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Obeticholic acid

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https://www.readbyqxmd.com/read/29765319/progression-and-regression-of-hepatic-lesions-in-a-mouse-model-of-nash-induced-by-dietary-intervention-and-its-implications-in-pharmacotherapy
#1
Zhi-Ming Ding, Yue Xiao, Xikun Wu, Haixia Zou, Shurong Yang, Yiyun Shen, Juehua Xu, Heather C Workman, Amy L Usborne, Haiqing Hua
Understanding of the temporal changes of hepatic lesions in the progression and regression of non-alcoholic steatohepatitis (NASH) is vital to elucidation of the pathogenesis of NASH, and critical to the development of a strategy for NASH pharmacotherapy. There are challenges in studying hepatic lesion progression and regression in NASH patients due to the slow development of NASH in humans, one being the requirement for multiple biopsies during the longitudinal follow-up. Here we studied lesion progression and regression in the diet-induced animal model of NASH by application or removal of the pathogenic diet for multiple time periods...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29761165/a-real-world-observational-cohort-of-patients-with-primary-biliary-cholangitis-target-primary-biliary-cholangitis-study-design-and-rationale
#2
Cynthia Levy, Christopher L Bowlus, Elizabeth Carey, Julie M Crawford, Karen Deane, Marlyn J Mayo, W Ray Kim, Michael W Fried
Primary biliary cholangitis (PBC) is a rare chronic cholestatic liver disease that may progress to biliary cirrhosis if left untreated. The first-line therapy for PBC is ursodeoxycholic acid (UDCA). Unfortunately, 1 of 3 patients does not respond to UDCA. These patients are at risk for developing clinical events, including cirrhosis, complications of portal hypertension, hepatocellular carcinoma, liver transplant, or death. Recently, the U.S. Food and Drug Administration approved obeticholic acid to be used in certain patients with PBC...
May 2018: Hepatology Communications
https://www.readbyqxmd.com/read/29758112/novel-and-emerging-therapies-for-cholestatic-liver-diseases
#3
Jordan Goldstein, Cynthia Levy
While bile acids are important for both digestion and signaling, hydrophobic bile acids can be harmful especially when in high concentrations. Mechanisms for protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signaling, among others. By altering or overwhelming these defense mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation...
May 14, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29743187/the-effects-of-farnesoid-x-receptor-activation-on-arachidonic-acid-metabolism-nf-kb-signaling-and-hepatic-inflammation
#4
Zhibo Gai, Michele Visentin, Ting Gui, Lin Zhao, Wolfgang E Thasler, Stephanie Hausler, Ivan Hartling, Alessio Cremonesi, Christian Hiller, Gerd A Kullak-Ublick
Inflammation has a recognized role in non-alcoholic fatty liver disease (NAFLD) progression. The present work studied the effect of high fat diet (HFD) on arachidonic acid metabolism in the liver and investigated the role of the farnesoid X receptor (FXR, NR1H4) in eicosanoid biosynthetic pathways and NF-kB signaling, major modulators of the inflammatory cascade. Mice were fed a HFD to induce NAFLD, then, treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue...
May 9, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29736833/are-clinicians-ready-for-safe-use-of-stratified-therapy-in-primary-biliary-cholangitis-pbc-a-study-of-educational-awareness
#5
Laura Jopson, Amardeep Khanna, Patricia Peterson, Elaine Rudell, Margaret Corrigan, David Jones
BACKGROUND: Primary Biliary Cholangitis (PBC, formerly cirrhosis), is a chronic cholestatic liver disease which until spring 2016 had a single licensed therapy, Ursodeoxycholic acid (UDCA). Approximately 30% of patients do not respond to UDCA, and are high-risk for progressing to end stage liver disease, transplantation or death. A new era of stratified medicine with second-line therapies to treat high-risk disease is emerging, with the first such second-line agent obeticholic acid recently receiving FDA and EMA approval and entering practice...
May 8, 2018: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/29733835/mechanisms-of-mafg-dysregulation-in-cholestatic-liver-injury-and-development-of-liver-cancer
#6
Ting Liu, Heping Yang, Wei Fan, Jian Tu, Tony W H Li, Jiaohong Wang, Hong Shen, JinWon Yang, Ting Xiong, Justin Steggerda, Zhenqiu Liu, Mazen Noureddin, Stephanie S Maldonado, Alagappan Annamalai, Ekihiro Seki, José M Mato, Shelly C Lu
BACKGROUND & AIMS: MAF bZIP transcription factor G (MAFG) is activated by the farnesoid X receptor (FXR) to repress bile acid synthesis. However, expression of MAFG increases during cholestatic liver injury in mice and in cholangiocarcinomas. MAFG interacts directly with methionine adenosyltransferase 1A (MAT1A) and other transcription factors at the E-box element to repress transcription. We studied mechanisms of MAFG upregulation in cholestatic tissues and the pathways by which S-adenosylmethionine (SAMe) and ursodeoxycholic acid (UDCA) prevent the increase in MAFG expression...
