promoter region in the presence of T3 and that Retinoid X Receptor (RXR, a heterodimerization partner for both TR and LXR, was never recruited simultaneously with LXR. Interactions between the TR and LXR pathways were confirmed by qPCR experiments. T3 treatment of newborn mice induced hypothalamic expression of certain key LXR target genes implicated in metabolism and inflammation. Taken together the results indicate that the crosstalk between LXR and TR signalling in the hypothalamus centres on metabolic and inflammatory pathways.

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

    Science.gov (United States)

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

    2011-02-25

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

  12. Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice

    Science.gov (United States)

    Zhang, Yuan; Breevoort, Sarah R.; Angdisen, Jerry; Fu, Mingui; Schmidt, Daniel R.; Holmstrom, Sam R.; Kliewer, Steven A.; Mangelsdorf, David J.; Schulman, Ira G.

    2012-01-01

    Liver X receptors (LXRα and LXRβ) are important regulators of cholesterol and lipid metabolism, and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Small molecule agonists of LXR activity are therefore of great therapeutic interest. However, the finding that such agonists also promote hepatic lipogenesis has led to the idea that hepatic LXR activity is undesirable from a therapeutic perspective. To investigate whether this might be true, we performed gene targeting to selectively delete LXRα in hepatocytes. Liver-specific deletion of LXRα in mice substantially decreased reverse cholesterol transport, cholesterol catabolism, and cholesterol excretion, revealing the essential importance of hepatic LXRα for whole body cholesterol homeostasis. Additionally, in a pro-atherogenic background, liver-specific deletion of LXRα increased atherosclerosis, uncovering an important function for hepatic LXR activity in limiting cardiovascular disease. Nevertheless, synthetic LXR agonists still elicited anti-atherogenic activity in the absence of hepatic LXRα, indicating that the ability of agonists to reduce cardiovascular disease did not require an increase in cholesterol excretion. Furthermore, when non-atherogenic mice were treated with synthetic LXR agonists, liver-specific deletion of LXRα eliminated the detrimental effect of increased plasma triglycerides, while the beneficial effect of increased plasma HDL was unaltered. In sum, these observations suggest that therapeutic strategies that bypass the liver or limit the activation of hepatic LXRs should still be beneficial for the treatment of cardiovascular disease. PMID:22484817

  13. Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist: Protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study – the TAO study

    DEFF Research Database (Denmark)

    Ishøy, Pelle Lau; Knop, Filip Krag; Broberg, Brian Villumsen

    Introduction: Antipsychotic medication is widely associated with dysmetabolism including obesity and type 2 diabetes, cardiovascular-related diseases and early death. Obesity is considered the single most important risk factor for cardiovascular morbidity and mortality. Interventions against...... with a GLP-1 receptor agonist (exenatide once-weekly) is safe and facilitates weight loss in non-diabetic schizophrenia patients with antipsychotic-associated obesity. Methods and analysis: Forty obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs will be randomised...

  14. Modulación de lxrα por polifenoles y ácido oleico mediada por proteínas quinasas en células fagocíticas humanas

    OpenAIRE

    Sáenz Coronilla, Francisco Javier

    2015-01-01

    Los receptores nucleares LXR (Liver X receptors) están implicados en la regulación de numerosos procesos fisiológicos, fundamentalmente la homeostasis del colesterol y ácidos grasos, y la expresión de genes implicados en las respuesta inflamatoria. Las enzimas quinasas son proteínas que también están comprometidas con el metabolismo energético (Ej.: AMPK) y la regulación de la respuesta inflamatoria (Ej.: p38 y ERK1/2), entre otras muchas funciones. La activación de las proteínas quinasas...

  15. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice

    Science.gov (United States)

    Sharma, Pawan; Yi, Roslyn; Nayak, Ajay P.; Wang, Nadan; Tang, Francesca; Knight, Morgan J.; Pan, Shi; Oliver, Brian; Deshpande, Deepak A.

    2017-01-01

    Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.

  16. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice.

    Science.gov (United States)

    Sharma, Pawan; Yi, Roslyn; Nayak, Ajay P; Wang, Nadan; Tang, Francesca; Knight, Morgan J; Pan, Shi; Oliver, Brian; Deshpande, Deepak A

    2017-04-11

    Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.

  17. AGONISTIC BEHAVIOR OF LABORATORY MICE

    Directory of Open Access Journals (Sweden)

    D. Cinghiţă

    2005-01-01

    Full Text Available In this work we study agonistic behavior of laboratory white mice when they are kept in captivity. For all this experimental work we used direct observation of mice, in small lists, because we need a reduced space to emphasize characteristics of agonistic behavior. Relations between members of the same species that live in organized groups are based in most cases on hierarchical structure. Relations between leader and subservient, decided by fighting, involve a thorough observation between individuals. Each member of a group has its own place on the ierarchical scale depending on resultes of fhights – it can be leader or it can be subsurvient, depending on if it wines or looses the fight. Once hierarchical scale made, every animal will adjust its behavior. After analyzing the obtained data we have enough reasons to believe that after fights the winner, usually, is the massive mouse, but it is also very important the sexual ripeness, so the immature male will be beaten. The leader male had a big exploring area and it checks up all territory.The females can be more aggressive, its fights are more brutal, than male fights are, when they fight for supremacy, but in this case fights are not as frequent as in the case of males. Always the superior female, on hierarchical scale, shows males its own statute, so the strongest genes will be perpetuated.

  18. 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...

  19. Small molecule fluoride toxicity agonists.

    Science.gov (United States)

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

    2015-04-23

    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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. 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

  1. 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.

  2. Which medications are suitable for agonist drug maintenance?

    Science.gov (United States)

    Darke, Shane; Farrell, Michael

    2016-05-01

    We examine the feasibility of agonist maintenance treatment for the major psychoactive drug classes: opioids, nicotine, benzodiazepines, cannabis, psychostimulants and alcohol. Eight clinical criteria for an agonist maintenance drug were assessed for each major drug class. These related to pharmacological aspects of the drug (agonist, pharmacological stability, dose-response, non-toxic) and neurocognitive sequelae (psychiatric, cognitive, craving, salience). Opioids and nicotine met all eight criteria for a maintenance drug. While nicotine has not been promoted widely or used for maintenance, it has the potential to fulfil that role. Cannabis met five criteria and has potential, but long-term data on cognitive impairment are required. Benzodiazepine maintenance would appear an option for the high-dose chaotic abuser, also meeting five criteria, although clinic dosing appears the safest option. Psychostimulants (three of eight criteria) and alcohol (one of eight) appear poor propositions for maintenance, in terms of both their pharmacological and their neurocognitive characteristics. Drug classes have properties that distinguish them in their suitability for maintenance treatment. Some classes not yet used for maintenance (notably nicotine and cannabis) have potential to fulfil such a role. Others, however, by their inherent nature, appear unsuitable for such a treatment regimen. © 2015 Society for the Study of Addiction.

  3. Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) agonists

    DEFF Research Database (Denmark)

    Madsbad, Sten

    2012-01-01

    Incretin-based therapies, which include the GLP-1 receptor agonists and DPP-4 inhibitors, use the antidiabetic properties of potentiating the GLP-1 receptor signalling via the regulation of insulin and glucagon secretion, inhibition of gastric emptying and suppression of appetite. Most physicians...... a DPP-4 inhibitor in obese type 2 diabetic patients, who want to lose weight. Furthermore, the GLP-1 receptor agonists cover the whole spectrum of treatment from time of diagnosis with lifestyle treatment to combination treatment with basal insulin....... are also more effective in weight and systolic blood pressure control than DPP-4 inhibitors. The side effects of the GLP-1 receptor agonists are primarily nausea and vomiting, which is less pronounced with the long acting agonists and often transient. A GLP-1 receptor agonist can be recommended before...

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

    Science.gov (United States)

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

    2010-03-15

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

  5. 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.

  6. 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

  7. Identification of PPARγ Agonists from Natural Sources Using Different In Silico Approaches.

    Science.gov (United States)

    El-Houri, Rime B; Mortier, Jérémie; Murgueitio, Manuela S; Wolber, Gerhard; Christensen, Lars P

    2015-04-01

    Peroxisome proliferator-activated receptor γ plays an important role in lipid and glucose homeostasis and is the target of many drug discovery investigations because of its role in diseases such as type 2 diabetes. Activation of peroxisome proliferator-activated receptor γ by agonists leads to a conformational change in the ligand-binding domain altering the transcription of several target genes involved in glucose and lipid metabolism, resulting in, for example, facilitation of glucose and lipid uptake and amelioration of insulin resistance, and other effects that are important in the treatment of type 2 diabetes. Peroxisome proliferator-activated receptor γ partial agonists are compounds with diminished agonist efficacy compared to full agonists; however, they maintain the antidiabetic effect of full agonists but do not induce the same magnitude of side effects. This mini-review gives a short introduction to in silico screening methods and recent research advances using computational approaches to identify peroxisome proliferator-activated receptor γ agonists, especially partial agonists, from natural sources and how these ligands bind to the peroxisome proliferator-activated receptor γ in order to better understand their biological effects. Georg Thieme Verlag KG Stuttgart · New York.

  8. 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.

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

    Science.gov (United States)

    Maguire, David R; France, Charles P

    2014-11-01

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

  10. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Hayley Patricia Ellis

    2014-03-01

    Full Text Available Glioblastoma Multiforme (GBM is the most common primary intrinsic CNS tumour and has an extremely poor overall survival, despite advances in neurosurgery, chemotherapy and radiation therapy. There has been interesting preliminary evidence suggesting that patients receiving the group of anti-diabetic drugs known as PPARγ (Peroxisome proliferator-activated receptor gamma agonists have a lower incidence of glioma. The nuclear hormone receptor PPARγ has been found to be expressed in high grade gliomas, and its activation has been shown to have several antineoplastic effects on human and rat glioma cell lines, and in some instances an additional protective increase in antioxidant enzymes has been observed in normal astrocytes. At present, no clinical trials are underway with regards to treating glioma patients using PPARγ agonists, as Pioglitazone and Rosiglitazone are only FDA-approved for use in treatment of type-2 diabetes. This review presents the case for evaluating the potential of PPARγ agonists as novel adjuvants in the treatment of high grade glioma. We introduce the PPARγ pathway, PPARγ gene and its products and examine recent research in glioblastoma.

  11. Clinical Study of Budesonide Combined With β2 Receptor Agonist Inhalation in the Treatment of Acute Exacerbations of COPD%布地奈德联合β2受体激动剂雾化吸入治疗COPD急性发作临床研究

    Institute of Scientific and Technical Information of China (English)

    魏会英

    2015-01-01

    ObjectiveThe curative effect of budesonide inhalation of β2 agonists in the treatment of COPD exacerbation were observed.Methods 46 cases of COPD patients, randomly divided them into observation group and control group, two groups of efficacy and safety analysis.Results Compared with the control group and the observation group the total effective rate, respectively 82.6% and 69.1%.Conclusion budesonide inhalation of β2agonists for the treatment of COPD can make the treatment effect was strengthened, the two combined treatment of COPD should be widely used in the clinical medicine.%目的:对布地奈德联合雾化吸入β2受体激动剂治疗慢性阻塞性肺病(COPD)急性发作的疗效进行观察。方法46例COPD患者,将其分为观察组与对照组,对两组疗效和安全性进行分析。结果对比观察组和对照组总有效率,分别为82.6%和69.1%。结论布地奈德联合雾化吸入β2受体激动剂对于治疗COPD能使治疗效果得到加强,将二者联合治疗COPD应在临床医学中广泛应用。

  12. 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.

  13. 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.

  14. Research progress of glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes mellitus%胰高血糖素样肽1受体激动剂在2型糖尿病治疗中的研究进展

    Institute of Scientific and Technical Information of China (English)

    秦荣浦; 杨宇峰(综述); 楼觉人(审校)

    2016-01-01

    Glucagon‐like peptide‐1 receptor agonist (GLP‐1RA ) has become an important thera‐peutic approach for type 2 diabetes .Evidence suggests that GLP‐1RA can improve glycemic control while decrease risk of hypoglycemia ,reduce body weight ,and protecting cardiovascular system .This review presents the efficacy and tolerability of various GLP‐1RA drugs available for clinical practice or under clinical trials ,and concludes that optimized usage of GLP‐1RA drugs could represent a significant para‐digm shift for the treatment of type 2 diabetes .%胰高血糖素样肽1受体激动剂(glucagon‐like peptide‐1 receptor agonist ,GLP‐1RA)是近年来2型糖尿病药物开发领域的研究热点。作为一种降血糖药物,GLP‐1RA 在增强患者血糖调控能力的同时,还能降低患者低血糖风险,减轻体重,保护心血管系统。此文对已上市和部分正处于临床试验阶段的 GLP‐1RA 的疗效及安全性做一综述,并对 GLP‐1RA 药物的发展趋势进行探讨。

  15. Ombuin-3-O-β-D-glucopyranoside from Gynostemma pentaphyllum is a dual agonistic ligand of peroxisome proliferator-activated receptors α and δ/β.

    Science.gov (United States)

    Malek, Mastura Abd; Hoang, Minh-Hien; Jia, Yaoyao; Lee, Ji Hae; Jun, Hee Jin; Lee, Dong-Ho; Lee, Hak Ju; Lee, Chul; Lee, Myung Koo; Hwang, Bang Yeon; Lee, Sung-Joon

    2013-01-25

    We demonstrated that ombuin-3-O-β-D-glucopyranoside (ombuine), a flavonoid from Gynostemma pentaphyllum, is a dual agonist for peroxisome proliferator-activated receptors (PPARs) α and δ/β. Using surface plasmon resonance (SPR), time-resolved fluorescence resonance energy transfer (FRET) analyses, and reporter gene assays, we showed that ombuine bound directly to PPARα and δ/β but not to PPARγ or liver X receptors (LXRs). Cultured HepG2 hepatocytes stimulated with ombuine significantly reduced intracellular concentrations of triglyceride and cholesterol and downregulated the expression of lipogenic genes, including sterol regulatory element binding protein-1c (SREBP1c) and stearoyl-CoA desaturase-1 (SCD-1), with activation of PPARα and δ/β. Activation of LXRs by ombuine was confirmed by reporter gene assays, however, SPR and cell-based FRET assays showed no direct binding of ombuine to either of the LXRs suggesting LXR activation by ombuine may be operated via PPARα stimulation. Ombuine-stimulated macrophages showed significantly induced transcription of ATP binding cassette cholesterol transporter A1 (ABCA1) and G1 (ABCG1), the key genes in reverse cholesterol transport, which led to reduced cellular cholesterol concentrations. These results suggest that ombuine is a dual PPAR ligand for PPARα and δ/β with the ability to decrease lipid concentrations by reducing lipogenic gene expression in hepatocytes and inducing genes involved in cholesterol efflux in macrophages. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

    DEFF Research Database (Denmark)

    Goncalves de Azavedo, Carlos M. B. P.; Watterson, Kenneth R; Wargent, Ed T

    2016-01-01

    The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure......-activity relationship studies of a previously disclosed non-acidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although...... a significant fraction of these non-carboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice...

