1,721,018 research outputs found
Probiotics VSL#3 protect against development of visceral pain in murine model of irritable bowel syndrome.
No full textTargetting farnesoid-X-receptor: from medicinal chemistry to disease treatment.
No full textAbstract
The farnesoid X receptor (FXRalpha) is a metabolic nuclear receptor and bile acid sensor expressed in the liver and intestine. Physiological studies have shown that FXRalpha exerts regulatory roles in bile acids, lipid and glucose homeostasis. FXR ligands of steroidal and non-steroidal structure have been described. Both ligand groups have shown limitations in preclinical studies regarding their absorption, metabolism, target interactions and intrinsic toxicity. Inhibition of bile acid synthesis and basolateral transporters in the liver as well as reduction of high density lipoprotein (HDL) in the plasma are the major unwanted effect seen with these ligands. Several FXRalpha modulators are currently being generated with the aim of targeting FXRalpha isoforms by exploiting the relative unselectivity of the ligand binding domain of the receptor. Structure-activity relationship studies have shown that FXRalpha could be activated by structurally different ligands and that receptor occupancy by these ligands generate different patterns of gene activation as a results of specific conformational changes of the receptor or differential dislodgement of co-repressor or recruitment of co-activators. Generation of modulators that selectively target specific FXRalpha responsive elements are an interesting strategy to overcome the limitations of currently available FXR ligands
Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders.
No full textAbstract
Bile acids are a family of steroid molecules generated in the liver by cholesterol oxidation. In addition to their role in nutrient absorption, bile acids are signaling molecules that exert genomic and non-genomic effects by activating TGR5 (M-BAR, GP-BAR1 or BG37) a G-protein-coupled receptor, and farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily. Ligands for these receptors might be beneficial in treating disorders of lipid and glucose homeostasis. TGR5 ligands decrease blood glucose levels and increase energy expenditure by promoting intracellular thyroid hormone activation in thermogenically competent tissues. FXR agonists repress the synthesis of endogenous bile acids and reduce triglyceride, cholesterol and glucose plasma levels and are currently being tested in nonalcoholic steatohepatitis. FXR modulators are being developed to target selective gene clusters and avoid the negative impact of FXR on HDL biosynthesis. The development of dual FXR and TGR5 ligands could provide new opportunities for the treatment of lipid and glucose disorders
FXR Activation Reverses Insulin Resistance and Protects Against NASH Development
No full textConference: Digestive Disease Week/110th Annual Meeting of the American-Gastroenterological-Association Location: Chicago, IL Date: MAY 30-JUN 04, 2009
Sponsor(s): Amer Gastroenterol Assoc
Accession Number: WOS:000275277202108
Document Type:Meeting Abstract
Language: Englis
The Bile Acids Receptor TGR5 is an Essential Modulator of Intestinal Membrane Permeability and Exerts Anti-Inflammatory Activities in Rodent Model of Colitis
No full textEssential Role of DNAX Adaptor Protein 12 (DAP12) and Spleen Tyrosine Kinase (Syk) in Inflammation-Driven Immune Dysfunction in Rodent Model of Colitis
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Decoding the role of the nuclear receptor SHP in regulating hepatic stellate cells and liver fibrogenesis
No full textThe small heterodimer partner (SHP) is an orphan nuclear receptor that lacks the DNA binding domain while conserves a putative ligand-binding site, thought that endogenous ligands for this receptor are unknown. Previous studies have determined that SHP activation protects against development of liver fibrosis a process driven by trans-differentiation and activation of hepatic stellate cells (HSCs), a miofibroblast like cell type, involved in extracellular matrix (ECM) deposition. To dissect signals involved in this activity we generated SHP-overexpressing human and rat HSCs. Forced expression of SHP in HSC-T6 altered the expression of 574 genes. By pathway and functional enrichment analyses we detected a cluster of 46 differentially expressed genes involved in HSCs trans-differentiation. Using a isoxazole scaffold we designed and synthesized a series of SHP agonists. The most potent member of this group, ISO-COOH (EC50: 9 μM), attenuated HSCs trans-differentiation and ECM deposition in vitro, while in mice rendered cirrhotic by carbon tetrachloride (CCl4) or α-naphthyl-isothiocyanate (ANIT), protected against development of liver fibrosis as measured by morphometric analysis and expression of α-SMA and α1-collagen mRNAs. In aggregate, present results identify SHP as a counter-regulatory signal for HSCs transactivation and describe a novel class of SHP agonists endowed with anti-fibrotic activity
BAR 501, a Novel GPBAR1 Ligand, Reverses Intestinal and Liver Inflammatory Models Demonstrating That GPBAR1 Is an Essential Modulator of Innate Immunity in Entero-Hepatic Tissues
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