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Xuan Wang, Shuo Li, Man Chen, Jing Liu, Ruirui Dong, Humin Wang, Shigong Zhu
The farnesoid X receptor (FXR) plays an important role in bile acid metabolism, intestinal homeostasis, and intestinal ischemia-reperfusion (I/R) injury. We aimed to clarify the potential effects of FXR on intestinal epithelial cell tolerance to intestinal I/R injury and reveal the underlying mechanisms. An intestinal I/R injury model was established by the occlusion of the superior mesenteric artery for ischemia for 1 h, followed by reperfusion for 4 h in C57BL/6 (wild-type; WT)and FXR mice. The small intestine injury was assessed by histological analysis...
October 12, 2017: Shock
Laurent Ehrlich, Shannon S Glaser
No abstract text is available yet for this article.
October 10, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Kris V Kowdley, Velimir Luketic, Roger Chapman, Gideon M Hirschfield, Raoul Poupon, Christoph Schramm, Catherine Vincent, Christian Rust, Albert Parés, Andrew Mason, David Shapiro, Luciano Adorini, Cathi Sciacca, Tessa Beecher-Jones, Olaf Böhm, Richard Pencek, David Jones
BACKGROUND: Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled Phase 2 study in patients with primary biliary cholangitis (PBC) who were then reported for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of UDCA, which is relevant for patients who are intolerant of UDCA and at higher risk of disease progression. METHODS: Patients were randomized and dosed with placebo (n=23), OCA 10-mg (n=20), or OCA 50-mg (n=16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing)...
October 10, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Wei Jia, Guoxiang Xie, Weiping Jia
Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states...
October 11, 2017: Nature Reviews. Gastroenterology & Hepatology
Xiaoguang Gao, Ting Fu, Changyuan Wang, Chenqing Ning, Yulong Kong, Zhihao Liu, Huijun Sun, Xiaodong Ma, Kexin Liu, Qiang Meng
Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a novel therapeutic strategy against cholestasis. Herein, we used a novel computational strategy with two-dimensional virtual screening for FXR agonists. For the first time, we found that auraptene (AUR), a natural product, can activate FXR to exert hepatoprotective effect against cholestatic liver injury in vivo and in vitro. Importantly, AUR was found to significantly decrease the mortality of cholestatic mice...
October 4, 2017: Biochemical Pharmacology
Ying-Duo Gao, Yuan Hu, Alejandro Crespo, Deping Wang, Kira A Armacost, James I Fells, Xavier Fradera, Hongwu Wang, Huijun Wang, Brad Sherborne, Andreas Verras, Zhengwei Peng
The 2016 D3R Grand Challenge 2 includes both pose and affinity or ranking predictions. This article is focused exclusively on affinity predictions submitted to the D3R challenge from a collaborative effort of the modeling and informatics group. Our submissions include ranking of 102 ligands covering 4 different chemotypes against the FXR ligand binding domain structure, and the relative binding affinity predictions of the two designated free energy subsets of 15 and 18 compounds. Using all the complex structures prepared in the same way allowed us to cover many types of workflows and compare their performances effectively...
October 6, 2017: Journal of Computer-aided Molecular Design
Vittoria Massafra, Saskia van Mil
The Farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids (BAs). BAs are amphipathic molecules that serve as fat solubilizers in the intestine under postprandial conditions. In the post-absorptive state, BAs bind FXR in the hepatocytes, which in turn provides feedback signals on BA synthesis and transport and regulates lipid, glucose and amino acid metabolism. Therefore, FXR acts as a homeostat of all three classes of nutrients, fats, sugars and proteins. Here we re-analyze the function of FXR in the perspective of nutritional metabolism, and discuss the role of FXR in liver energy homeostasis in postprandial, post-absorptive and fasting/starvation states...
October 3, 2017: Biochimica et Biophysica Acta
David Vauzour, Ildefonso Rodriguez-Ramiro, Simon Rushbrook, Ignacio R Ipharraguerre, Damon Bevan, Susan Davies, Noemi Tejera, Pedro Mena, Sonia de Pascual-Teresa, Daniele Del Rio, Jelena Gavrilovic, Anne Marie Minihane
Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects...