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

    Science.gov (United States)

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

    2011-03-01

    Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5'-γ-thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M₂ muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [³⁵S]GTPγS and [³H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M₂ muscarinic acetylcholine receptor. Agonists displayed biphasic competition curves with the antagonist [³H]-N-methylscopolamine. GTPγS (1 µM) changed the competition curves to monophasic with low affinity and 50 µM GDP produced a similar effect. Depletion of membrane-bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [³H]GDP from membranes. The inverse agonist N-methylscopolamine slowed GDP dissociation and GTPγS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from G(i/o) G-proteins but only its dissociation from G(s/olf) G-proteins. These findings suggest the existence of a low-affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G-protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of G(i/o) versus G(s/olf) G-proteins that are not identified by conventional GTPγS binding. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  18. PPAR{gamma} activates ABCA1 gene transcription but reduces the level of ABCA1 protein in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Mogilenko, Denis A., E-mail: denis@iem.sp.ru [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation); Shavva, Vladimir S. [Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation); Dizhe, Ella B. [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Orlov, Sergey V., E-mail: serge@iem.sp.ru [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation); Perevozchikov, Andrej P., E-mail: app@iem.sp.ru [Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg (Russian Federation); Department of Embryology, St. Petersburg State University, 199034 St. Petersburg (Russian Federation)

    2010-11-19

    Research highlights: {yields} PPAR{gamma} activates ABCA1 gene expression but decreases ABCA1 protein content in human hepatoma cell line HepG2. {yields} Treatment of HepG2 cells with PPAR{gamma} agonist GW1929 leads to dissociation of LXR{beta} from ABCA1-LXR{beta} complex. {yields} Inhibition of protein kinases MEK1/2 abolishes PPAR{gamma}-mediated dissociation of LXR{beta} from ABCA1/LXR{beta} complex. {yields} Activation of PPAR{gamma} leads to increasing of the level of LXR{beta} associated with LXRE within ABCA1 gene promoter. -- Abstract: Synthesis of ABCA1 protein in liver is necessary for high-density lipoproteins (HDL) formation in mammals. Nuclear receptor PPAR{gamma} is known as activator of ABCA1 expression, but details of PPAR{gamma}-mediated regulation of ABCA1 at both transcriptional and post-transcriptional levels in hepatocytes have not still been well elucidated. In this study we have shown, that PPAR{gamma} activates ABCA1 gene transcription in human hepatoma cells HepG2 through increasing of LXR{beta} binding with promoter region of ABCA1 gene. Treatment of HepG2 cells with PPAR{gamma} agonist GW1929 leads to dissociation of LXR{beta} from ABCA1/LXR{beta} complex and to nuclear translocation of this nuclear receptor resulting in reduction of ABCA1 protein level 24 h after treatment. Inhibition of protein kinases MEK1/2 abolishes PPAR{gamma}-mediated dissociation of LXR{beta} from ABCA1/LXR{beta} complex, but does not block PPAR{gamma}-dependent down-regulation of ABCA1 protein in HepG2 cells. These data suggest that PPAR{gamma} may be important for regulation of the level of hepatic ABCA1 protein and indicate the new interplays between PPAR{gamma}, LXR{beta} and MEK1/2 in regulation of ABCA1 mRNA and protein expression.

  19. PPAR Agonists and Cardiovascular Disease in Diabetes.

    Science.gov (United States)

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

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

  20. PPAR Agonists and Cardiovascular Disease in Diabetes

    Directory of Open Access Journals (Sweden)

    Anna C. Calkin

    2008-01-01

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

  1. PPAR Agonists and Cardiovascular Disease in Diabetes

    Science.gov (United States)

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  2. Inhalation of beta 2 agonists impairs the clearance of nontypable Haemophilus influenzae from the murine respiratory tract

    NARCIS (Netherlands)

    Maris, N.A.; Florquin, S.; van 't Veer, C.; de Vos, A.F.; Buurman, W.; Jansen, H.M.; van der Poll, T.

    2006-01-01

    BACKGROUND: Nontypable Haemophilus influenzae (NTHi) is a common bacterial pathogen causing human respiratory tract infections under permissive conditions such as chronic obstructive pulmonary disease. Inhalation of beta2-receptor agonists is a widely used treatment in patients with chronic obstruct

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

    Science.gov (United States)

    Xia, Yang; Kellems, Rodney E

    2013-06-21

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

  4. The inhibitory effect of combination treatment with leptin and cannabinoid CB1 receptor agonist on food intake and body weight gain is mediated by serotonin 1B and 2C receptors.

    Science.gov (United States)

    Wierucka-Rybak, M; Wolak, M; Juszczak, M; Drobnik, J; Bojanowska, E

    2016-06-01

    Previous studies reported that the co-injection of leptin and cannabinoid CB1 receptor antagonists reduces food intake and body weight in rats, and this effect is more profound than that induced by these compounds individually. Additionally, serotonin mediates the effects of numerous anorectic drugs. To investigate whether serotonin interacts with leptin and endocannabinoids to affect food intake and body weight, we administered 5-hydroxytryptamine(HT)1B and 5-hydroxytryptamine(HT)2C serotonin receptor antagonists (3 mg/kg GR 127935 and 0.5 mg/kg SB 242084, respectively) to male Wistar rats treated simultaneously with leptin (100 μg/kg) and the CB1 receptor inverse agonist AM 251 (1 mg/kg) for 3 days. In accordance with previous findings, the co-injection of leptin and AM 251, but not the individual injection of each drug, resulted in a significant decrease in food intake and body weight gain. Blockade of the 5-HT1B and 5-HT2C receptors completely abolished the leptin- and AM 251-induced anorectic and body-weight-reducing effects. These results suggest that serotonin mediates the leptin- and AM 251-dependent regulation of feeding behavior in rats via the 5-HT1B and 5-HT2C receptors.

  5. GLP-1 receptor agonists or DPP-4 inhibitors: how to guide the clinician?

    Science.gov (United States)

    Scheen, André J

    2013-12-01

    Pharmacological treatment of type 2 diabetes has been enriched during recent years, with the launch of incretin therapies targeting glucagon-like peptide-1 (GLP-1). Such medications comprise either GLP-1 receptor agonists, with short (one or two daily injections: exenatide, liraglutide, lixisenatide) or long duration (one injection once weekly: extended-released exenatide, albiglutide, dulaglutide, taspoglutide); or oral compounds inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that inactives GLP-1, also called gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin). Although both pharmacological approaches target GLP-1, important differences exist concerning the mode of administration (subcutaneous injection versus oral ingestion), the efficacy (better with GLP-1 agonists), the effects on body weight and systolic blood pressure (diminution with agonists versus neutrality with gliptins), the tolerance profile (nausea and possibly vomiting with agonists) and the cost (higher with GLP-1 receptor agonists). Both agents may exert favourable cardiovascular effects. Gliptins may represent a valuable alternative to a sulfonylurea or a glitazone after failure of monotherapy with metformin while GLP-1 receptor agonists may be considered as a good alternative to insulin (especially in obese patients) after failure of a dual oral therapy. However, this scheme is probably too restrictive and modalities of using incretins are numerous, in almost all stages of type 2 diabetes. Physicians may guide the pharmacological choice based on clinical characteristics, therapeutic goals and patient's preference.

  6. CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain.

    Science.gov (United States)

    Khasabova, Iryna A; Gielissen, James; Chandiramani, Anisha; Harding-Rose, Catherine; Odeh, Desiree Abu; Simone, Donald A; Seybold, Virginia S

    2011-09-01

    In light of the adverse side-effects of opioids, cannabinoid receptor agonists may provide an effective alternative for the treatment of cancer pain. This study examined the potency and efficacy of synthetic CB1 and CB2 receptor agonists in a murine model of tumor pain. Intraplantar injection of the CB1 receptor agonist arachidonylcyclopropylamide (ED(50) of 18.4 μg) reduced tumor-related mechanical hyperalgesia by activation of peripheral CB1 but not CB2 receptors. Similar injection of the CB2 receptor agonist AM1241 (ED50 of 19.5 μg) reduced mechanical hyperalgesia by activation of peripheral CB2 but not CB1 receptors. Both agonists had an efficacy comparable with that of morphine (intraplantar), but their analgesic effects were independent of opioid receptors. Isobolographic analysis of the coinjection of arachidonylcyclopropylamide and AM1241 determined that the CB1 and CB2 receptor agonists interacted synergistically to reduce mechanical hyperalgesia in the tumor-bearing paw. These data extend our previous findings that the peripheral cannabinoid receptors are a promising target for the management of cancer pain and mixed cannabinoid receptor agonists may have a therapeutic advantage over selective agonists.

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

    Science.gov (United States)

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

    2012-07-01

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

  8. Discovery of a potent and selective GPR120 agonist.

    Science.gov (United States)

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel; Milligan, Graeme; Ulven, Trond

    2012-05-10

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

  9. Chronic treatment with meta-chlorophenylpiperazine (m-CPP) alters behavioral and cerebral metabolic responses to the serotonin agonists m-CPP and quipazine but not 8-hydroxy-2(di-N-propylamino)tetralin.

    Science.gov (United States)

    Freo, U; Holloway, H W; Greig, N H; Soncrant, T T

    1992-01-01

    The effects of the serotonin (5-HT) agonists meta-chlorophenylpiperazine (m-CPP), quipazine and 8-hydroxy-2(di-n-propylamino)tetralin (DPAT) on behavior and on regional cerebral metabolic rates for glucose (rCMRglc) were measured in control rats or in rats pretreated for 2 weeks with continuous infusion of saline or m-CPP (2.5 mg/kg/day, subcutaneously). rCMRglc was measured in 71 brain regions, using the quantitative autoradiographic [14C]2-deoxy-D-glucose technique, at 15 min after acute administration of m-CPP 2.5 mg/kg, 60 min after quipazine 20 mg/kg, or 10 min after DPAT 1 mg/kg. Behavioral effects were assessed for m-CPP with an activity monitor, for quipazine by counting head shakes and for DPAT by scoring the serotonin syndrome. Chronic m-CPP pretreatment produced tolerance to hypolocomotion induced by acute m-CPP and to head shakes caused by acute quipazine, but did not alter the serotonin syndrome produced by DPAT. m-CPP 2.5 mg/kg IP produced widespread rCMRglc reductions in control rats but failed to modify rCMRglc in any region after chronic m-CPP pretreatment. Quipazine increased rCMRglc in 4 regions in control rats, but reduced rCMRglc in 14 brain areas of chronically m-CPP-pretreated animals. DPAT altered rCMRglc to the same degree in control (25 regions affected) and in chronically m-CPP-pretreated rats (28 regions affected). Reduced behavioral and metabolic effects of acute m-CPP in chronically m-CPP-pretreated rats were not due to pharmacokinetic alterations. These results demonstrate that chronic administration of m-CPP produces behavioral and metabolic tolerance to acute administration of m-CPP, but not of DPAT.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. 2型糖尿病应用胰高血糖素样肽-1受体激动剂治疗的效果探讨%Discussion Glucagon-Like Peptide-1 Receptor Agonist Treatment of Type 2 Diabetes Application Effect

    Institute of Scientific and Technical Information of China (English)

    敖文

    2015-01-01

    Objective To study the glucagon-like peptide -1 (GLP-1) receptor agonist clinical efficacy in patients with type 2 diabetes.Methods June 2008~June 2009 was diagnosed with type 2 diabetes in 54 patients for the study, and were randomly divided into two groups, the control group were treated with oral medications metformin, the test group of patients affected by the addition of GLP-1 agonist treatment.Results The experimental group in triglycerides, LDL, total cholesterol, transaminases, apolipoprotein -2 aspect compared with the control group, the experimental group was significantly lower, but little change in the control group, a statisticaly significant difference between groups (P<0.05); overal patient outcomes after the experimental group Mann-Whitney U rank sum test was significantly better than the control group, there was a significant difference statisticaly significant (P<0.01).Conclusion The clinical efficacy of GLP-1 receptor agonists in patients with type 2 diabetes significantly help to reduce the incidence of complications. worth in the clinical application and promotion.%目的 研究胰高血糖素样肽-1(GLP-1)受体激动剂对2型糖尿病患者的临床疗效.方法 选取2008年6月~2009年6月被确诊为2型糖尿病的54例患者为研究对象,并随机分为两组,对照组患者给予口服二甲双胍药物,试验组患者加用GLP-1受体激动剂治疗.结果试验组在甘油三酯、低密度脂蛋白、总胆固醇、转氨酶、载脂蛋白-2方面与对照组相比,试验组明显降低,而对照组变化不大,组间差异具有统计学意义(P<0.05);试验组患者整体治疗效果经Mann-Whitney U秩和检验后显著性优于对照组,存在显著性差异,具有统计学意义(P<0.01).结论 GLP-1受体激动剂对2型糖尿病患者的临床疗效显著,有利于减少并发症的发生.

  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. 多巴胺受体激动剂治疗对帕金森病患者非运动症状的影响%Role of dopaminergic agonists in the treatment of non-motor symptoms of Parkinson’s disease

    Institute of Scientific and Technical Information of China (English)

    刘振洋; 王坚

    2015-01-01

    帕金森病患者常伴发非运动症状,会对患者的生活质量造成不良影响。临床研究显示,多巴胺受体激动剂治疗能在一定程度上改善或缓解帕金森病患者的部分非运动症状,如抑郁、焦虑、快感缺失、失眠、不明原因的痛感和膀胱功能失常等,但也会带来一些非运动症状性不良反应,如精神异常、组织纤维化、日间过度嗜睡和冲动强迫行为等。因此,临床医生应善用多巴胺受体激动剂,避免严重不良反应的发生。%Non-motor symptoms are common in Parkinson’s disease (PD) and can significantly affect the quality of life in those patients. Dopaminergic agonists are able to alleviate some non-motor symptoms in PD including depression, anxiety, anhedonia, insomnia, pain etc. On the other hand, adverse effects such as psychosis, ifbrotic reactions, daytime excessive sleepiness, impulse control syndrome may occur with the treatment, therefore, clinicians should make good use of dopaminergic agonists so as to avoid the occurrence of serious adverse reactions.

