31 research outputs found
IUPHAR-DB: new receptors and tools for easy searching and visualization of pharmacological data
The IUPHAR database is an established online reference resource for several important classes of human drug targets and related proteins. As well as providing recommended nomenclature, the database integrates information on the chemical, genetic, functional and pathophysiological properties of receptors and ion channels, curated and peer-reviewed from the biomedical literature by a network of experts. The database now includes information on 616 gene products from four superfamilies in human and rodent model organisms: G protein-coupled receptors, voltage- and ligand-gated ion channels and, in a recent update, 49 nuclear hormone receptors (NHRs). New data types for NHRs include details on co-regulators, DNA binding motifs, target genes and 3D structures. Other recent developments include curation of the chemical structures of approximately 2000 ligand molecules, providing electronic descriptors, identifiers, link-outs and calculated molecular properties, all available via enhanced ligand pages. The interface now provides intelligent tools for the visualization and exploration of ligand structure-activity relationships and the structural diversity of compounds active at each target. The database is freely available at http://www.iuphar-db.org
Caracterisation pharmacologique des canaux calciques voltage-dependants dans les myocytes vasculaires lisses
SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc
Sexual Dimorphism in Circadian Physiology Is Altered in LXRα Deficient Mice.
The mammalian circadian timing system coordinates key molecular, cellular and physiological processes along the 24-h cycle. Accumulating evidence suggests that many clock-controlled processes display a sexual dimorphism. In mammals this is well exemplified by the difference between the male and female circadian patterns of glucocorticoid hormone secretion and clock gene expression. Here we show that the non-circadian nuclear receptor and metabolic sensor Liver X Receptor alpha (LXRα) which is known to regulate glucocorticoid production in mice modulates the sex specific circadian pattern of plasma corticosterone. Lxrα(-/-) males display a blunted corticosterone profile while females show higher amplitude as compared to wild type animals. Wild type males are significantly slower than females to resynchronize their locomotor activity rhythm after an 8 h phase advance but this difference is abrogated in Lxrα(-/-) males which display a female-like phenotype. We also show that circadian expression patterns of liver 11ÎČ-hydroxysteroid dehydrogenase type 1 (11ÎČ-HSD1) and Phosphoenolpyruvate carboxykinase (Pepck) differ between sexes and are differentially altered in Lxrα(-/-) animals. These changes are associated with a damped profile of plasma glucose oscillation in males but not in females. Sex specific alteration of the insulin and leptin circadian profiles were observed in Lxα(-/-) females and could be explained by the change in corticosterone profile. Together this data indicates that LXRα is a determinant of sexually dimorphic circadian patterns of key physiological parameters. The discovery of this unanticipated role for LXRα in circadian physiology underscores the importance of addressing sex differences in chronobiology studies and future LXRα targeted therapies
Analysis of Sterol-Regulatory Element-Binding Protein 1c Target Genes in Mouse Liver during Aging and High-Fat Diet
International audienceBackground: The sterol regulatory element-binding protein (SREBP) 1c contributes to the transcriptional coordination of cholesterol, fatty acid, and carbohydrate metabolisms. Alterations in these processes accelerate the progression of hepatic steatosis and insulin resistance during aging and obesity. Methods: Using an ex vivo chromatin immunoprecipitation coupled to microarray (ChIP-on-chip) technique combined with genome-wide gene expression analysis, we analyzed the transcriptomic adaptations mediated by Srebp-1c binding to gene promoters in the liver of mice fed with a low-fat diet or a high-fat diet (HFD) for either 1 or 12 months. Results: Aging had a higher transcriptional impact than HFD and modified the expression of genes involved in fatty acid oxidation and oxidative stress. HFD was associated with a marked induction of genes involved in lipid and cholesterol metabolism. The prolonged high-fat feeding together with the aging effects stimulates inflammatory pathways. ChIP-on-chip applied to aging and HFD analyses revealed that the binding of SREBP-1c to a series of promoters accompanied a paralleled modification of gene expression. Therefore, SREBP-1c could play a role in aging and high-fat feeding through the regulation of genes involved in lipid metabolism and inflammatory response. Conclusions: This study represents an original ex vivo experiment to elucidate the molecular events involved in metabolic disorders. Copyright (C) 2013 S. Karger AG, Base