October 3, 2017: Biochimica et Biophysica Acta
Hervé Hogues, Traian Sulea, Francis Gaudreault, Christopher R Corbeil, Enrico O Purisima
The Farnesoid X receptor (FXR) exhibits significant backbone movement in response to the binding of various ligands and can be a challenge for pose prediction algorithms. As part of the D3R Grand Challenge 2, we tested Wilma-SIE, a rigid-protein docking method, on a set of 36 FXR ligands for which the crystal structures had originally been blinded. These ligands covered several classes of compounds. To overcome the rigid protein limitations of the method, we used an ensemble of publicly available structures for FXR from the PDB...
October 5, 2017: Journal of Computer-aided Molecular Design
Laura E Armstrong, Grace L Guo
PURPOSE OF REVIEW: About 15-25% of patients with simple steatosis of non-alcoholic fatty liver disease progresses to non-alcoholic steatohepatitis (NASH), and the underlying mechanism for this progression has not been elucidated. NASH ultimately could progress to cirrhosis, an irreversible condition. RECENT FINDINGS: Farnesoid X receptor (FXR) has been studied for its role in modulating inflammation, and the expression of FXR is down-regulated during NASH development...
April 2017: Current Pharmacology Reports
Shijuan Yan, Cui Zhu, Ting Yu, Wenjie Huang, Jianfeng Huang, Qian Kong, Jingfang Shi, Zhongjian Chen, Qinjian Liu, Shaolei Wang, Zongyong Jiang, Zhuang Chen
This study was conducted to compare the microbiome and metabolome differences in the colon lumen from two pig breeds with different genetic backgrounds. Fourteen weaned piglets at 30 days of age, including seven Landrace piglets (a lean-type pig breed with a fast growth rate) and seven Meihua piglets (a fatty-type Chinese local pig breed with a slow growth rate), were fed the same diets for 35 days. Untargeted metabolomics analyses showed that a total of 401 metabolites differed between Landrace and Meihua...
2017: Frontiers in Microbiology
Jianlong Du, Xiaojun Xiang, Yongnan Li, Renlei Ji, Hanlin Xu, Kangsen Mai, Qinghui Ai
In the present study, farnesoid X receptor (FXR) was cloned and characterized from liver of large yellow croaker (L crocea) and the effects of dietary chenodeoxycholic acid (CDCA), a nature ligand of FXR, on the inflammatory genes expression in the intestine and spleen of large yellow croaker were investigated. Multiple alignments showed that FXR of large yellow croaker contained highly conserved DNA-binding domain and ligand binding domain compared with other species. The subcellular localization analysis showed that FXR-GFP fusion protein could target to the nucleus in HEK 293t...
October 2, 2017: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
Amit D Kandhare, Subhash Laxmanrao Bodhankar, Vishwaraman Mohan, Prasad A Thakurdesai
BACKGROUND: Liver fibrosis a complex process of excess collagen deposition resulted in disturbance of hepatic cellar function. Glycosides based standardized fenugreek seed extract (SFSE-G) has potent anti-inflammatory, antioxidant, and anti-fibrotic properties. OBJECTIVE: The aim of this study is to evaluate the hepatoprotective potential of SFSE-G against bleomycin (BLM)-induced liver fibrosis in laboratory animals. MATERIALS AND METHODS: Sprague-Dawley rats (180-220 g) were assigned to various groups, namely, normal, sham, BLM control, SFSE-G (5, 10, 20, and 40 mg/kg, p...
July 2017: Journal of Pharmacy & Bioallied Sciences
Youcai Zhang, Andrew J Lickteig, Iván L Csanaky, Curtis D Klaassen
Fibrates and their receptor, namely peroxisome proliferator-activated receptor α (PPARα), have been reported to regulate bile acid (BA) synthesis and transport. However, the effect of fibrate treatment and PPARα activation on BA homeostasis remains controversial. In the present study, both wild-type (WT) and PPARα-null male mice were treated with clofibrate (CLOF) for 4 days to evaluate the effects of short-term PPARα activation on bile acid (BA) homeostasis. While a decrease in total BAs was observed in livers of CLOF-treated WT mice, it was not observed in PPARα-null mice...