  13. Muscimol as an ionotropic GABA receptor agonist.

    Science.gov (United States)

    Johnston, Graham A R

    2014-10-01

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

  14. Gonadotropin-releasing Hormone Agonists, Orchiectomy, and Risk of Cardiovascular Disease

    DEFF Research Database (Denmark)

    Thomsen, Frederik Birkebæk; Sandin, Fredrik; Garmo, Hans

    2017-01-01

    : To investigate the association of type of androgen deprivation therapy (ADT) with risk of CVD while minimising selection bias. DESIGN, SETTING, AND PARTICIPANTS: Semi-ecologic study of 6556 men who received GnRH agonists and 3330 men who underwent orchiectomy as primary treatment during 1992-1999 in the Prostate...... with high and units with low use of GnRH agonists were compared. Net and crude probabilities were also analysed. RESULTS AND LIMITATIONS: The risk of CVD was similar between units with the highest and units with the lowest proportion of GnRH agonist use (relative risk 1.01, 95% confidence interval [CI] 0...... found a similar risk of cardiovascular disease between medical and surgical treatment as androgen deprivation therapy for prostate cancer....

  15. 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

  16. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver.

    Science.gov (United States)

    Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

    2016-01-01

    Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis.

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

    Directory of Open Access Journals (Sweden)

    Seong-Jin Yu

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

  18. The Effect of PPARα, PPARδ, PPARγ, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice

    Directory of Open Access Journals (Sweden)

    W. Wallace Harrington

    2007-01-01

    Full Text Available Activation of peroxisome proliferator-activated receptor (PPAR α, δ, and γ subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPARγ agonists. Herein we report the effects of selective PPAR agonists (GW9578, a PPARα agonist, GW0742, a PPARδ agonist, GW7845, a PPARγ agonist, combination of PPARα and δ agonists, and PPARpan (PPARα/γ/δ activators (GW4148 or GW9135 on body weight (BW, body composition, food consumption, fatty acid oxidation, and serum chemistry of diet-induced obese AKR/J mice. PPARα or PPARδ agonist treatment induced a slight decrease in fat mass (FM while a PPARγ agonist increased BW and FM commensurate with increased food consumption. The reduction in BW and food intake after cotreatment with PPARα and δ agonists appeared to be synergistic. GW4148, a PPARpan agonist, induced a significant and sustained reduction in BW and FM similar to an efficacious dose of rimonabant, an antiobesity compound. GW9135, a PPARpan agonist with weak activity at PPARδ, induced weight loss initially followed by rebound weight gain reaching vehicle control levels by the end of the experiment. We conclude that PPARα and PPARδ activations are critical to effective weight loss induction. These results suggest that the PPARpan compounds may be expected to maintain the beneficial insulin sensitization effects of a PPARγ agonist while either maintaining weight or producing weight loss.

  19. 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.

  20. 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.

  1. Identification of Selective ERRγ Inverse Agonists

    Directory of Open Access Journals (Sweden)

    Jina Kim

    2016-01-01

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

  2. The long-acting β2 -adrenoceptor agonist, indacaterol, enhances glucocorticoid receptor-mediated transcription in human airway epithelial cells in a gene- and agonist-dependent manner.

    Science.gov (United States)

    Joshi, T; Johnson, M; Newton, R; Giembycz, M A

    2015-05-01

    Inhaled glucocorticoid (ICS)/long-acting β2 -adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone-inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)-mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism. BEAS-2B human airway epithelial cells stably transfected with a 2× glucocorticoid response element luciferase reporter were used to model gene transcription together with an analysis of several glucocorticoid-inducible genes. Indacaterol augmented glucocorticoid-induced reporter activation in a manner that was positively related to the intrinsic activity of the GR agonist. This effect was demonstrated by an increase in response maxima without a change in GR agonist affinity or efficacy. Indacaterol also enhanced glucocorticoid-inducible gene expression. However, the magnitude of this effect was dependent on both the GR agonist and the gene of interest. These data suggest that indacaterol activates a molecular rheostat, which increases the transcriptional competency of GR in an agonist- and gene-dependent manner without apparently changing the relationship between fractional GR occupancy and response. These findings provide a platform to rationally design ICS/LABA combination therapy that is based on the generation of agonist-dependent gene expression profiles in target and off-target tissues. © 2015 The British Pharmacological Society.

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

    Directory of Open Access Journals (Sweden)

    Maria Grazia Perrone

    2013-07-01

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

  4. Identification of human dopamine receptors agonists from Chinese herbs

    Institute of Scientific and Technical Information of China (English)

    Yi-lin ZHANG; Hai-qing ZHANG; Xiao-yu LIU; Shi-neng HUA; Lu-bing ZHOU; Jun YU; Xue-hai TAN

    2007-01-01

    Aim: To find human dopamine receptors, especially D1-like receptor specific ago-nists from Chinese herbs as potential antihypertension drug leads. Methods: Two D1-like receptor cell lines carrying a β-lactamase reporter gene, and a D2 receptor cell line coexpressing a promiscuous G protein G15 were constructed using HEK293 cells. A natural compound library made from fractionated samples of herbal ex-tracts was used for high-throughput screening (HTS) against one of the cell lines,HEK/D5R/CRE-blax. The interested hits were evaluated for their activities against various dopamine receptors. Results: Fourteen hits were identified from primary screening, of which 2 of the better hit samples, HD0522 and HD0059, were selected for further material and activity analysis, and to obtain 2 compounds that ap-peared as 2 single peaks in HPLC, HD0522H01 and HD0059H01. HD0059H01 could activate D1, D2, and D5 receptors, with EC50 values of 2.28 μg/mL, 0.85 μg/mL, and 1.41 μg/mL, respectively. HD0522H01 could only activate D1R and D5R with EC50 values of 2.95 μg/mL and 8.38 μg/mL. Conclusion: We established cell-based assays for 3 different human dopamine receptors and identified specific agonists HD0522H01 and HD0059H01 through HTS. The specific agonist to D1-like receptors, HD0522H01, may become a new natural product-based drug lead for antihypertension treatment.

  5. Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats.

    Science.gov (United States)

    Huizenga, Megan N; Wicker, Evan; Beck, Veronica C; Forcelli, Patrick A

    2017-09-01

    Although drugs targeting the cannabinoid system (e.g., CB1 receptor agonists) display anticonvulsant efficacy in adult animal models of seizures/epilepsy, they remain unexplored in developing animal models. However, cannabinoid system functions emerge early in development, providing a rationale for targeting this system in neonates. We examined the therapeutic potential of drugs targeting the cannabinoid system in three seizure models in developing rats. Postnatal day (P) 10, Sprague-Dawley rat pups were challenged with the chemoconvulsant methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) or pentylenetetrazole (PTZ), after treatment with either CB1/2 mixed agonist (WIN 55,212-2), CB1 agonist (arachidonyl-2'-chloroethylamide [ACEA]), CB2 agonist (HU-308), CB1 antagonist (AM-251), CB2 antagonist (AM-630), fatty acid amide hydrolase inhibitor (URB-597), or G protein-coupled receptor 55 agonist (O-1602). P20 Sprague-Dawley pups were challenged with DMCM after treatment with WIN, ACEA, or URB. Finally, after pretreatment with WIN, P10 Sprague-Dawley rats were challenged against acute hypoxia-induced seizures. The mixed CB1/2 agonist and the CB1-specific agonist, but no other drugs, displayed anticonvulsant effects against clonic seizures in the DMCM model. By contrast, both CB1 and CB2 antagonism increased seizure severity. Similarly, we found that the CB1/2 agonist displayed antiseizure efficacy against acute hypoxia-induced seizures (automatisms, clonic and tonic-clonic seizures) and tonic-clonic seizures evoked by PTZ. Anticonvulsant effects were seen in P10 animals but not P20 animals. Early life seizures represent a significant cause of morbidity, with 30-40% of infants and children with epilepsy failing to achieve seizure remission with current pharmacotherapy. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority. These data indicate that the anticonvulsant action of the CB system is specific to CB1

  6. 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.

  7. Therapeutic efficacy of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) against organophosphate intoxication

    NARCIS (Netherlands)

    Bueters, T.J.H.; Groen, B.; Danhof, M.; IJzerman, A.P.; Helden, H.P.M. van

    2002-01-01

    The objective of the present study was to investigate whether reduction of central acetylcholine (ACh) accumulation by adenosine receptor agonists could serve as a generic treatment against organophosphate (OP) poisoning. The OPs studied were tabun (O-ethyl-N-dimethylphosphoramidocyanidate), sarin (

  8. 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

    and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose...

  9. 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...

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

    NARCIS (Netherlands)

    Swart, Pieter Jacob

    1992-01-01

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

  11. Long-acting β-adrenoceptor agonists in the management of COPD: focus on indacaterol

    Science.gov (United States)

    Beier, Jutta; Beeh, Kai M

    2011-01-01

    Bronchodilators are the cornerstone of severe chronic obstructive pulmonary disease (COPD) treatment to improve airflow, symptoms, exercise tolerance, and exacerbations. There is convincing evidence that regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators. Long-acting β-2-agonists include the twice-daily drugs formoterol and salmeterol and, more recently, once-daily indacaterol. Studies with head-to-head comparisons of long-acting bronchodilators are scant, but novel data from controlled trials with the once-daily β(2)-agonist indacaterol indicate superior bronchodilation and clinical efficacy of indacaterol at recommended doses over twice-daily long-acting β(2)-agonists, and at least equipotent bronchodilation compared with once-daily tiotropium. The recent therapeutic developments in COPD underscore a shift from short-acting bronchodilators with multiple dosings per day to reduced dosing frequency and prolonged duration of action, including once-daily treatment, with more consistent effects on various clinical outcomes. This review summarizes relevant clinical data for twice-daily β-2-agonists in COPD, and further focuses on novel data for once-daily indacaterol, including head-to-head comparison trials. PMID:21814459

  12. Therapeutic efficacy of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) against organophosphate intoxication

    NARCIS (Netherlands)

    Bueters, T.J.H.; Groen, B.; Danhof, M.; IJzerman, A.P.; Helden, H.P.M. van

    2002-01-01

    The objective of the present study was to investigate whether reduction of central acetylcholine (ACh) accumulation by adenosine receptor agonists could serve as a generic treatment against organophosphate (OP) poisoning. The OPs studied were tabun (O-ethyl-N-dimethylphosphoramidocyanidate), sarin (

  13. 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 b

  14. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Body Weight: A Meta-Analysis

    OpenAIRE

    Matteo Monami; Ilaria Dicembrini; Niccolò Marchionni; Rotella, Carlo M.; Edoardo Mannucci

    2012-01-01

    Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for “exenatide,” “liraglutide,” “albiglutide,” “semaglutide,” and “lixisenatide” was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or...

  15. 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.

  16. Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold.

    Science.gov (United States)

    Li, He; Huang, Qi; Chen, Cheng; Xu, Bin; Wang, He-Yao; Long, Ya-Qiu

    2017-04-13

    The free fatty acid receptor GPR40 is predominantly expressed in pancreatic β-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically and structurally diverse GPR40 agonists with high safety are pursued for the clinical development of GPR40-based pharmacotherapeutics. Herein we report our design and discovery of a new chemotype of GPR40 agonists free of the typical phenylpropanoic acid scaffold. The thiophen-2-ylpropanoic acid containing GPR40 modulators functioned as full agonists with high-efficacy response (Emax) and reduced lipophilicity. Significantly, the lead compound in this series, (R)-7k, exhibited more potent in vitro glucose-stimulated insulin secretion and in vivo glucose-lowering effects (10 mg/kg, po) than the GPR40 partial agonist TAK-875, which was once in phase III clinical trials, and high selectivity over the relevant receptors GPR120 and PPARγ.

  17. 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.

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

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    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......, 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......-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...

  19. beta2 adrenergic agonists in acute lung injury? The heart of the matter.

    Science.gov (United States)

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of beta2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to increase the resolution of pulmonary edema. However, the results of clinical trials of beta agonist therapy for ALI/ARDS have been conflicting in terms of benefit. In the previous issue of Critical Care, Briot and colleagues present evidence that may help clarify the inconsistent results. The authors demonstrate that, in oleic acid lung injury in dogs, the inotropic effect of beta agonists may recruit damaged pulmonary capillaries, leading to increased lung endothelial permeability.

  20. Improved posttraumatic acquisition of a place learning task after repeated administration of a serotonergic agonist 8-OH-DPA

    DEFF Research Database (Denmark)

    Mala, Hana; Mogensen, Jesper

    2008-01-01

    Introduction/Objectives Studies have indicated that serotonergic agonists may act neuroprotectively against neurochemical and mechanical injury to the brain, and diminish the negative consequences of secondary tissue response to the initial insult. Little is known about the mechanisms...... of such effects. Likewise, it is presently uncertain to what extent serotonergic agonists can reduce the functional consequences of focal brain injury. In this study, we have addressed the neuroprotective potential of 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT), which is a serotonin agonist binding....... The performance of the sham-operated controls was unaffected by 8-OH-DPAT treatment.   Conclusion: Serotonergic agonists represent a new target for potential therapeutic strategies in the treatment of consequences after brain injury. In particular, 5-HT1A receptor agonists appear promising, and more research...

  1. PPARγ agonists promote oligodendrocyte differentiation of neural stem cells by modulating stemness and differentiation genes.

    Directory of Open Access Journals (Sweden)

    Saravanan Kanakasabai

    Full Text Available Neural stem cells (NSCs are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS. Peroxisome proliferator-activated receptor gamma (PPARγ is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF and basic fibroblast growth factor (bFGF induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA and PPARγ agonist ciglitazone or 15-Deoxy-Δ(12,14-Prostaglandin J(2 (15d-PGJ2 resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3-7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal β-III tubulin and astrocyte-specific GFAP in NSCs in 3-7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases.

  2. Partial nicotinic acetylcholine (α4β2 agonists as promising new medications for smoking cessation

    Directory of Open Access Journals (Sweden)

    Singh J

    2008-01-01

    Full Text Available Objective: To review the pharmacology, clinical efficacy and safety of partial agonists of a4β 2 nicotinic acetylcholine receptor. Data Sources: Primary literature and review articles were obtained via a PUBMED search (1988-August 2006 using the key terms smoking cessation, partial agonist alpha4beta2 nicotinic acetylcholine receptor, varenicline, cytisine and SSR591813. Additional studies and abstracts were identified from the bibliographies of reviewed literature. Study Selection and Data Extraction: Studies and review articles related to varenicline, cytisine and the partial agonist alpha4beta2 nicotinic acetylcholine receptor were reviewed. Data Synthesis: Smoking is widely recognized as a serious health problem. Smoking cessation has major health benefits. According to the US Public Health Services, all patients attempting to quit smoking should be encouraged to use one or more effective pharmacotherapy. Currently, along with nicotine replacement therapy, bupropion, nortriptyline and clonidine, are the mainstay of pharmacotherapy. More than ¾ of patients receiving treatment for smoking cessation return to smoking within the first year. Nicotine, through stimulating α4β 2 nAChR, releases dopamine in the reward pathway. Partial agonist of α4β 2 nAChR elicits moderate and sustained release of dopamine, which is countered during the cessation attempts; it simultaneously blocks the effects of nicotine by binding with α4β 2 receptors during smoking. Recently, varenicline, a partial agonist at α4β 2 nAChR, has been approved by the FDA (Food and Drug Administration for smoking cessation. Conclusion: Partial agonist α4β 2 nAChR appears to be a promising target in smoking cessation. Varenicline of this group is approved for treatment of smoking cessation by the FDA in May 2006.

