Abstract The hydrophilic bile acid ursodeoxycholic acid may dissolve cholesterol gallstones and is beneficial in cholestatic liver diseases. The C20 fatty acid‐bile acid conjugate arachidyl amido cholanoic acid (Aramchol) could be a more effective option. We therefore studied its effects on cholesterol crystallization and on bile salt‐induced cytotoxicity. Effects of Aramchol at therapeutically relevant concentrations on crystallization in supersaturated model biles (by microscopy and chemical measurement), on the ternary cholesterol‐taurocholate‐phosphatidylcholine phase diagram, and on micelle ↔ vesicle transitions (by serial dilution or by incubation of cholesterol‐phosphatidylcholine vesicles with taurocholate) were evaluated. Effects on bile salt‐induced cytotoxicity were determined in erythrocytes and CaCo2 cells. Incorporation of Aramchol in model biles did not change micellar cholesterol solubilization, induced a small rightward shift of crystal‐containing zones of the ternary phase diagram, exerted no appreciable effects on vesicle ↔ micelle transitions and had only minor effects on cholesterol crystallization. Bile salt‐induced cytotoxicity was increased by Aramchol in all models. Since Aramchol does not affect cholesterol crystallization, its previously reported beneficial effects in animal gallstone models should relate to other mechanisms. Since Aramchol increases bile salt detergency, it is not likely to be beneficial in cholestatic liver disease.
Two series of gemfibrozil chiral analogues were synthesized and evaluated for their agonistic activity on PPARα receptor, belonging to the transcription factor family. A simple method to synthesize ureidic and thioureidic fibrates is described. Their ability to interact with the PPARα receptor was evaluated by a transactivation assay in comparison with gemfibrozil, with the aim of obtaining new hypolipidemic compounds. Compounds characterized by a methyl and an ethyl group in α-position to the carboxylic group of gemfibrozil showed a good increase of the transcriptional activity of the receptor, and their capability to activate the receptor seems to be effected by the stereochemistry and the size of the substituent on chiral center. The ureidic and thioureidic compounds did not induce PPARα activity. Keywords: PPARs, PPAR agonists, Fibrates, Gemfibrozil chiral analogues, Ureidofibrates, Transactivation assay, gemfibrozil, PPAR receptor, hypolipidemic compounds, Peroxisome proliferator-activated receptors, X receptor, oxidation, fatty acids, lipoprotein metabolism, aryloxyacid, clofibric acid, ureido-thioisobutyric acid, phenylisocyanates, luciferase, alkylphenylthioureas, HDL cholesterol in the rat, GC Perkin-Elmer apparatus, calcium phosphate, Retinoid X Receptor, Peroxisome Proliferator-Activated Receptor, Fold Activation
Primary sclerosing cholangitis (PSC) is a chronic cholestatic syndrome of unknown origin mostly found in males, and characterized by diffuse inflammation and fibrosis of both intra-and extra-hepatic bile ducts.So far, PSC is considered as an autoimmune hepatobiliary disease.In most cases the progression of PSC towards liver cirrhosis and liver failure is slow but irreversible, and liver transplantation is currently the only definitive treatment.In recent years, PSC has been an area of active research worldwide with great interest in etiology, pathogenesis, diagnosis, and therapeutic options such as hydrophilic ursodeoxycholic acid and immunosuppressive agent tacrolimus.Recent updates on clinical and therapeutic aspects of PSC are discussed in the present review.
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