September 13, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Yasmeen M Attia, Rasha A Tawfiq, Aya A Ali, Mohamed M Elmazar
The nuclear receptor, farnesoid X receptor (FXR), has been recently considered as a tumor suppressor in HCC. IL-6/Janus kinase 2 (Jak-2)/signal transducer and activator of transcription 3 (STAT3) pathway has been implicated as a key player in many cancer types. This study aimed at investigating the potential effect of the FXR agonist, obeticholic acid (OCA), on HCC and the involvement of IL-6/STAT3 pathway. The potential regulation of STAT3 by its main feedback inhibitor target gene, the suppressor of cytokine signaling 3 (SOCS3), triggered by OCA was also explored...
October 2, 2017: Scientific Reports
Lijuan Cao, Yuan Che, Tuo Meng, Shanshan Deng, Jun Zhang, Min Zhao, Wanfeng Xu, Dandan Wang, Zhichen Pu, Guangji Wang, Haiping Hao
Bile acids (BAs) are important endogenous signaling molecules that play vital roles in the pathological development of various diseases including colitis-associated cancer (CAC). BAs were previously found dysregulated under conditions of CAC; however, the exact patterns and underlying molecular mechanisms remain largely elusive. Based on the development of a method for comprehensive analysis of BAs, this study aims to elucidate the dysregulation patterns and involved mechanisms in a typical CAC model induced by azoxymethane (AOM)/dextran sodium sulfate (DSS)...
September 8, 2017: Oncotarget
Marica Cariello, Elena Piccinin, Oihane Garcia-Irigoyen, Carlo Sabbà, Antonio Moschetta
The nuclear receptor farnesoid X receptor (FXR) is the master regulator of bile acids (BAs) homeostasis since it transcriptionally drives modulation of BA synthesis, influx, efflux, and detoxification along the enterohepatic axis. Due to its crucial role, FXR alterations are involved in the progression of a plethora of BAs associated inflammatory disorders in the liver and in the gut. The involvement of the FXR pathway in cholestasis development and management has been elucidated so far with a direct role of FXR activating therapy in this condition...
September 28, 2017: Biochimica et Biophysica Acta
Carla Vermeulen Carvalho Grade, Carolina Stefano Mantovani, Marina Alves Fontoura, Faisal Yusuf, Beate Brand-Saberi, Lúcia Elvira Alvares
Myostatin (MSTN) is a strong inhibitor of skeletal muscle growth in human and other vertebrates. Its transcription is controlled by a proximal promoter/enhancer (Mstn P/E) containing a TATA box besides CREB, NF-Y, MEIS1 and FXR transcription factor binding sites (TFBSs), which are conserved throughout evolution. The aim of this work was to investigate the role of these TFBSs on Mstn P/E activity and evaluate the potential of their putative ligands as Mstn trans regulators. Mstn P/E mutant constructs were used to establish the role of conserved TFBSs using dual-luciferase assays...
October 2017: Molecular Biology Reports
Hezhongrong Nie, Chunli Song, Daming Wang, Shengjin Cui, Tingyu Ren, Zhaopeng Cao, Qing Liu, Zeyan Chen, Xiaoyong Chen, Yiwen Zhou
Non-alcoholic fatty liver disease (NAFLD) affects obesity-associated metabolic syndrome, which exhibits hepatic steatosis, insulin insensitivity and glucose intolerance. Previous studies indicated that hepatic microRNAs (miRs) play critical roles in the development of NAFLD. In this study, we aim to explore the pathophysiological role of miR-194 in obesity-mediated metabolic dysfunction. Our findings show that the high fat diet or palmitic acid treatment significantly increase hepatic miR-194 levels in vivo and in vitro...
September 22, 2017: Biochimica et Biophysica Acta
Paolo Comeglio, Annamaria Morelli, Luciano Adorini, Mario Maggi, Linda Vignozzi
Bile acids act as steroid hormones, controlling lipid, glucose and energy metabolism, as well as inflammation and fibrosis. Their actions are implemented through activation of nuclear (FXR, VDR, PXR) and membrane G protein-coupled (TGR5, S1PR2) receptors. Areas covered: This review discusses the potential of FXR and TGR5 as therapeutic targets in the treatment of pulmonary disorders linked to metabolism and/or inflammation. Obeticholic acid (OCA) is the most clinically advanced bile acid-derived agonist for FXR-mediated anti-inflammatory and anti-fibrotic effects...
November 2017: Expert Opinion on Investigational Drugs
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