  3. The evolution of histamine H₃ antagonists/inverse agonists.

    Science.gov (United States)

    Lebois, Evan P; Jones, Carrie K; Lindsley, Craig W

    2011-01-01

    This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H₃ antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H₃R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H₃ ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H₃ ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H₃R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists.

  4. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    Science.gov (United States)

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

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

    Science.gov (United States)

    Bishop, Michael J

    2007-01-01

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

  6. Agonistic and reproductive interactions in Betta splendens.

    Science.gov (United States)

    Bronstein, P M

    1984-12-01

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

  7. 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...

  8. Signal Use by Octopuses in Agonistic Interactions.

    Science.gov (United States)

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

    2016-02-08

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

  9. A prospective study of GnRH long agonist versus flexible GnRH antagonist protocol in PCOS: Indian experience

    Directory of Open Access Journals (Sweden)

    Harpreet Kaur

    2012-01-01

    Full Text Available Background: Polycystic ovarian syndrome is a common endocrine disorder of reproductive age women. Many controlled ovarian stimulation (COS strategies have been offered for the treatment of patients with PCOS undergoing in vitro fertilization, but the optimal protocol is still a controversy. There is no compelling evidence for the advantage of one stimulation protocol over the other. Materials and Methods: This is a single-center prospective controlled study comparing long agonist and antagonist protocol in PCOS women. Results: There was no significant difference in live birth rate and clinical pregnancy rate. Rate of ovarian hyperstimulation syndrome was significantly higher in the agonist group. Number of oocytes retrieved, number of follicles and peak estradiol levels were significantly more in the agonist group. Conclusion: The GnRH antagonist protocol is an equally effective but safer protocol in PCOS patients compared with the long agonist protocol.

  10. The progress of inhaled corticosteroid/long-actingβ2-agonist combinations in the treatment of asthma%吸入糖皮质激素和长效β2-受体激动剂复方制剂治疗哮喘的研究进展

    Institute of Scientific and Technical Information of China (English)

    孙伟; 揭志军

    2014-01-01

    联合使用吸入糖皮质激素和长效β2-受体激动剂对控制哮喘的气道炎症和改善气道平滑肌功能具有协同和互补作用。吸入糖皮质激素和长效β2-受体激动剂复方制剂是目前哮喘维持治疗的重要药物,主要包括丙酸氟替卡松/沙美特罗、布地奈德/福莫特罗、二丙酸倍氯松/福莫特罗和糠酸莫米松/福莫特罗等。本文就此类复方制剂在哮喘治疗中的临床地位和研究进展作一概述。%Inhaled corticosteroid/long-actingβ2-agonist (ICS/LABA) combinations play synergic and complementary roles in controlling airway inlfammation and improving the function of airway smooth muscle. They are very important drugs for asthma maintenance. The different combinations of ICS/LABA, such as lfuticasone propionate/salmeterol, budesonide/formoterol, beclomethasones dipropionate/formoterol, mometasone furoate/formoterol, have different pharmacological features. This review summarizes the features and progress of these ICS/LABA in the treatment of asthma.

  11. Dopamine agonists increase perseverative instrumental responses but do not restore habit formation in a rat model of Parkinsonism.

    Science.gov (United States)

    Faure, A; Leblanc-Veyrac, P; El Massioui, N

    2010-06-30

    Dopamine (DA) deafferentation of the dorsolateral striatum has been shown to prevent habit development, leaving instrumental behavior under action-outcome control that is persistently sensitive to modification of the motivational value of the reward. The present experiment further explored the basis of this dysfunction by examining the ability of intrastriatal DA agonist injections (D1 SKF 38393 or D2/D3 Quinpirole) during overtraining of a signaled instrumental task to restore habit formation in rats subjected to bilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic pathway. Overtraining was followed by a test of goal sensitivity by satiety-specific devaluation of the reward. The results confirmed the impaired shift in performance from action to habit in control lesioned rats. However, lesioned rats repeatedly injected with quinpirole D2/D3 agonist showed an increase in non-rewarded instrumental responses (intertrials periods) during overtraining, suggesting the development of perseverative behavior. Following the procedure of devaluation, quinpirole D2/D3 agonist treatment, and to a lesser extent SKF 38393 D1 agonist, caused the persistence of sensitivity to reward devaluation, indicating clear goal-directed behavior despite extended training. This absence of restoration of habit formation by DA agonist treatment is discussed in the light of DA agonist effects in Parkinson patients.

  12. Ombuin-3-O-β-D-glucopyranoside from Gynostemma pentaphyllum is a dual agonistic ligand of peroxisome proliferator-activated receptors α and δ/β

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-01-25

    Highlights: ► Ombuin-3-O-β-D-glucopyranoside is a dual ligand for PPARα and δ/β. ► Ombuin-3-O-β-D-glucopyranoside reduces cellular lipid levels in multiple cell types. ► Cells stimulated with ombuine up-regulated target genes in cholesterol efflux. ► Cells stimulated with ombuine regulated target fatty acid β-oxidation and synthesis. ► Ombuin-3-O-β-D-glucopyranoside could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: We demonstrated that ombuin-3-O-β-D-glucopyranoside (ombuine), a flavonoid from Gynostemma pentaphyllum, is a dual agonist for peroxisome proliferator-activated receptors (PPARs) α and δ/β. Using surface plasmon resonance (SPR), time-resolved fluorescence resonance energy transfer (FRET) analyses, and reporter gene assays, we showed that ombuine bound directly to PPARα and δ/β but not to PPARγ or liver X receptors (LXRs). Cultured HepG2 hepatocytes stimulated with ombuine significantly reduced intracellular concentrations of triglyceride and cholesterol and downregulated the expression of lipogenic genes, including sterol regulatory element binding protein-1c (SREBP1c) and stearoyl-CoA desaturase-1 (SCD-1), with activation of PPARα and δ/β. Activation of LXRs by ombuine was confirmed by reporter gene assays, however, SPR and cell-based FRET assays showed no direct binding of ombuine to either of the LXRs suggesting LXR activation by ombuine may be operated via PPARα stimulation. Ombuine-stimulated macrophages showed significantly induced transcription of ATP binding cassette cholesterol transporter A1 (ABCA1) and G1 (ABCG1), the key genes in reverse cholesterol transport, which led to reduced cellular cholesterol concentrations. These results suggest that ombuine is a dual PPAR ligand for PPARα and δ/β with the ability to decrease lipid concentrations by reducing lipogenic gene expression in hepatocytes and inducing genes involved in cholesterol efflux in macrophages.

  13. In vivo and in vitro evaluation of novel μ-opioid receptor agonist compounds.

    Science.gov (United States)

    Nikaido, Yoshiaki; Kurosawa, Aya; Saikawa, Hitomi; Kuroiwa, Satoshi; Suzuki, Chiharu; Kuwabara, Nobuo; Hoshino, Hazime; Obata, Hideaki; Saito, Shigeru; Saito, Tamio; Osada, Hiroyuki; Kobayashi, Isao; Sezutsu, Hideki; Takeda, Shigeki

    2015-11-15

    Opioids are the most effective and widely used drugs for pain treatment. Morphine is an archetypal opioid and is an opioid receptor agonist. Unfortunately, the clinical usefulness of morphine is limited by adverse effects such as analgesic tolerance and addiction. Therefore, it is important to study the development of novel opioid agonists as part of pain control. The analgesic effects of opioids are mediated by three opioid receptors, namely opioid μ-, δ-, and κ-receptors. They belong to the G protein-coupled receptor superfamily and are coupled to Gi proteins. In the present study, we developed a ligand screening system to identify novel opioid μ-receptor agonists that measures [(35)S]GTPγS binding to cell membrane fractions prepared from the fat body of transgenic silkworms expressing μ-receptor-Gi1α fusion protein. We screened the RIKEN Natural Products Depository (NPDepo) chemical library, which contains 5848 compounds, and analogs of hit compounds. We successfully identified a novel, structurally unique compound, that we named GUM1, with agonist activity for the opioid μ-receptor (EC50 of 1.2 µM). The Plantar Test (Hargreaves' Method) demonstrated that subcutaneous injection of 3mg/kg of GUM1 into wild-type rats significantly extended latency time. This extension was also observed in a rat model of morphine tolerance and was inhibited by pre-treatment of naloxone. The unique molecular skeleton of GUM1 makes it an attractive molecule for further ligand-opioid receptor binding studies.

  14. Effects of salvinorin A on locomotor sensitization to D2/D3 dopamine agonist quinpirole.

    Science.gov (United States)

    Beerepoot, Pieter; Lam, Vincent; Luu, Alice; Tsoi, Bernice; Siebert, Daniel; Szechtman, Henry

    2008-12-03

    Locomotor sensitization induced by the dopamine agonist quinpirole can be potentiated by co-treatment with the synthetic kappa opioid agonist U69593. The identification of salvinorin A, an active component of the psychotropic sage Salvia divinorum, as a structurally different agonist of kappa-opioid receptors raised the question of whether this compound would similarly potentiate sensitization to quinpirole. Rats were co-treated with 0.5 mg/kg quinpirole and either salvinorin A (0.04, 0.4 or 2.0 mg/kg) or U69593 (0.3 mg/kg). Control groups were co-treated with vehicle and saline, vehicle and quinpirole (0.5 mg/kg), or saline and salvinorin A (0.4 mg/kg). Rats were injected biweekly for a total of 10 injections and locomotor activity measured after each treatment. Results showed that the highest dose of salvinorin A potentiated sensitization to quinpirole as did U69593, the middle salvinorin A dose had no effect on quinpirole sensitization, and the lowest dose of salvinorin A attenuated sensitization to quinpirole. These findings indicate that structural differences between salvinorin A and U69593 do not affect the potentiation of quinpirole sensitization. Moreover, the opposite effects of high and low salvinorin A doses suggest that salvinorin A can produce bidirectional modulation of sensitization to dopamine agonists.

  15. STING agonists induce an innate antiviral immune response against hepatitis B virus.

    Science.gov (United States)

    Guo, Fang; Han, Yanxing; Zhao, Xuesen; Wang, Jianghua; Liu, Fei; Xu, Chunxiao; Wei, Lai; Jiang, Jian-Dong; Block, Timothy M; Guo, Ju-Tao; Chang, Jinhong

    2015-02-01

    Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted.

  16. Inhibitory effects of peroxisome proliferator-activated receptor γ agonists on collagen IV production in podocytes.

    Science.gov (United States)

    Li, Yanjiao; Shen, Yachen; Li, Min; Su, Dongming; Xu, Weifeng; Liang, Xiubin; Li, Rongshan

    2015-07-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-γ agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-γ was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-γ agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-β. In contrast, adding PPAR-γ antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-β in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-β-induced SBE4-luciferase activity. In conclusion, PPAR-γ activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-β-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-γ agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-γ agonists as podocyte protective agents.

  17. Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery?

    Science.gov (United States)

    Riese, David J.

    2010-01-01

    Introduction Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. Areas covered Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. Expert opinion While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and –independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics. PMID:21532939

  18. 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

  19. 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.)...

  20. Urinary hMG versus recombinant FSH for controlled ovarian hyperstimulation following an agonist long down-regulation protocol in IVF or ICSI treatment: a systematic review and meta-analysis.

    Science.gov (United States)

    Coomarasamy, Arri; Afnan, Masoud; Cheema, Deepti; van der Veen, Fulco; Bossuyt, Patrick M M; van Wely, Madelon

    2008-02-01

    Since the most recent Cochrane review on hMG versus rFSH for controlled ovarian hyperstimulation following a long down-regulation protocol, several new trials have emerged. We conducted a systematic review and meta-analysis of randomized trials comparing the effectiveness of hMG versus rFSH following a long down-regulation protocol in IVF-ICSI cycles, on the primary outcome of live birth per woman randomized, as well as several other secondary outcomes. Searches were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library and databases of abstracts (last search January 2007). Seven randomized trials, consisting of a total of 2159 randomized women, were identified. A meta-analysis of these trials showed a significant increase in live birth rate with hMG when compared with rFSH (relative risk, RR = 1.18, 95% CI: 1.02-1.38, P = 0.03). The heterogeneity test was non-significant (P = 0.97), suggesting that there was no statistical inconsistency between the seven studies. The pooled risk difference (RD) for the outcome of live birth rate was 4% (95% CI: 1-7%) for these study populations. There was an increase in clinical pregnancy rates with hMG when compared with rFSH (RR = 1.17, 95% CI 1.03-1.34). No significant differences were noted for gonadotrophin use, spontaneous abortion, multiple pregnancy, cancellation and ovarian hyperstimulation syndrome rates. For the populations in the randomized trials, hMG was associated with a pooled 4% increase in live birth rate when compared with rFSH in IVF-ICSI treatment following a long down-regulation protocol.

  1. Clinical curative effect of pramipexole dopamine receptor agonist in the treatment of advanced Parkinson's disease%普拉克索联合美多巴治疗晚期帕金森病临床疗效观察

    Institute of Scientific and Technical Information of China (English)

    朱爱军; 谭绍云; 张双双

    2015-01-01

    目的:探讨普拉克索联合美多巴治疗晚期帕金森病( PD )的临床疗效。方法选择2010年3月—2013年9月收治的晚期PD患者93例为研究对象,采用随机分层法分为对照组(46例)和观察组(47例)。对照组予以美多巴治疗,观察组在美多巴基础上联合普拉克索,共治疗12周,每4周评定2组患者汉密尔顿抑郁量表( HAMD)、PD评分量表第 III 部分( UPDRS III )变化,比较疗期间临床疗效、不良反应。结果观察组显效率(72?.34%)、总有效率(89.36%)明显高于对照组(47.83%、60.87%),差异有统计学意义( P <0.05, P <0.01);2组治疗8周、12周UPDRS III评分分别为(20.12±5.31、18.56±4.37)和(24.5±5.29、21.54±4.35)、HAMD评分分别为(9.37±4.35、7.07±4.63)和(13.51±4.32、10.92±4.59),不良反应分别为21.28%(10/47)和54.35%(25/46),观察组均明显低于对照组( P <0.05)。结论普拉克索联合美多巴治疗中晚期PD,可显著改善患者运动症状,缓解抑郁情绪,提高治疗效果。%Objective To investigate the therapeutic effect of pramipexole combined with Madopar in the treatment of advanced Parkinson 's disease ( PD) .Methods Ninty-three cases with advanced PD were randomly divided into control group (46 cases) and observation group (47 cases), control group was given Madopar treatment , observation group was given pramipexole combined with Madopar , Hamilton Depression Scale ( HAMD) , PD rating scale Part III ( UPDRS III) changes , adverse reactions between two groups were compared .Results The observation group's efficiency (72.34%), the total effec-tive rate (89.36%) was significantly higher than that of the control group (47.83%, 60.87%), the difference was statisti-cally significant ( P <0.05, P <0.01);at the 8th weeks, 12th weeks, the 2 groups'UPDRS III score were (20.12 ±5.31, 18.56 ±4.37) and (24.15 ±5.29, 21.54

  2. 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.