May 4, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29697548/bile-acids-and-the-gut-microbiome-as-potential-targets-for-nafld-treatment
#7
Lixin Zhu, Robert D Baker, Ruixin Zhu, Susan S Baker
Semi-synthetic bile acid (BA) obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, exhibited beneficial effects on non-alcoholic fatty liver disease (NAFLD). However, OCA did not cause a resolution of non-alcoholic steatohepatitis (NASH). Here we discuss several prominent knowledge gaps in BA/FXR biology. Firstly, although many groups reported elevated serum BA levels, there are reports of decreased or normal serum BA levels in NAFLD, underlining the complexity of BA regulation by environmental and genetic factors...
April 23, 2018: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/29691599/-primary-biliary-cholangitis-established-and-novel-therapies
#8
REVIEW
M Vetter, A E Kremer
BACKGROUND: Patients with primary biliary cholangitis (PBC, formerly primary biliary cirrhosis) and insufficient treatment response or risk factors exhibit a remarkably increased risk for disease progression and associated complications. Furthermore, extrahepatic manifestations may considerably reduce quality of life in affected patients. OBJECTIVES: This article presents an overview on standard therapy with ursodeoxycholic acid (UDCA) and further therapeutic options in patients with insufficient treatment response...
April 24, 2018: Der Internist
https://www.readbyqxmd.com/read/29660435/yangonin-protects-against-cholestasis-and-hepatotoxity-via-activation-of-farnesoid-x-receptor-in-vivo-and-in-vitro
#9
Xiaoguang Gao, Ting Fu, Changyuan Wang, Chenqing Ning, Kexin Liu, Zhihao Liu, Huijun Sun, Xiaodong Ma, Xiaokui Huo, Xiaobo Yang, Ming Zou, Qiang Meng
Cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. 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 newly therapeutic strategy against cholestasis. The purpose of the current study is to screen novel FXR agonists and verify the anti-cholestasis effect of yangonin in vivo and in vitro. The computational strategy of two-dimensional virtual screening was used to search for new FXR agonists, and dual-luciferase reporter gene assay was used to further demonstrate FXR activation by yangonin...
April 13, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29649907/farnesoid-x-receptor-modulators-2014-present-a-patent-review
#10
Valentina Sepe, Eleonora Distrutti, Stefano Fiorucci, Angela Zampella
The nuclear receptor FXR regulates the expression of genes involved in bile acids, glucose and lipid homeostasis. For its role as guardian of metabolism, FXR has been identified a promising pharmacological target in liver bile acid and lipid accumulation, such as cholestasis and non-alcoholic fatty liver disease (NAFLD). The field of FXR research is extremely competitive with a large number of patents and articles published in the last decades identifying promising hit compounds. Areas covered. The present review summarizes recent patent activity (2014-to date) filing for synthetic and natural FXR ligands, including bile acid derivatives and non-steroidal compounds, alongside their in vitro and in vivo efficacy as well as their therapeutic applications...
April 13, 2018: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/29593060/the-british-society-of-gastroenterology-uk-pbc-primary-biliary-cholangitis-treatment-and-management-guidelines
#11
Gideon M Hirschfield, Jessica K Dyson, Graeme J M Alexander, Michael H Chapman, Jane Collier, Stefan Hübscher, Imran Patanwala, Stephen P Pereira, Collette Thain, Douglas Thorburn, Dina Tiniakos, Martine Walmsley, George Webster, David E J Jones
Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome...
March 28, 2018: Gut
https://www.readbyqxmd.com/read/29559521/fxr-activation-by-obeticholic-acid-or-non-steroidal-agonists-induces-a-human-like-lipoprotein-cholesterol-change-in-mice-with-humanized-chimeric-liver
#12
Romeo Papazyan, Xueqing Liu, Jingwen Liu, Bin Dong, Emily M Plummer, Ronald D Lewis, Jonathan D Roth, Mark A Young
Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in high-density lipoproteins. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes...
March 20, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29536837/-new-name-and-new-treatments-for-primary-biliary-cholangitits
#13
Lars Bossen, Henriette Ytting, Peter Jepsen, Ole Hamberg, Peter Ott, Henning Grønbæk
The name of chronic liver disease: primary biliary cirrhosis, has been changed to: primary biliary cholangitis, primarily because of the stigma associated with the word "cirrhosis", as only a minority of the patients develop cirrhosis. In this review we present data on epidemiology and discuss the current treatments with focus on ursodeoxycholic acid and the newly described effects of the farnesoid receptor agonist obeticholic acid.