Modulation of large dense core vesicle insulin content mediates rhythmic hormone release from pancreatic beta cells over the 24h cycle
International audienceThe rhythmic nature of insulin secretion over the 24h cycle in pancreatic islets has been mostly investigated using transcriptomics studies showing that modulation of insulin secretion over this cycle is achieved via distal stages of insulin secretion. We set out to measure ÎČ-cell exocytosis using in depth cell physiology techniques at several time points. In agreement with the activity and feeding pattern of nocturnal rodents, we find that C57/Bl6J islets in culture for 24h exhibit higher insulin secretion during the corresponding dark phase than in the light phase (Zeitgeber Time ZT20 and ZT8, respectively, in vivo). Glucose-induced insulin secretion is increased by 21% despite normal intracellular Ca2+ transients and depolarization-evoked exocytosis, as measured by whole-cell capacitance measurements. This paradox is explained by a 1.37-fold increase in beta cell insulin content. Ultramorphological analyses show that vesicle size and density are unaltered, demonstrating that intravesicular insulin content per granule is modulated over the 24h cycle. Proinsulin levels did not change between ZT8 and ZT20. Islet glucagon content was inversely proportional to insulin content indicating that this unique feature is likely to support a physiological role. Microarray data identified the differential expression of 301 transcripts, of which 26 are miRNAs and 54 are known genes (including C2cd4b, a gene previously involved in insulin processing, and clock genes such as Bmal1 and Rev-erbα). Mouse ÎČ-cell secretion over the full course of the 24h cycle may rely on several distinct cellular functions but late night increase in insulin secretion depends solely on granule insulin content
Analysis of <i>Lxrα</i> and <i>Cyp7α1</i> in liver.
<p><i>Lxrα</i> mRNA expression determined at ZT0 and ZT 12 in WT males and females using qRT-PCR (A). Diurnal mRNA expression of liver <i>Cyp7α1</i> was compared in males (B) and females (C) using qRT-PCR in WT (plain line) and <i>Lxrα</i><sup><i>-/-</i></sup> mice (dashed line). For each time point, 3â4 mice were used. For the <i>Cyp7α1</i> analysis, cosinor-based non-linear regression was used for curve fitting. The ZT0 time point is double plotted for visualization purposes. Expression data were normalized to the constitutively expressed <i>36B4</i> mRNA. The white and black bars represent the light and dark phases, respectively. Statistically significant differences in cosine fitting parameters (p<0.05) between wild type and <i>Lxrα</i><sup><i>-/-</i></sup> mice or between male and female of the same genotype is indicated in the grey box at the top of the corresponding graph or between graphs (WT: plain arrow, <i>Lxrα</i><sup><i>-/-</i></sup>: dashed arrow). ”, α and Ï indicate a difference in mean level, amplitude and acrophase, respectively.</p
Cosinor analysis of plasma CORT circadian pattern in WT and <i>Lxrα</i> <sup><i>-/-</i></sup> mice.
<p>Cosinor analysis of plasma CORT circadian pattern in WT and <i>Lxrα</i> <sup><i>-/-</i></sup> mice.</p
Analysis of circadian gene expression in the adrenals of WT and <i>Lxrα</i><sup><i>-/-</i></sup> mice.
<p>Diurnal mRNA expression of adrenal <i>StAR</i> (A, B), <i>MC2R</i> (C, D), <i>Bmal1</i> (E, F), <i>Per1</i> (G, H) and <i>Rev-erbα</i> (I, J) was compared using qRT-PCR in WT (plain line) and <i>Lxrα</i><sup><i>-/-</i></sup> mice (dashed line). For each time point, 3â4 mice were used. Cosinor-based non-linear regression was used for curve fitting. The ZT0 time point is double plotted for visualization purposes. Expression data were normalized to the constitutively expressed <i>36B4</i> mRNA. The white and black bars represent the light and dark phases, respectively. Statistically significant differences in cosine fitting parameters (p<0.05) between wild type and <i>Lxrα</i><sup><i>-/-</i></sup> mice or between male and female of the same genotype is indicated in the grey box at the top of the corresponding graph or between graphs (WT: plain arrow, <i>Lxrα</i><sup><i>-/-</i></sup>: dashed arrow). ”, α and Ï indicate a difference in mean level, amplitude and acrophase, respectively.</p
Cosinor analysis of circadian gene expression in the adrenals of WT and <i>Lxrα</i><sup><i>-/-</i></sup> mice.
<p>Cosinor analysis of circadian gene expression in the adrenals of WT and <i>Lxrα</i><sup><i>-/-</i></sup> mice.</p