  3. 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

  4. 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.

  5. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Christensen, Mikkel; Junker, Anders E;

    2012-01-01

    To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.......To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus....

  6. Small-molecule AT2 receptor agonists

    DEFF Research Database (Denmark)

    Hallberg, Mathias; Sumners, Colin; Steckelings, U Muscha

    2017-01-01

    with the highest affinity for the AT2R reported to date (Ki = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8......, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also...

  7. 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.

  8. SNC 80 and related delta opioid agonists.

    Science.gov (United States)

    Calderon, S N; Coop, A

    2004-01-01

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

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Subhrajit Saha

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

  11. Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells.

    Directory of Open Access Journals (Sweden)

    Lanlan Liu

    Full Text Available Emerging evidence suggests that tumor-initiating cells (TICs are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPARγ agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC cells. Reactive oxygen species (ROS initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPARγ agonists. However, PPARγ agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPARγ agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPARγ agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPARγ agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPARγ agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.

  12. Aromatase inhibitors with or without luteinizing hormone-releasing hormone agonist for metastatic male breast cancer: report of four cases and review of the literature.

    Science.gov (United States)

    Kuba, Sayaka; Ishida, Mayumi; Oikawa, Masahiro; Nakamura, Yoshiaki; Yamanouchi, Kosho; Tokunaga, Eriko; Taguchi, Kenichi; Esaki, Taito; Eguchi, Susumu; Ohno, Shinji

    2016-11-01

    The roles of aromatase inhibitors (AIs) and luteinizing hormone-releasing hormone (LH-RH) agonists in the management of male breast cancer remain uncertain, with no reports in Japanese men. We report four Japanese male patients with metastatic breast cancer treated with AIs with or without an LH-RH agonist, and consider the relationship between treatment effect and estradiol (E2) concentration. Three patients were initially treated with AI alone after selective estrogen receptor modulators (SERMs), and one received AIs plus an LH-RH agonist after a SERM. Two patients treated with an AI alone responded, one patient with E2 levels below the lower assay limit and the other with levels above the limit. The other treated with an AI alone experienced progression regardless of the E2 levels below the lower assay limit, however, responded after the addition of an LH-RH agonist. E2 concentrations were related to the efficacy of treatment in one patient. The patient initially treated with an AI plus an LH-RH agonist also responded. No grade 3 or 4 adverse events were observed in any of the patients treated with AIs with or without an LH-RH agonist. AIs with or without an LH-RH agonist offer an effective treatment option for hormone receptor-positive metastatic male breast cancer.

  13. Effect of selective α1 receptor agonist in the treatment of children with postural orthostatic tachycardia syndrome%选择性α1受体激动剂对儿童体位性心动过速综合征的治疗研究

    Institute of Scientific and Technical Information of China (English)

    陈丽; 杜军保; 金红芳; 张清友; 李万镇; 汪立; 王瑜丽

    2008-01-01

    Objective The study was designed to examine the effect of selective α1 receptor agonist midodrine hydrochloride in the treatment of children with postural orthostatic tachyeardia syndrome.Methods Fifty-five children(23 male,32 female,age 5-19 yrs,nlean age 12.3±3.1 yrs)who came from Peking University First Hospital were included in the study and clinical investigations as well as standing test,basic head-up tilt test and sublingnal nitroglycerin-provocated head-up tilt test under quiet circumstance were conducted.They were randomly divided into treatment group(with midodrine hydrochloride and oral rehydration salt theatment)and control group(with oral rehydrafion salt treatment only).At last,the disease-free rate,improvement rate and effective rate of symptoms,and the rate of HUT from positive to negative response were compared between control group and treatment group.SPSS 10.0 software was used for the statistical analysis of these data.Results The symptom improvement rate in treatment group was significantly higher than that of control group after three and six weeks of treatment (100.0% vs.42.4%,P<0.001;100.0% vs.42.4%,X2=19.352,P<0.001).The disease-free rate at follow-up end-point in treatment group was significantly higher than that of control group(77.3% vs.27.3%,X2=13.239,P<0.001).The effective rato at follow-up end-point in treatment group was also significantly higher than that of control group(100.0% vs.36.4%,X2=22.647,P<0.001).The rate of HUT changing from positive to negative response between two groups after three weeks of treatment was not significantly different(31.8% vs.12.1%,P>0.05),but it was significantly different(81.1% vs. 48.5%,P<0.05)after six weeks of treatment.Conclusion Selective α1 receptor agonist midodrine hydroehloride is effective in the treatment of children with postural orthostatic taehycardia syndrome.%目的 探讨选择性α1受体激动剂盐酸米多君对体位性心动过速综

  14. 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.

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

    OpenAIRE

    Maharjan Anu S; Pilling Darrell; Gomer Richard H

    2010-01-01

    Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fi...

  16. Transient occult cardiotoxicity in children receiving continuous beta-agonist therapy

    Institute of Scientific and Technical Information of China (English)

    Christopher L Carroll; Melinda Coro; Allison Cowl; Kathleen A Sala; Craig M Schramm

    2014-01-01

    Background: Continuous beta-agonist therapy, typically in the form of inhaled albuterol, is the first line therapy for the treatment of acute and severe bronchospasm in children. Although this treatment is commonly used, concerns about cardiotoxicity have been raised. We aimed to investigate the cardiotoxic effects of continuous beta-agonist therapy in children. Methods: We conducted a retrospective review of children admitted to the intensive care unit (ICU) between May 2008 and April 2009, who were treated with continuous beta-agonist therapy (intravenous and nebulized). Results: Twenty of the 36 children treated with continuous albuterol had repeated serum troponin-T and lactate levels measured. Eleven patients (55%) were also treated with continuous intravenous terbutaline. Elevated levels of troponin-T levels were found in 25% of children, and elevated lactate levels were found in 60%. However, all returned to normal levels within 48 hours of ICU admission, despite continued beta-agonist therapy. No children experienced arrhythmias during therapy. There was no association between intravenous terbutaline use and elevated troponin-T [odds ratio (OR), 1.3; 95% CI, 0.2-10.3] or with elevated serum lactate (OR, 0.6; 95% CI, 0.1-3.7). There was also no association between elevated troponin-T or lactate and ICU or hospital length of stay. Conclusions: In this small study, a significant proportion of children had elevated serum troponin-T and lactate levels while receiving inhaled continuous beta-agonist therapy, irrespective of intravenous therapy. However, these abnormal values all returned to normal within 48 hours of ICU admission and were not associated with increased duration of hospitalization.

  17. Limited β2-adrenoceptor haplotypes display different agonist mediated airway responses in asthmatics

    Directory of Open Access Journals (Sweden)

    Hart Guus AM

    2006-01-01

    Full Text Available Abstract Background In vitro and some in vivo studies suggested that genetic haplotypes may have an impact on β2-agonist mediated airway responses in asthmatics. Due to strong linkage disequilibrium the single nucleotide polymorphisms (SNPs in the β2-adrenoceptor gene result in only a limited number of haplotypes. We intended to evaluate the impact of β2-adrenoceptor haplotypes on β2-agonist mediated airway responses and the development of tolerance in mild to moderate asthmatics. Methods Patients were genotyped for the part of the β2-adrenoceptor gene with a known bearing on receptor function and regulation. Cumulative dose response curves of fenoterol versus PD20 methacholine and FEV1 were constructed after 2 week treatment periods with either terbutaline or placebo in a double blind, randomised and cross-over design. Analysis of the dose response curves was based on a repeated measurement analysis of covariance. Results In our study population comprising 45 asthmatic patients, we found three limited allelic haplotypes, resulting in six different genotypes. Our data support the existence of differences between these six genotypes both in the shape of the dose response relationship of the β2-adrenoceptor agonist fenoterol as well as in the propensity to develop tolerance for these effects by pre-treatment with terbutaline. However, this could only be substantiated for the endpoint PD20 methacholine. Conclusion Between β2-adrenoceptor genotypes differences exist both in baseline β2-agonist induced airway responses as well as in the propensity to develop tolerance during maintenance β2-agonist therapy. The net differences after two weeks of therapy are, however, of magnitudes that are unlikely to be of clinical significance.

  18. [Study of personal best value of peak expiratory flow in patients with asthma--comparison of the highest value of daily PEF under good control and the highest value of daily PEF obtained after using repeated inhaled beta2-agonist during high-dose inhaled steroid treatment].

    Science.gov (United States)

    Watanabe, Naoto; Makino, Sohei; Kihara, Norio; Fukuda, Takeshi

    2008-12-01

    In the guideline for asthma management, it is important to find the personal best value of peak expiratory flow (best PEF). Recently, we have substituted the highest value of PEF in daily life under good control (daily highest PEF) for the best PEF. In the present study, we considered whether the daily highest PEF could be used as the best PEF or not. Subjects were 30 asthmatics who were well controlled but whose baseline PEF values were less than 80 percent of predicted values. We compared the daily highest PEF and the highest of PEF obtained after repeated inhaled beta2-agonist (salbutamol MDI every 20 minutes three times). All subjects then received 1600 microg/day of beclomethasone dipropionate (BDP) for 4 to 8 weeks. We studied the effect of high-dose inhaled steroid treatment on each PEF value and compared the daily highest PEF and the highest PEF obtained after using repeated salbutamol MDI during high dose inhaled steroid therapy on the examination day again. The baseline PEF, daily highest PEF and the highest PEF obtained after salbutamol MDI were significantly less than the each values obtained after high-dose BDP. The best PEF value of them was the value obtained after repeated salbutamol MDI during high dose BDP. We suggest that the daily highest PEF under good control is not a substitute for best PEF because it changes according to the degree of improvement of airway inflammation. We recommend that a course of high dose inhaled steroid is effective in finding the best value of PEF for each individual with moderate asthma.

  19. A new angle for glp-1 receptor agonist: the medical economics argument. Editorial on: Huetson P, Palmer JL, Levorsen A, et al. Cost-effectiveness of the once-daily glp-1 receptor agonist lixisenatide compared to bolus insulin both in combination with basal insulin for the treatment of patients with type 2 diabetes in Norway. J Med Econ 2015: 1-13 [Epub ahead of print].

    Science.gov (United States)

    Valencia, Willy Marcos; Florez, Hermes Jose

    2015-01-01

    Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are relatively new medications for diabetes that offer a weight-loss profile that can be considered desirable for patients with both type 2 diabetes (T2D) and obesity. GLP-1 RA are effective in combination with insulin, and even slightly superior or at least equal to short-acting insulin in T2D; however, since they work in the incretin system, they may not be effective in long-standing disease. Additionally, only recently have publications reported their cardiovascular safety, and there is limited evidence for long-term effectiveness. The work presented by Huetson et al. offers a much needed perspective through a medical economic model for the long term cost-effectiveness of GLP-1 RA. The authors found benefits in quality-adjusted life years and reduced lifetime healthcare costs. While there are a few limitations, this study contributes to the understanding of these agents and their impact on the epidemics of obesity in T2D, where weight management is no longer an option, but an essential component of the diabetes plan of care.

  20. Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist.

    Science.gov (United States)

    Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

    2015-08-01

    Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.

  1. Beta2-agonists for acute cough or a clinical diagnosis of acute bronchitis.

    Science.gov (United States)

    Becker, Lorne A; Hom, Jeffrey; Villasis-Keever, Miguel; van der Wouden, Johannes C

    2015-09-03

    The diagnosis of acute bronchitis is made on clinical grounds and a variety of clinical definitions have been used. There are no clearly effective treatments for the cough of acute bronchitis. Beta2-agonists are often prescribed, perhaps because clinicians suspect many patients also have reversible airflow restriction (as seen in asthma or chronic obstructive pulmonary disease (COPD)) contributing to the symptoms. To determine whether beta2-agonists improve acute bronchitis symptoms in people with no underlying pulmonary disease (such as asthma, COPD or pulmonary fibrosis). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2015, Issue 5, MEDLINE (January 1966 to May 2015), EMBASE (1974 to May 2015), Web of Science (2011 to May 2015) and LILACS (1982 to May 2015). Randomised controlled trials (RCTs) which allocated people (adults, or children over two years of age) with acute bronchitis or acute cough and without known pulmonary disease to beta2-agonist versus placebo, no treatment or alternative treatment. Three review authors independently selected outcomes and extracted data while blinded to study results. Two review authors independently assessed each trial for risk of bias. We analysed trials in children and adults separately. Two trials of moderate quality in children (n = 134) with no evidence of airflow restriction did not find any benefits from oral beta2-agonists. Five trials in adults (n = 418) had mixed results but overall summary statistics did not reveal any significant benefits from oral (three trials) nor from inhaled (two trials) beta2-agonists. Three studies with low-quality evidence demonstrated no significant differences in daily cough scores, nor in the percentage of adults still coughing after seven days (control group 71%; risk ratio (RR) 0.86, 95% confidence interval (CI) 0.63 to 1.18; 220 participants). In one trial, subgroups with evidence of airflow limitation had lower symptom scores if given beta2-agonists. The

  2. Central precocious puberty and gonadotropin releasing hormone agonist treatment

    NARCIS (Netherlands)

    W. Oostdijk (Wilma)

    1996-01-01

    textabstractIn order to understand the processes occurring during precocious puberty, one needs to specify what is currently known about normal pubertal development. Puberty can be defined as a maturational process of the hypothalamic-pituitarygonadal axis, which results in the development of the go

  3. 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...... matter, metabolizable energy and digestible protein was of the same magnitude for all groups. The beta-agonist had no significant effect on protein digestibility and metabolizability of energy, but daily live weight gain was significantly higher in the treated bulls. The utilization of digested protein...... 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...

  4. The evolving world of GLP-1 agonist therapies for type 2 diabetes.

    Science.gov (United States)

    Baynes, Kevin C R

    2010-04-01

    The glucagon-like peptide-1 (GLP-1) agonist drugs have attractions as a treatment for type 2 diabetes since they positively alter a number of key pathophysiological defects. These include increasing insulin release, reducing glucagon release, slowing gastric emptying and reducing food intake. In numerous clinical trials these agents have been shown to reduce DCCT-aligned HbA(1c) between 0.8% and 1.1% in patients with moderately controlled type 2 diabetes, whilst also being associated with some weight loss. Whilst medium-term safety and side-effect profiles are now well established, there are as yet no long-term studies on the safety of this group of drugs. The place of the GLP-1 agonists in the treatment paradigm for type 2 diabetes will evolve over the next decade.