March 5, 2018: Ugeskrift for Laeger
https://www.readbyqxmd.com/read/29530598/disruption-of-tfg%C3%AE-smad3-pathway-by-the-nuclear-receptor-shp-mediates-the-antifibrotic-activities-of-bar704-a-novel-highly-selective-fxr-ligand
#14
Adriana Carino, Michele Biagioli, Silvia Marchianò, Paolo Scarpelli, Angela Zampella, Vittorio Limongelli, Stefano Fiorucci
Liver fibrosis, a major health concern worldwide, results from abnormal collagen deposition by activated hepatic stellate cells (HSCs) in an injured liver. The farnesoid-x-receptor (FXR) is a bile acid sensor that counteracts HSCs transdifferentiation. While targeting FXR holds promise, 6-ethyl-CDCA known as obeticholic acid, the first in class of FXR ligands, causes side effects, partially because the lack of selectivity toward GPBAR1, a putative itching receptor. Here, we describe the 3-deoxy-6-ethyl derivative of CDCA, BAR704, as a highly selective steroidal FXR agonist...
May 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29526309/primary-biliary-cholangitis
#15
REVIEW
Albert Parés
Primary cholangitis (cirrhosis) is a chronic cholestatic disease with an unquestionable female predominance. It is characterised by inflammation of the small and medium size bile ducts, and can eventually progress to cirrhosis. Most patients remain asymptomatic and are diagnosed by the casual finding of an anicteric biochemical cholestasis with increased alkaline phosphatase. The pathogenesis is unknown and of presumed autoimmune origin in genetic susceptible subjects. M2-type antimitochondrial antibodies, and specific antinuclear antibodies (gp210 and Sp100) are typical and specific of the disease...
March 8, 2018: Medicina Clínica
https://www.readbyqxmd.com/read/29512910/editorial-weight-change-liver-histology-and-the-metabolic-effects-of-obeticholic-acid-in-nash
#16
EDITORIAL
M Eslam, J George
No abstract text is available yet for this article.
April 2018: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29487110/farnesoid-x-receptor-agonists-obeticholic-acid-and-chenodeoxycholic-acid-increase-bile-acid-efflux-in-sandwich-cultured-human-hepatocytes-functional-evidence-and-mechanisms
#17
Cen Guo, Carl LaCerte, Jeffrey E Edwards, Kenneth R Brouwer, Kim L R Brouwer
The farnesoid X receptor (FXR) is a nuclear receptor that regulates genes involved in bile acid homeostasis. FXR agonists, obeticholic acid (OCA) and chenodeoxycholic acid (CDCA), increase mRNA expression of efflux transporters in sandwich-cultured human hepatocytes (SCHH). This study evaluated the effects of OCA and CDCA treatment on the uptake, basolateral efflux, and biliary excretion of a model bile acid, taurocholate (TCA), in SCHH. In addition, changes in the protein expression of TCA uptake and efflux transporters were investigated...
May 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29413959/role-of-gut-microbiota-and-oxidative-stress-in-the-progression-of-non-alcoholic-fatty-liver-disease-to-hepatocarcinoma-current-and-innovative-therapeutic-approaches
#18
REVIEW
Antonella Borrelli, Patrizia Bonelli, Franca Maria Tuccillo, Ira D Goldfine, Joseph L Evans, Franco Maria Buonaguro, Aldo Mancini
Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory"...
May 2018: Redox Biology
https://www.readbyqxmd.com/read/29375205/int-767-improves-histopathological-features-in-a-diet-induced-ob-ob-mouse-model-of-biopsy-confirmed-non-alcoholic-steatohepatitis
#19
Jonathan D Roth, Michael Feigh, Sanne S Veidal, Louise Kd Fensholdt, Kristoffer T Rigbolt, Henrik H Hansen, Li C Chen, Mathieu Petitjean, Weslyn Friley, Niels Vrang, Jacob Jelsing, Mark Young
AIM: To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis (NASH). METHODS: The effects of INT-767 on histological features of NASH were assessed in two studies using Lepob/ob ( ob/ob ) NASH mice fed the AMLN diet (high fat with trans-fat, cholesterol and fructose). In a proof-of-concept study, Lepob/ob ( ob/ob ) NASH mice were first dosed with INT-767 (3 or 10 mg/kg for 8 wk)...
January 14, 2018: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29375204/metabolic-and-hepatic-effects-of-liraglutide-obeticholic-acid-and-elafibranor-in-diet-induced-obese-mouse-models-of-biopsy-confirmed-nonalcoholic-steatohepatitis
#20
Kirstine S Tølbøl, Maria Nb Kristiansen, Henrik H Hansen, Sanne S Veidal, Kristoffer Tg Rigbolt, Matthew P Gillum, Jacob Jelsing, Niels Vrang, Michael Feigh
AIM: To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis (NASH) in obese mouse models of biopsy-confirmed NASH. METHODS: Male wild-type C57BL/6J mice (DIO-NASH) and Lep ob/ob ( ob/ob -NASH) mice were fed a diet high in trans-fat (40%), fructose (20%) and cholesterol (2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score (NAS) and fibrosis staging system...
January 14, 2018: World Journal of Gastroenterology: WJG
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