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      Effect of Enterohepatic Circulation on the Accumulation of Per- and Polyfluoroalkyl Substances: Evidence from Experimental and Computational Studies

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          pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures

          Drug development has a high attrition rate, with poor pharmacokinetic and safety properties a significant hurdle. Computational approaches may help minimize these risks. We have developed a novel approach (pkCSM) which uses graph-based signatures to develop predictive models of central ADMET properties for drug development. pkCSM performs as well or better than current methods. A freely accessible web server (http://structure.bioc.cam.ac.uk/pkcsm), which retains no information submitted to it, provides an integrated platform to rapidly evaluate pharmacokinetic and toxicity properties.
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            Bile acids: regulation of synthesis.

            Bile acids are physiological detergents that generate bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of bile acids exerts important physiological functions not only in feedback inhibition of bile acid synthesis but also in control of whole-body lipid homeostasis. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4alpha and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7alpha-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome.
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              Is Open Access

              ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties

              Because undesirable pharmacokinetics and toxicity of candidate compounds are the main reasons for the failure of drug development, it has been widely recognized that absorption, distribution, metabolism, excretion and toxicity (ADMET) should be evaluated as early as possible. In silico ADMET evaluation models have been developed as an additional tool to assist medicinal chemists in the design and optimization of leads. Here, we announced the release of ADMETlab 2.0, a completely redesigned version of the widely used AMDETlab web server for the predictions of pharmacokinetics and toxicity properties of chemicals, of which the supported ADMET-related endpoints are approximately twice the number of the endpoints in the previous version, including 17 physicochemical properties, 13 medicinal chemistry properties, 23 ADME properties, 27 toxicity endpoints and 8 toxicophore rules (751 substructures). A multi-task graph attention framework was employed to develop the robust and accurate models in ADMETlab 2.0. The batch computation module was provided in response to numerous requests from users, and the representation of the results was further optimized. The ADMETlab 2.0 server is freely available, without registration, at https://admetmesh.scbdd.com/ . Graphical Abstract ADMETlab 2.0 assists medicinal chemists in the design and optimization of lead compounds.
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                Author and article information

                Contributors
                Journal
                Environmental Science & Technology
                Environ. Sci. Technol.
                American Chemical Society (ACS)
                0013-936X
                1520-5851
                March 01 2022
                February 09 2022
                March 01 2022
                : 56
                : 5
                : 3214-3224
                Affiliations
                [1 ]Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Institute of Environment and Health, Jianghan University, Wuhan 430056, China
                [2 ]Key Laboratory of Optoelectronic Chemical Materials and Devices, Ministry of Education, School of Chemical and Environmental Engineering, Jianghan University, Wuhan 430056, China
                [3 ]College of Resources and Environment, Huazhong Agricultural University, Wuhan 430070, China
                [4 ]State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
                [5 ]MTM Research Centre, School of Science and Technology, Örebro University, Örebro 70182, Sweden
                Article
                10.1021/acs.est.1c07176
                35138827
                3157c381-5fa0-459e-bda6-d5f5db527347
                © 2022

                https://doi.org/10.15223/policy-029

                https://doi.org/10.15223/policy-037

                https://doi.org/10.15223/policy-045

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