  5. 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.

  6. CPG-7909 (PF-3512676, ProMune): toll-like receptor-9 agonist in cancer therapy.

    Science.gov (United States)

    Murad, Yanal M; Clay, Timothy M; Lyerly, H Kim; Morse, Michael A

    2007-08-01

    Stimulation of toll-like receptor (TLR)9 activates human plasmacytoid dendritic cells and B cells, and induces potent innate immune responses in preclinical tumor models and in patients. CpG oligodeoxynucleotides (ODNs) are TLR9 agonists that show promising results as vaccine adjuvants and in the treatment of cancers, infections, asthma and allergy. PF-3512676 (ProMune) was developed as a TLR9 agonist for the treatment of cancer as monotherapy and as an adjuvant in combination with chemo- and immunotherapy. Phase I and II trials have tested this drug in several hematopoietic and solid tumors. Pfizer has initiated Phase III trials to test PF-3512676 in combination with standard chemotherapy for non-small-cell lung cancer.

  7. Therapeutic effects of melatonin receptor agonists on sleep and comorbid disorders.

    Science.gov (United States)

    Laudon, Moshe; Frydman-Marom, Anat

    2014-09-09

    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.

  8. 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

  9. β2 adrenergic agonists in acute lung injury? The heart of the matter

    OpenAIRE

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of β2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to in...

  10. Drug evaluation: PRX-00023, a selective 5-HT1A receptor agonist for depression.

    Science.gov (United States)

    de Paulis, Tomas

    2007-01-01

    EPIX Pharmaceuticals Inc (formerly Predix Pharmaceuticals Inc) is developing PRX-00023, an oral aryl piperazine 5-HT1A agonist, for the potential treatment of depression. While initially in development for generalized anxiety disorder, EPIX is now only focusing on the development of PRX-00023 for depression. In November 2006, EPIX reported that it planned to initiate a phase II trial in patients with depression in the first half of 2007.

  11. 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

    2017-08-21

    similar treatment with CP-55,940. PNR-4-20 (i.p.) is active in the cannabinoid tetrad in mice and chronic treatment results in development of less persistent tolerance and no significant withdrawal signs when compared to animals repeatedly exposed to the non-biased full agoinst JWH-018 or Δ(9)-THC. Finally, studies of a structurally similar analog PNR- 4-02 show that it is also a G protein biased hCB1R agonist. It is predicted that cannabinoid agonists that bias hCB1R activation toward G protein, relative to β-arrestin 2 signaling, will produce fewer and less severe adverse effects both acutely and chronically. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. μ-Opioid Agonist Inhibition of κ-Opioid Receptor-Stimulated Extracellular Signal-Regulated Kinase Phosphorylation Is Dynamin-Dependent in C6 Glioma Cells

    OpenAIRE

    Bohn, Laura M.; Belcheva, Mariana M.; Coscia, Carmine J.

    2000-01-01

    In previous studies we found that μ-opioids, acting via μ-opioid receptors, inhibit endothelin-stimulated C6 glioma cell growth. In the preceding article we show that the κ-selective opioid agonist U69,593 acts as a mitogen with a potency similar to that of endothelin in the same astrocytic model system. Here we report that C6 cell treatment with μ-opioid agonists for 1 h results in the inhibition of κ-opioid mitogenic signaling. The μ-selective agonist endomorphin-1 attenuates κ-opioid-stimu...

  13. The importance of β2-agonists in myocardial infarction

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  14. Estrogen receptor beta agonists in neurobehavioral investigations.

    Science.gov (United States)

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

    2008-07-01

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

  15. Combining GLP-1 receptor agonists with insulin

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Vilsbøll, T

    2013-01-01

    Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among...... physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose......, compared with insulin, the antihyperglycaemic efficacy of GLP-1RAs is limited. The combination of a GLP-1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic...

  16. Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes.

    Science.gov (United States)

    Hinnen, Deborah

    2017-08-01

    The incretin system has become an important target in the treatment of type 2 diabetes in recent years, and glucagon-like peptide 1 (GLP-1) is of particular interest for its glucose-lowering effects. The physiological response to oral ingestion of nutrients, involving the incretin system, is reduced in some patients with type 2 diabetes but may be augmented by administration of GLP-1 receptor agonists. The GLP-1 receptor agonists currently approved in the United States for the treatment of type 2 diabetes include exenatide (administered twice daily), liraglutide and lixisenatide (administered once daily), and the once-weekly agents exenatide extended-release, albiglutide, and dulaglutide. These agents have been shown to reduce A1C (by ∼0.8-1.6%), body weight (by ∼1-3 kg), blood pressure, and lipids. GLP-1 receptor agonists are associated with a low risk of hypoglycemia, and the most common adverse effects are gastrointestinal. Proper patient selection and education can assist in achieving positive treatment outcomes.

  17. A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent

    Directory of Open Access Journals (Sweden)

    Eun Ju Oh

    2016-04-01

    Full Text Available BW723C86, a serotonin receptor 2B agonist, has been investigated as a potential therapeutic for various conditions such as anxiety, hyperphagia and hypertension. However, the functional role of BW723C86 against melanogenesis remains unclear. In this study, we investigate the effect of serotonin receptor 2B (5-HTR2B agonist on melanogenesis and elucidate the mechanism involved. BW723C86 reduced melanin synthesis and intracellular tyrosinase activity in melan-A cells and normal human melanocytes. The expression of melanogenesis-related proteins (tyrosinase, TRP-1 and TRP-2 and microphthalmia-associated transcription factor (MITF in melan-A cells decreased after BW723C86 treatment. The promoter activity of MITF was also reduced by BW723C86 treatment. The reduced level of MITF was associated with inhibition of protein kinase A (PKA and cAMP response element-binding protein (CREB activation by BW723C86 treatment. These results suggest that the serotonin agonist BW723C86 could be a potential therapeutic agent for skin hyperpigmentation disorders.

  18. 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.

  19. Modification of formalin-induced nociception by different histamine receptor agonists and antagonists.

    Science.gov (United States)

    Farzin, Davood; Nosrati, Farnaz

    2007-01-15

    The present study evaluated the effects of different histamine receptor agonists and antagonists on the nociceptive response in the mouse formalin test. Intracerebroventricular (20-40 microg/mouse i.c.v.) or subcutaneous (1-10 mg/kg s.c.) injection of HTMT (H(1) receptor agonist) elicited a dose-related hyperalgesia in the early and late phases. Conversely, intraperitoneal (20 and 30 mg/kg i.p.) injection of dexchlorpheniramine (H(1) receptor antagonist) was antinociceptive in both phases. At a dose ineffective per se, dexchlorpheniramine (10 mg/kg i.p.) antagonized the hyperalgesia induced by HTMT (40 mug/mouse i.c.v. or 10 mg/kg s.c.). Dimaprit (H(2) receptor agonist, 30 mg/kg i.p.) and ranitidine (H(2) receptor antagonist, 20 and 40 mg/kg i.p.) reduced the nociceptive responses in the early and late phases. No significant change in the antinociceptive activity was found following the combination of dimaprit (30 mg/kg i.p.) with ranitidine (10 mg/kg i.p.). The antinociceptive effect of dimaprit (30 mg/kg i.p.) was prevented by naloxone (5 mg/kg i.p.) in the early phase or by imetit (H(3) receptor agonist, 25 mg/kg i.p.) in both early and late phases. The histamine H(3) receptor agonist imetit was hyperalgesic following i.p. administration of 50 mg/kg. Imetit-induced hyperalgesia was completely prevented by treatment with a dose ineffective per se of thioperamide (H(3) receptor antagonist, 5 mg/kg i.p.). The results suggest that histamine H(1) and H(3) receptor activations increase sensitivity to nociceptive stimulus in the formalin test.

  20. Antineoplastic Effects of PPARγ Agonists, with a Special Focus on Thyroid Cancer.

    Science.gov (United States)

    Ferrari, Silvia Martina; Materazzi, Gabriele; Baldini, Enke; Ulisse, Salvatore; Miccoli, Paolo; Antonelli, Alessandro; Fallahi, Poupak

    2016-01-01

    Peroxisome Proliferator-Activated Receptor-γ (PPARγ) is a ligand-activated nuclear hormone receptor that functions as transcription factor and plays an important role in lipid metabolism and insulin sensitization. Recent studies have shown that PPARγ is overexpressed in many tumor types, including cancers of breast, lung, pancreas, colon, glioblastoma, prostate and thyroid differentiated/anaplastic cancers. These data suggest a role of PPARγ in tumor development and/or progression. PPARγ is emerging as a growth-limiting and differentiation-promoting factor, and it exerts a tumor suppressor role. Moreover, naturally-occurring and synthetic PPARγ agonists promote growth inhibition and apoptosis. Thiazolidinediones (TZDs) are synthetic agonists of PPARγ that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPARγ agonist activity. Various preclinical and clinical studies strongly suggest a role for TZDs both alone and in combination with existing chemotherapeutic agents, for the treatment of cancer. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells, targeting pathways capable of re-activating blocked terminal differentiation programs. PPARγ agonists have been shown to induce differentiation in solid tumors such as thyroid differentiated/ anaplastic cancers and sarcomas. However, emerging data suggest that chronic use of TZDs is associated with increased risk of adverse cardiovascular events. The exploration of newer PPARγ agonists can help in unveiling the underlying mechanisms of these drugs, providing new molecules that are able to treat cancer, without increasing the cardiovascular risk of neoplastic patients.

  1. The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa.

    Science.gov (United States)

    Frank, Guido K W; Shott, Megan E; Hagman, Jennifer O; Schiel, Marissa A; DeGuzman, Marisa C; Rossi, Brogan

    2017-04-01

    Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience-based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine-related reward circuits are hypersensitive and could provide a treatment target. Here, we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program. The results show that aripiprazole treatment was associated with greater increase in body mass index (BMI) during treatment. The use of dopamine receptor agonists may support treatment success in anorexia nervosa and should be further investigated. © 2017 Wiley Periodicals, Inc.

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

    Science.gov (United States)

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

    2011-09-01

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

  3. GnRHa联合反向添加疗法治疗子宫内膜异位症对腰椎骨量的影响%Effect of gonadotropin releasing hormone agonist combined with add - back therapy on bone mineral density of lumbar vertebrae in treatment of endometriosis

    Institute of Scientific and Technical Information of China (English)

    陈珣; 张绍芬

    2012-01-01

    Objective; To research and compare the effects of gonadotropin releasing hormone agonist (GnRHa) combined with percutaneous injection of estrogen and add - back therapy with oral administration of medroxyprogesterone acetate and GnRHa alone on bone mineral density of lumbar vertebrae in treatment of endometriosis. Methods; Twenty - eight patients with endometriosis were selected, all of them were diagnosed definitely by laparoscopy within two months, then they were randomly divided into CnRHa alone group (group A) and GnRHa plus add -back therapy group (group B) . The patients in group A were treated with percutaneous injection of Zoladex on the second day during menstrual cycle or at 3 - 5 days after operation; percutaneous injection was conducted every 28 days for three times; while the patients in group B were treated with percutaneous injection of Zoladex on the second day during menstrual cycle or at 3 - 5 days after operation, percutaneous injection was conducted every 28 days for three times, at the same time, half of patch was pasted on the abdominal skin every week from percutaneous injection for the first time, and they were treated with oral administration of medroxyprogesterone acetate (6 mg) every night until the end of treatment Bone mineral density of lumbar vertebrae was measured before treatment, at the same time, peripheral venous blood samples were obtained to detect the levels of estradiol and serum BGP; the above - mentioned indexes were reexam-ined at three months after treatment Results-. In group A, the bone mineral densities of LI - L4 at three months after treatment were significantly lower than those before treatment (P < 0. 01); while in group B, compared with before treatment, the bone mineral densities of LI -L4 at three months after treatment showed decreasing trends, but there was no significant difference (P =0. 201) . In group A, the serum level of BGP after treatment was significantly higher than that before treatment ( P < 0. 01

  4. An in vivo pharmacological evaluation of pardoprunox (SLV308)--a novel combined dopamine D(2)/D(3) receptor partial agonist and 5-HT(1A) receptor agonist with efficacy in experimental models of Parkinson's disease.

    Science.gov (United States)

    Jones, C A; Johnston, L C; Jackson, M J; Smith, L A; van Scharrenburg, G; Rose, S; Jenner, P G; McCreary, A C

    2010-08-01

    Partial D(2/3) dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease (PD) that may avoid common dopaminergic side-effects, including dyskinesia and psychosis. The present study focussed on the in vivo pharmacological and therapeutic characterisation of the novel D(2/3) receptor partial agonist and full 5-HT(1A) receptor agonist pardoprunox (SLV308; 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monochloride). Pardoprunox induced contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED=0.03mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED=0.03mg/kg; po) and decreased motor disability (MED=0.03mg/kg; po). The effects of pardoprunox were reversed by the D(2) antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED=0.01mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED=0.3mg/kg; po) and apomorphine-induced climbing (MED=0.6mg/kg; po) in rodents. Pardoprunox also induced 5-HT(1A) receptor-mediated behaviours, including flat body posture and lower lip retraction (MED=0.3mg/kg; po) and these were reversed by the 5-HT(1A) receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional DA D(2) receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD. The presence of functional 5-HT(1A) agonist activity might confer anti-dyskinetic activity and have effects that control neuropsychiatric components of PD.

  5. Extract of Kuding tea prevents high-fat diet-induced metabolic disorders in C57BL/6 mice via liver X receptor (LXR β antagonism.

    Directory of Open Access Journals (Sweden)

    Shengjie Fan

    Full Text Available OBJECTIVE: To investigate the effects of ilex kudingcha C. J. Tseng (kuding tea, a traditional beverage in China, on the metabolic disorders in C57BL/6 mice induced by high-fat diets. DESIGN: For the preventive experiment, the female C57BL/6 mice were fed with a standard diet (Chow, high-fat diet (HF, and high-fat diet mixed with 0.05% ethanol extract of kuding tea (EK for 5 weeks. For the therapeutic experiment, the C57BL/6 mice were fed high-fat diet for 3 months, and then mice were split and EK was given with oral gavages for 2 weeks at 50 mg/day/kg. Body weight and daily food intake amounts were measured. At the end of treatment, the adipocyte images were assayed with a scanning electron microscope, and the fasting blood glucose, glucose tolerance test, serum lipid profile and lipids in the livers were analyzed. A reporter gene assay system was used to test the whether EK could act on nuclear receptor transcription factors, and the gene expression analysis was performed with a quantitative PCR assay. RESULTS: In the preventive treatment, EK blocked the body weight gain, reduced the size of the adipocytes, lowered serum triglyceride, cholesterol, LDL-cholesterol, fasting blood glucose levels and glucose tolerance in high-fat diet-fed C57BL/6 mice. In the therapeutic treatment, EK reduced the size of the white adipocytes, serum TG and fasting blood glucose levels in obese mice. With the reporter assay, EK inhibited LXRβ transactivity and mRNA expression of LXRβ target genes. CONCLUSION: We observed that EK has both preventive and therapeutic roles in metabolic disorders in mice induced with high-fat diets. The effects appear to be mediated through the antagonism of LXRβ transactivity. Our data indicate that kuding tea is a useful dietary therapy and a potential source for the development of novel anti-obesity and lipid lowering drugs.

