1,721,086 research outputs found
Cyclo-oxygenase (COX) inhibiting nitric oxide donating (CINODs) drugs: a review of their current status
No full textBile Acid-Activated Receptors, Intestinal Microbiota, and the Treatment of Metabolic Disorders
No full textThe composition of the bile acid pool is a function of the microbial metabolism of bile acids in the intestine. Perturbations of the microbiota shape the bile acid pool and modulate the activity of bile acid-activated receptors (BARs) even beyond the gastrointestinal tract, triggering various metabolic axes and altering host metabolism. Bile acids, in turn, can also regulate the composition of the gut microbiome at the highest taxonomic levels. Primary bile acids from the host are preferential ligands for the farnesoid X receptor (FXR), while secondary bile acids from the microbiota are ligands for G-protein-coupled bile acid receptor 1 (GPBAR1). In this review, we examine the role of bile acid signaling in the regulation of intestinal microbiota and how changes in bile acid composition affect human metabolism. Bile acids may offer novel therapeutic modalities in inflammation, obesity, and diabetes
Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders.
No full textThe farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/ activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on hepatocyte's basolateral transporters. Because these effects might worsen liver injury in a subset of patients with obstructive cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however specific FXR antagonists that are currently used in pre-clinical models of liver injury have been identified from marine organisms. PXR agonists are endowed with a wide array of biological activities but their effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development. Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset of patients with liver disorders. In addition, development of tissue specific FXR antagonists is an attractive opportunity to target subsets of genes in the intestine and liver avoiding sideeffects linked to FXR activation
Targetting 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 acids and their receptors in metabolic disorders
No full textBile acids are a large family of atypical steroids which exert their functions by binding to a family of ubiquitous cell membrane and nuclear receptors. There are two main bile acid activated receptors, FXR and GPBAR1, that are exclusively activated by bile acids, while other receptors CAR, LXRs, PXR, RORγT, S1PR2and VDR are activated by bile acids in addition to other more selective endogenous ligands. In the intestine, activation of FXR and GPBAR1 promotes the release of FGF15/19 and GLP1 which integrate their signaling with direct effects exerted by theother receptors in target tissues. This network is tuned in a time ordered manner by circadian rhythm and is critical for the regulation of metabolic process including autophagy, fast-to-feed transition, lipid and glucose metabolism, energy balance and immune responses. In the last decade FXR ligands have entered clinical trials but development of systemic FXR agonists has been proven challenging because their side effects including increased levels of cholesterol and Low Density Lipoproteins cholesterol (LDL-c) and reduced High-Density Lipoprotein cholesterol (HDL-c). In addition, pruritus has emerged as a common, dose related, side effect of FXR ligands. Intestinal-restricted FXR and GPBAR1 agonists and dual FXR/GPBAR1 agonists have been developed. Here we review the last decade in bile acids physiology and pharmacology
Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH)
No full textIntroduction: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) for which therapy is suboptimal. The farnesoid-X-receptor (FXR) and the G protein bile acid receptor (GPBAR)1 are two bile acid-activated receptors that exert regulatory effects on lipid, glucose, energy, and immune homeostasis. GPBAR1 and FXR ligands have shown efficacy in reversing steatohepatitis and fibrosis in preclinical models of NASH. Area covered: This article evaluates the efficacy and pitfalls of GPBAR1 and FXR-based therapies in the treatment of NASH. While there are no GPBAR1 agonist in clinical development, several FXR ligands have completed phase 2 and phase 3 trials in NASH. EDP305, tropifexor, cilofexor, nidufexor, TERN.101, Px-104, EYP001, MET409. Individual FXR agonists have shown variable efficacy in reversing liver steatohepatitis and fibrosis. Class-related, dose-dependent side effects: pruritus, increased plasma levels of cholesterol and LDLc, and reduction of HDL have been reported. Expert opinion: Efficacy of FXR agonists as stand-alone therapy is limited by dose-related side effects. Efficacy of combining an FXR agonist with statins, CCR2, and ACC inhibitors is currently investigated. Identification of patient subsets would allow development of patients tailored therapy using a combination of drugs acting on different molecular mechanisms
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