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| 1 | INT-767 improves histopathological features in a dietinduced ob/ob mouse model of biopsy-confirmed nonalcoholic steatohepatitis显示文摘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 Lep^(ob/ob)(ob/ob) NASH mice fed the AMLN diet(high fat with transfat, cholesterol and fructose). In a proof-of-conceptstudy, Lep^(ob/ob)(ob/ob) NASH mice were first dosed with INT-767(3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767(3 and 10 mg/kg) to obeticholic acid(OCA)(10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57 Bl/6 mice on standard chow. C57 Bl/6 mice were orally dosed with INT-767 or OCA(1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.RESULTS INT-767 dose-dependently(3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation(assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study(16 wk), the FXR agonists OCA(10 and 30 mg/kg) and INT-767(3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function. CONCLUSION These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH. | 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 | 2018 | World Journal of Gastroenterology2018，24，2： | 7 |
| 2 | 卵巢黏液性肿瘤中的间变性癌显示文摘 | Provenza C Young R H Prat J. 黄文斌(摘译) | 2008 | 临床与实验病理学杂志2008，24，3： | 5 |
| 3 | 伴有浆细胞分化的套细胞淋巴瘤显示文摘 | Young K H Chan W C Fu K 黄文斌(摘译) | 2006 | 临床与实验病理学杂志2006，22，5： | 2 |
| 4 | Reconstruction for renal artery aneurysm: Operative techniques and long-term results显示文摘 | Jong A H Young K W | 2003 | J Vas Surg2003，37，2： | 1 |
| 5 | Shared Vision:Con- cordance among Fathers,Mothers and Pediatricians about Unmet Needs of Children with Chronic Health Conditions 显示文摘 | Perrin E C Lewkowicz C Young M H | 2000 | Pediatrics2000，105，1： | 1 |
| 6 | Vertical vibration analysis of vehicle/imperfect track systems 显示文摘 | YOUNG T H LI C Y | 2003 | Vehicle System Dynamics2003，40，5： | 1 |
| 7 | Endothelium-ameliora ting effects of statin therapy and coenzyme Q10 reductions in chron- ic heart failure显示文摘 | Strey C H Young M Molyneux S L | 2005 | Atheroselerosis2005，179，1： | 1 |
| 8 | Variable tensility of the ligaments in the stalk of a sea-lily显示文摘 | WILKIE I C EMSON R H YOUNG C M | 1994 | Comparative Biochemistry and Physiology (Part A):Physiology1994，109，3： | 1 |
| 9 | Survival,migration and differentiation of retinal progenitor cellstransplanted on micro-machined poly (methyl methacrylate)scaffolds to the subretinal space显示文摘 | Tao S Young C Redenti S Zhang Y Klassen H Desai T | | 0，，06： | 1 |
| 10 | Numerical solution of three-dimensional backward heat conduction problems by the time evolution method of fundamental solutions 显示文摘 | Tsai C H Young D L Kolibal J | 2011 | International Journal of Heat and Mass Transfer2011，54，1112： | 1 |
| 11 | Tolerability of high-dose venlafaxine in depressed patients显示文摘 | HARRISON C L FERRIER N YOUNG A H | 2004 | J Psychopharmacol2004，18，： | 1 |
| 12 | Tyrosinase inhibitory polyphenols from roots of morus lhou 显示文摘 | Seong H J Young B R Marcus J C et a1 | 2009 | Journal of Agricultural and Food Chemistry2009，57，4： | 1 |
| 13 | Effect of competitive exclusion treatment on colonization of early-weaned pigs by Salmonella serovar choleraesuis 显示文摘 | ANDERSON R C STANKER L H YOUNG C R | 1999 | Swine Health Prod1999，7，4： | 1 |
| 14 | Distributioan of damaged ooaks and annual oak biomass removal by oak nut weevil ( Mechoris ursulus ) in Korea 显示文摘 | You H Y Young J C Hee S L | 2001 | Korean J Ecol2001，24，6： | 1 |
| 15 | Enrichment of bioactive isoflavones in soymilk fermented withβ - glucosidase - producing lactic acid bacteria 显示文摘 | Young H P Tung C L Young - Chul L | 2005 | Food Research International2005，38，： | 1 |
| 16 | An examination of food tourist’sbehavior : Using the modified theory of reasoned action显示文摘 | YOUNG H K MIN C K BEN K G | | Tourism0，，： | 1 |
| 17 | Matching familiar and unfamiliar faces on identity and expression显示文摘 | Young A W McWeeny K H Hay D C | 1986 | Psychological Re- search1986，48，： | 1 |
| 18 | Project Delivery Systems and Project Change:Quantitative Analysis显示文摘 | WILLIAM C I YOUNG H K TZEYU N MURATO A | 2003 | Journal Of Construction Engineering And Management2003，，4： | 1 |
| 19 | Surrogate markers of health after titanium dental implant placement显示文摘 | Young C W Lee J S Le H | 2004 | J Oral Maxillofac Surg2004，62，11： | 1 |
| 20 | Upstream regulation of matrix metalloproteinase by EMMPRIN:extracellular matrix metalloproteinase inducer in advanced atherosclerotic plaque显示文摘 | YOUNG Y W KWON H M HWANG K C | 2005 | Atherosclerosis2005，180，1： | 1 |
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