  6. 肝X受体激动剂诱导获得的小鼠耐受性树突状细胞与天然耐受性树突状细胞的比较%Comparison between mouse tolerant dendritic cells induced by liver X receptor agonist and natural tolerant dendritic cells

    Institute of Scientific and Technical Information of China (English)

    徐海燕; 马旭怡; 董盼盼; 薛冬; 何小舟

    2015-01-01

    目的 通过与天然耐受性树突状细胞(N-tDCs)比较来探讨肝X受体(LXR)激动剂诱导获得的小鼠耐受性树突状细胞T-tDCs的免疫耐受特性.方法 获取小鼠骨髓来源单个核细胞,以白细胞介素(IL)-4和粒细胞-巨噬细胞集落刺激因子(GM-CSF)辅以LXR激动剂(T0901317)诱导7d后,检测细胞表型、进行混合淋巴细胞反应、调节性T细胞(Tregs)体外诱导实验等;或继续以脂多糖(LPS)诱导其成熟,进行表型分析.利用BALB/c DO11.10 RAG-/-小鼠来源的CD4+T细胞进行Tregs诱导实验,并与磁珠阴性分选从小鼠脾脏获得CD4+ DCs (N-tDCs)进行对照研究.结果 与N-tDCs比较,T0901317诱导7d时的T-tDCs形态更接近普通DCs,CD80、CD86、MHC-Ⅱ类分子表达略低,但均为中低表达,CCR7表达水平相近.N-tDCs具有更强的抑制能力,当特异性抗原鸡卵清白蛋白(OVA)存在时,N-tDCs可以更强地诱导Tregs的生成,而T-tDCs可以分泌更高水平的IL-10.结论 T-tDCs与N-tDCs以不同的方式发挥免疫抑制作用.%Objective To explore the characteristics of tolerant dendritic cells (tDCs) induced by liver X receptor (LXR) agonist by comparing with natural tDCs (N-DCs).Methods Mononuclear cells from mouse bone marrow were stimulated by interleukin (IL)-4 and granulocyte-macrophage colony stimulating factor (GM-CSF) in the presence or absence of the stimulation by LXR agonist-T0901317 for 7 days,or induced by lipopolysaccharide (LPS) for 3 days.Then phenotype detection,mixed lymphocyte reaction (MLR),and regulatory T cells (Tregs) induction assay were performed.CD4 + T cells purified from BALB/c DO11.10 RAG-/-mouse were used in Tregs induction assay.N-tDCs isolated from mouse spleen were used as controls.Results Compared with N-tDCs,the morphology of T-tDCs induced by T0901317 for 7 days were similar to normal DCs',but with little lower or moderate expression levels of CD80,CD86 and MHC-Ⅱ.Stronger inhibitory effect of N-tDCs was observed,and their

  7. Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 in Regulating Central Nervous System Function

    OpenAIRE

    Noetzel, Meredith J.; Rook, Jerri M.; Vinson, Paige N.; Cho, Hyekyung P.; Days, Emily; Zhou, Y.; Rodriguez, Alice L.; Lavreysen, Hilde; Stauffer, Shaun R.; Niswender, Colleen M.; Xiang, Zixiu; Daniels, J. Scott; Jones, Carrie K.; Lindsley, Craig W.; Weaver, C. David

    2012-01-01

    Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have emerged as an exciting new approach for the treatment of schizophrenia and other central nervous system (CNS) disorders. Of interest, some mGlu5 PAMs act as pure PAMs, only potentiating mGlu5 responses to glutamate whereas others [allosteric agonists coupled with PAM activity (ago-PAMs)] potentiate responses to glutamate and have intrinsic allosteric agonist activity in mGlu5-expressing cell lines....

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

    NARCIS (Netherlands)

    Schmidt, Martina; Michel, Martin C.

    2011-01-01

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

  9. 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

    The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previous...

  10. Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats

    DEFF Research Database (Denmark)

    Castoldi, Giovanna; di Gioia, Cira Rt; Bombardi, Camila

    2014-01-01

    Aim of the study was to evaluate the effect of compound 21 (C21), selective AT2 receptor agonist, in diabetic nephropathy and the potential additive effect of C21, when associated to losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The ...

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

    NARCIS (Netherlands)

    Schmidt, Martina; Michel, Martin C.

    2011-01-01

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

  12. Exenatide, a Glucagon-like Peptide-1 Receptor Agonist, Acutely Inhibits Intestinal Lipoprotein Production in Healthy Humans

    NARCIS (Netherlands)

    Xiao, Changting; Bandsma, Robert H. J.; Dash, Satya; Szeto, Linda; Lewis, Gary F.

    Objective-Incretin-based therapies for the treatment of type 2 diabetes mellitus improve plasma lipid profiles and postprandial lipemia, but their exact mechanism of action remains unclear. Here, we examined the acute effect of the glucagon-like peptide-1 receptor agonist, exenatide, on intestinal

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  14. The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Andersen, Maibritt B; Fink-Jensen, Anders; Peacock, Linda

    2003-01-01

    Xanomeline is a muscarinic M(1)/M(4) preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects ...... that xanomeline inhibits D-amphetamine- and (-)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis....

  15. Short-term desensitization of muscarinic cholinergic receptors in mouse neuroblastoma cells: selective loss of agonist low-affinity and pirenzepine high-affinity binding sites

    Energy Technology Data Exchange (ETDEWEB)

    Cioffi, C.L.; el-Fakahany, E.E.

    1986-09-01

    The effects of brief incubation with carbamylcholine on subsequent binding of (/sup 3/H)N-methylscopolamine were investigated in mouse neuroblastoma cells (clone N1E-115). This treatment demonstrated that the muscarinic receptors in this neuronal clone can be divided into two types; one which is readily susceptible to regulation by receptor agonists, whereas the other is resistant in this regard. In control cells, both pirenzepine and carbamylcholine interacted with high- and low-affinity subsets of muscarinic receptors. Computer-assisted analysis of the competition between pirenzepine and carbamylcholine with (/sup 3/H)N-methylscopolamine showed that the receptor sites remaining upon desensitization are composed mainly of pirenzepine low-affinity and agonist high-affinity binding sites. Furthermore, there was an excellent correlation between the ability of various muscarinic receptor agonists to induce a decrease in consequent (/sup 3/H)N-methylscopolamine binding and their efficacy in stimulating cyclic GMP synthesis in these cells. Thus, only the agonists that are known to recognize the receptor's low-affinity conformation in order to elicit increases in cyclic GMP levels were capable of diminishing ligand binding. Taken together, our present results suggest that the receptor population that is sensitive to regulation by agonists includes both the pirenzepine high-affinity and the agonist low-affinity receptor binding states. In addition, the sensitivity of these receptor subsets to rapid regulation by agonists further implicates their involvement in desensitization of muscarinic receptor-mediated cyclic GMP formation.

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

    Science.gov (United States)

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

    2012-02-01

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

  17. Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity-related metabolic disease.

    Science.gov (United States)

    Abegg, Kathrin; Bernasconi, Lara; Hutter, Melanie; Whiting, Lynda; Pietra, Claudio; Giuliano, Claudio; Lutz, Thomas A; Riediger, Thomas

    2017-05-24

    Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand-independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR-IA) might be effective for the treatment of obesity-related metabolic disease, we tested 2 novel synthetic compounds GHSR-IA1 and GHSR-IA2. In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR-IA1 and GHSR-IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet-induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids. Both compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR-IA1 increased metabolic rate in chow-fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR-IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair-fed and vehicle-treated mice. GHSR-IA2-treated DIO mice showed decreased blood lipids. GHSR-IA1 treatment markedly decreased HS in DIO mice. Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity-related metabolic disorders including diabetes mellitus. © 2017 John Wiley & Sons Ltd.

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

    Science.gov (United States)

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

    2016-09-01

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

  19. Effects of histamine H1R-H4R-agonist on the airway epithelium of rabbits

    Institute of Scientific and Technical Information of China (English)

    Naushad A Dilkash; Trivendra Tripathi; Aijaz Ahmed Khan; Mohd Shahid; Haris M Khan; Mashiatullah Siddiqui; Rahat Ali Khan

    2010-01-01

    Objective: To explore the exact role of histamine receptors in respiratory system. Methods:The cohort comprised of six groups (group I control and group II-VI treated) containing five rabbits in each group. Control-group received vehicle (sterile distilled water) and treated groups received subcutaneous histamine (100μg/kg, b.i.d.), and H1R-agonist (HTMT), H2R-agonist (amthamine), H3R-agonist (R-(-)-α-methylhistamine) and H4R-agonist (clobenpropit) each in a dose of 10μg/kg, b.i.d. for 30 subsequent days. After completion of treatment, animals were euthanized and perfused with 10%buffered formalin. Small tissue blocks of trachea and lungs were processed for paraffin embedding. Observations were recorded in sample photomicrographs taken from 10μm thick. Haematoxylin and eosin stained sections. Results:It was observed that trachea and bronchi from histamine, H1R and H4R groups had only patches of hyperplastic and hypertrophied epithelium and in general, cells in the affected region were taller heaped up. The bronchiolar epithelia from all treated groups showed hypertrophy and hyperplasia throughout with most of the cells having rounded profile and appeared to bud out from the basal cells. Conclusions:It is concluded that histamine receptors on induction via its specific agonist can induce hypertrophy, hyperplasia of respiratory tract epithelia suggesting its role akin to growth stimulating factor and warranting further long-term study.

  20. Role of indacaterol and the newer very long-acting β2-agonists in patients with stable COPD: a review

    Directory of Open Access Journals (Sweden)

    Ridolo E

    2013-09-01

    Full Text Available Erminia Ridolo,1 Marcello Montagni,1 Elisa Olivieri,1 Gian Galeazzo Riario-Sforza,2 Cristoforo Incorvaia2 1Department of Clinical and Experimental Medicine, University of Parma, Parma, 2Pulmonary Rehabilitation Unit, ICP Hospital, Milan, Italy Abstract: Bronchodilators are central drugs in the management of patients with chronic obstructive pulmonary disease (COPD. Indacaterol was the first agent of the novel family of very long-acting β2-agonists to be used as an inhaled bronchodilator for COPD and provides 24-hour therapeutic action, thus allowing once-daily administration. Data from clinical trials show that indacaterol has a bronchodilator effect similar to that of the anticholinergic tiotropium bromide and slightly higher efficacy compared with the long-acting β2-agonists, salmeterol and formoterol. Moreover, the safety profile is excellent and comparable with that of placebo. Concerning adherence with drug treatment and real-life management in respect to long-acting β2-agonists, once-daily dosing makes indacaterol more convenient for COPD patients and is likely to enhance patient adherence. Other very long-acting β2-agonists currently in development include vilanterol, olodaterol, and carmoterol, and these have shown good characteristics for clinical use in the studies reported thus far. Keywords: chronic obstructive pulmonary disease, bronchodilators, very long-acting β2-agonists

  1. Identification of oligomer proanthocyanidins (F2) isolated from grape seeds as a formyl peptide receptor 1 partial agonist.

    Science.gov (United States)

    Yang, Jingyu; Wang, Qing; Zhao, Ruijun; Sun, Baoshan; Wang, Lihui; Hou, Yue; Li, Xiaoqin; Wu, Chunfu

    2013-04-01

    Formyl peptide receptor 1 (FPR1) plays an important role in the rapid progression of glioblastoma and has been considered as a molecular target for the treatment. Previously, we have shown that oligomer proanthocyanidins (F2, degree of polymerization 2-15), isolated from grape seeds, inhibited FPR1-mediated chemotaxis of U-87 glioblastoma cells. In the present study, we investigated the capacity of F2 to interact with FPR1. The cross attenuation of chemotaxis revealed that F2 shared FPR1 with formyl-methionyl-leucyl-phenylalanine (fMLF), which is a prototype agonist of FPR1. F2 was chemotactic for U-87 cells, and the chemotactic response was abolished when FPR1 gene was silenced or FPR1 was competitively occupied. We further show that F2 specifically blocked the binding of fluorescent agonist to FPR1. Interestingly, F2 exhibited the characteristic of a partial agonist for FPR1, as shown by its capacity to activate FPR1-mediated PI3K-PKC-MAPK pathways. Meanwhile, F2 also attenuated fMLF-triggered MAPK activation, suggesting that F2 could antagonize the effect of an agonist. Furthermore, F2 abolished the invasion of U-87 cells induced by fMLF. Thus, we have identified F2 as a novel, partial agonist for FPR1, which may be useful for glioblastoma therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

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

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    Maharjan Anu S

    2010-11-01

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

  3. 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.

  4. Agonistic antibodies reveal the function of GPR56 in human glioma U87-MG cells.

    Science.gov (United States)

    Ohta, Shigeyuki; Sakaguchi, Sayaka; Kobayashi, Yuki; Mizuno, Norikazu; Tago, Kenji; Itoh, Hiroshi

    2015-01-01

    GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) and is highly expressed in parts of tumor cells. The involvement of GPR56 in tumorigenesis has been reported. We generated agonistic monoclonal antibodies against human GPR56 and analyzed the action and signaling pathway of GPR56. The antibodies inhibited cell migration through the Gq and Rho pathway in human glioma U87-MG cells. Co-immunoprecipitation analysis indicated that the interaction between the GPR56 extracellular domain and transmembrane domain was potentiated by agonistic antibodies. These results demonstrated that functional antibodies are invaluable tools for GPCR research and should open a new avenue for therapeutic treatment of tumors.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

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

    Science.gov (United States)

    Kreek, M J

    2000-01-01

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

  7. A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis.

    Science.gov (United States)

    Kao, W; Gu, R; Jia, Y; Wei, Xuemin; Fan, H; Harris, J; Zhang, Zhiyi; Quinn, J; Morand, E F; Yang, Y H

    2014-09-01

    Annexin A1 (AnxA1) is an endogenous anti-inflammatory protein and agonist of the formyl peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune-mediated disease has been little explored. We investigated the effects of a synthetic FPR agonist on joint disease in the K/BxN model of rheumatoid arthritis (RA) and RA fibroblast-like synoviocytes (FLS). Arthritis was induced by injection of K/BxN serum at day 0 and 2 in wild-type (WT) or AnxA1(-/-) mice and clinical and histopathological manifestations measured 8-11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg·kg(-1) i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL-induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages. Treatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF-α and osteoclast-associated gene expression. Deletion of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL-6 secretion by mouse macrophages. In human RA joint-derived FLS and monocyte-derived macrophages, Cpd43 treatment inhibited IL-6 release, while blocking FPR2 or silencing AnxA1 increased this release. The FPR agonist Cpd43 reduced osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti-inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents capable of ameliorating inflammation and bone damage in RA. © 2014 The British Pharmacological Society.

  8. Effects of GABAB receptor agonists and antagonists on glycemia regulation in mice.

    Science.gov (United States)

    Bonaventura, María M; Crivello, Martín; Ferreira, María Laura; Repetto, Martín; Cymeryng, Cora; Libertun, Carlos; Lux-Lantos, Victoria A

    2012-02-29

    γ-Aminobutyric acid (GABA) inhibits insulin secretion through GABA(B) receptors in pancreatic β-cells. We investigated whether GABA(B) receptors participated in the regulation of glucose homeostasis in vivo. BALB/c mice acutely pre-injected with the GABA(B) receptor agonist baclofen (7.5mg/kg, i.p.) presented glucose intolerance and diminished insulin secretion during a glucose tolerance test (GTT, 2g/kg body weight, i.p.). The GABA(B) receptor antagonist 2-hydroxysaclofen (15 mg/kg, i.p.) improved the GTT and reversed the baclofen effect. Also a slight increase in insulin secretion was observed with 2-hydroxysaclofen. In incubated islets 1.10(-5)M baclofen inhibited 20mM glucose-induced insulin secretion and this effect was reversed by coincubation with 1.10(-5)M 2-hydroxysaclofen. In chronically-treated animals (18 days) both the receptor agonist (5mg/kg/day i.p.) and the receptor antagonist (10mg/kg/day i.p.) induced impaired GTTs; the receptor antagonist, but not the agonist, also induced a decrease in insulin secretion. No alterations in insulin tolerance tests, body weight and food intake were observed with the treatments. In addition glucagon, insulin-like growth factor I, prolactin, corticosterone and growth hormone, other hormones involved in glucose metabolism regulation, were not affected by chronic baclofen or 2-hydroxysaclofen. In islets obtained from chronically injected animals with baclofen, 2-hydroxysaclofen or saline (as above), GABA(B2) mRNA expression was not altered. Results demonstrate that GABA(B) receptors are involved in the regulation of glucose homeostasis in vivo. Treatment with receptor agonists or antagonists, given acutely or chronically, altered glucose homeostasis and insulin secretion alerting to the need to evaluate glucose metabolism during the clinical use of these drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Comparison of efficacy of bromocriptine and cabergoline to GnRH agonist in a rat endometriosis model.

    Science.gov (United States)

    Ercan, Cihangir Mutlu; Kayaalp, Oya; Cengiz, Mehmet; Keskin, Ugur; Yumusak, Nihat; Aydogan, Umit; Ide, Tayfun; Ergun, Ali

    2015-05-01

    To determine the effect of dopamine agonists in a surgically induced endometriosis model on rats. In this prospective randomized experimental study, surgical induction of endometriosis was performed by autotransplantation technique on 52 adult female Wistar-Albino rats. Endometriosis formation was confirmed by a second-look laparotomy (n:48) 1 month later. Four study groups were randomly generated according to their treatment regimens: group 1 (leuprolide acetate, n = 12), group 2 (bromocriptine, n = 12), group 3 (cabergoline, n = 12) and group 4 (control, n = 12). Endometriotic implants were excised for histopathological examination after treatment at the setting of laparotomy. The mean surface areas and histopathological glandular tissue (GT) and stromal tissue (ST) scores of endometriotic implants were studied and compared among groups. After 30 days of treatment, the mean surface area of the endometriotic implants of leuprolide acetate, bromocriptine and cabergoline groups was significantly decreased. The regression of endometriotic foci size in comparison to control was highest in group 1, followed by group 2, then group 3. In the histopathological evaluation both the ST and GT scores of group 1, 2 and 3 were significantly decreased in comparison to controls without a statistically significant difference between the groups. Dopamine agonists are as effective as GnRH agonists in the regression of experimental endometriotic implants in rats. Further trials are needed to elucidate the pathways affected by dopamine agonists.

  10. Delayed cardioprotection is mediated via a non-peptide delta opioid agonist, SNC-121, independent of opioid receptor stimulation.

    Science.gov (United States)

    Patel, Hemal H; Hsu, Anna; Gross, Garrett J

    2004-01-01

    Acute cardioprotection is mediated primarily through delta opioid receptor stimulation independent of micro or kappa opioid receptor stimulation. Delayed cardioprotection is mediated by delta opioid receptor agonists but ambiguity remains about direct receptor involvement. Therefore, we investigated the potential of SNC-121, a non-peptide delta opioid agonist, to produce delayed cardioprotection and characterized the role of opioid receptors in this delayed response. All rats underwent 30 minutes of ischemia followed by 2 hours of reperfusion. SNC-121 induced a significant delayed cardioprotective effect. To determine the nature of this SNC-121-induced delayed cardioprotection, rats were treated with specific opioids receptor antagonists and underwent pertussis toxin (PT) treatment prior to opioid agonist stimulation. Control rats were injected with saline and allowed to recover for 24 hours. Pretreatment and early treatment with opioid receptor antagonists failed to inhibit the delayed protective effects of SNC-121, as did pretreatment with PT. Treatment with a free radical scavenger, 2-mercaptopropionyl glycine, at the time of opioid stimulation attenuated the delayed cardioprotective effects of SNC-121. These data suggest that delayed cardioprotection is stimulated via non-peptide delta opioid agonists by a mechanism unrelated to opioid receptor activation. The mechanism appears to be a non-opioid receptor mediated production of reactive oxygen species that triggers the signaling cascade leading to delayed cardioprotection.

  11. A novel TRPM8 agonist relieves dry eye discomfort.

    Science.gov (United States)

    Yang, Jee Myung; Li, Fengxian; Liu, Qin; Rüedi, Marco; Wei, Edward Tak; Lentsman, Michael; Lee, Hyo Seok; Choi, Won; Kim, Seong Jin; Yoon, Kyung Chul

    2017-06-26

    Physical cooling of the eye surface relieves ocular discomfort, but translating this event to drug treatment of dry eye discomfort not been studied. Here, we synthesized a water-soluble TRPM8 receptor agonist called cryosim-3 (C3, 1-diisopropylphosphorylnonane) which selectively activates TRPM8 (linked to cooling) but not TRPV1 or TRPA1 (linked to nociception) and tested C3 in subjects with mild forms of dry eye disease. A set of 1-dialkylphosphoryalkanes were tested for activation of TRPM8, TRPV1 and TRPA1 receptors in transfected cells. The bioactivity profiles were compared by perioral, topical, and intravenous delivery to anesthetized rats. The selected lead candidate C3 or vehicle (water) was applied with a cotton gauze pad to upper eyelids of patients with dry eye disease (n = 30). Cooling sensation, tear film break-up time (TBUT), basal tear secretion, and corneal staining were evaluated. C3 was then applied four times daily for 2 weeks to patients using a pre-loaded single unit applicator containing 2 mg/mL of C3 in water (n = 20) or water only. TBUT, basal tear secretion, and corneal staining, and three questionnaires surveys of ocular discomfort (VAS scale, OSDI, and CVS symptoms) were analyzed before and at 1 and 2 weeks thereafter. C3 was a selective and potent TRPM8 agonist without TRPV1 or TRPA1 activity. In test animals, the absence of shaking behavior after C3 perioral administration made it the first choice for further study. C3 increased tear secretion in an animal model of dry eye disease and did not irritate when wiped on eyes of volunteers. C3 singly applied (2 mg/ml) produced significant cooling in irritation or pain were reported by any subject. C3 is a promising candidate for study of TRPM8 function on the eye surface and for relief of dry eye discomfort. ISRCTN24802609 and ISRCTN13359367 . Registered 23 March 2015 and 2 September 2015.

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

    Science.gov (United States)

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

    2012-01-12

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

  13. 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.  

  14. Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats.

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    Danielle Doucet

    Full Text Available BACKGROUND: Acute lung injury (ALI and the development of the multiple organ dysfunction syndrome (MODS is a major cause of death in trauma patients. Earlier studies in trauma hemorrhagic shock (T/HS have documented that splanchnic ischemia leading to gut inflammation and loss of barrier function is an initial triggering event that leads to gut-induced ARDS and MODS. Since sex hormones have been shown to modulate the response to T/HS and proestrous (PE females are more resistant to T/HS-induced gut and distant organ injury, the goal of our study was to determine the contribution of estrogen receptor (ERalpha and ERbeta in modulating the protective response of female rats to T/HS-induced gut and lung injury. METHODS/PRINCIPAL FINDINGS: The incidence of gut and lung injury was assessed in PE and ovariectomized (OVX female rats subjected to T/HS or trauma sham shock (T/SS as well as OVX rats that were administered estradiol (E2 or agonists for ERalpha or ERbeta immediately prior to resuscitation. Marked gut and lung injury was observed in OVX rats subjected to T/HS as compared to PE rats or E2-treated OVX rats subjected to T/HS. Both ERalpha and ERbeta agonists were equally effective in limiting T/HS-induced morphologic villous injury and bacterial translocation, whereas the ERbeta agonist was more effective than the ERalpha agonist in limiting T/HS-induced lung injury as determined by histology, Evan's blue lung permeability, bronchoalevolar fluid/plasma protein ratio and myeloperoxidase levels. Similarly, treatment with either E2 or the ERbeta agonist attenuated the induction of the intestinal iNOS response in OVX rats subjected to T/HS whereas the ERalpha agonist was only partially protective. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that estrogen attenuates T/HS-induced gut and lung injury and that its protective effects are mediated by the activation of ERalpha, ERbeta or both receptors.

  15. Toll-like receptor agonists in cancer therapy

    OpenAIRE

    Adams, Sylvia

    2009-01-01

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

  16. Restoration of brain protein synthesis in mature and aged rats by a DA agonist, piribedil.

    Science.gov (United States)

    Bustany, P; Trenque, T; Crambes, O; Moulin, M

    1995-01-01

    Brain ageing affects numerous cerebral metabolic pathways such as cerebral glucose consumption or protein synthesis rate. The pharmacological effect of a mixed D1-D2 dopaminergic agonist, piribedil, on this last metabolism is reported. Cerebral Protein Synthesis Rate (CPSR) was measured by the [35S]L-methionine autoradiographic procedure in 38 main brain regions of 11 and 26-month-old Wistar rats after a 2-month treatment per os at 9 and 30 mg/kg/day with piribedil. Mean decrease of CPSR was -21% during the 15-month ageing we followed, with important local variations. Mean CPSR increased with the two treatments, +25% in mature and +35% in aged rats. Treatments restored CPSR of aged rats to the exact mature subjects levels in quite all the brain regions. No dose-effect or asymetrical modification was statistically revealed for the two treatments. Metabolic increases involved particularly central brain gray structures, especially some DA-targeted brain nuclei concerned with behaviour and learning. This effect argued for a general metabotrophic effect of D1-D2 dopamine stimulation of the brain. The original pattern of local ageing of brain protein synthesis in rat was also incidentally reported. This was the first direct report of a wide and effective metabolic activation of CPSR in the brain during ageing by a curative dopaminergic agonist treatment.

  17. Indacaterol, a once-daily beta2-agonist, versus twice-daily beta₂-agonists or placebo for chronic obstructive pulmonary disease.

    Science.gov (United States)

    Geake, James B; Dabscheck, Eli J; Wood-Baker, Richard; Cates, Christopher J

    2015-01-10

    Indacaterol is an inhaled long-acting beta2-agonist that is administered once daily and has been investigated as a treatment for chronic obstructive pulmonary disease (COPD). Four different doses have been investigated (75 mcg, 150 mcg, 300 mcg and 600 mcg). The relative effects of different doses of once-daily indacaterol in the management of patients with COPD are uncertain. To compare the efficacy and safety of indacaterol versus placebo and alternative twice-daily long-acting beta2-agonists for the treatment of patients with stable COPD. We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), handsearched respiratory journals and meeting abstracts and searched the Novartis trials registry and ClinicalTrials.gov. The date of the most recent search was 8 November 2014. We included all randomised controlled trials comparing indacaterol at any dose versus placebo or alternative long-acting beta2-agonists. Trials were required to be of at least 12 weeks' duration and had to include adults older than 18 years with a confirmed spirometric diagnosis of COPD. Two review authors (JBG, EJD) independently assessed for possible inclusion all citations identified as a result of the search. Disagreements were resolved through discussion or, if required, through resolution by a third review author (RWB). One review author (JBG) extracted data from trials identified by the search and entered these data into Review Manager 5.1 for statistical analysis. Data entry was cross-checked by a second review author (EJD, CJC). A total of 13 trials with 9961 participants were included in the review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta2-agonist comparison. The comparator beta2-agonists were salmeterol, formoterol and eformoterol. One of these trials, with a total of 90 participants, provided no data

  18. 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

    2009-01-01

    A library of robust ghrelin receptor mutants with single substitutions at 22 positions in the main ligand-binding pocket was employed to map binding sites for six different agonists: two peptides (the 28-amino-acid octanoylated endogenous ligand ghrelin and the hexapeptide growth hormone......, and PheVI:23 on the opposing face of transmembrane domain (TM) VI. Each of the agonists was also affected selectively by specific mutations. The mutational map of the ability of L-692,429 and GHRP-6 to act as allosteric modulators by increasing ghrelin's maximal efficacy overlapped with the common....... It is concluded that although each of the ligands in addition exploits other parts of the receptor, a large, common binding site for both small-molecule agonists--including ago-allosteric modulators--and the endogenous agonist is found on the opposing faces of TM-III and -VI of the ghrelin receptor....

  19. nAChR agonist-induced cognition enhancement: integration of cognitive and neuronal mechanisms.

    Science.gov (United States)

    Sarter, Martin; Parikh, Vinay; Howe, William M

    2009-10-01

    The identification and characterization of drugs for the treatment of cognitive disorders has been hampered by the absence of comprehensive hypotheses. Such hypotheses consist of (a) a precisely defined cognitive operation that fundamentally underlies a range of cognitive abilities and capacities and, if impaired, contributes to the manifestation of diverse cognitive symptoms; (b) defined neuronal mechanisms proposed to mediate the cognitive operation of interest; (c) evidence indicating that the putative cognition enhancer facilitates these neuronal mechanisms; (d) and evidence indicating that the cognition enhancer facilitates cognitive performance by modulating these underlying neuronal mechanisms. The evidence on the neuronal and attentional effects of nAChR agonists, specifically agonists selective for a