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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 | Maintenance of Remission Among Patients With Crohn’s Disease on Antimetabolite Therapy After Infliximab Therapy Is Stopped显示文摘 | Edouard Louis Jean–Yves Mary Gwenola Vernier–Massouille Jean–Charles Grimaud Yoram Bouhnik David Laharie Jean–Louis Dupas Hélène Pillant Laurence Picon Michel Veyrac Mathurin Flamant Guillaume Savoye Raymond Jian Martine DeVos Rapha?l Porcher Gilles Paint | 2012 | Gastroenterology2012，，1： | 4 |
| 3 | WHO Classiication of Turmours of the Central Nervous System显示文摘 | Louis DN Ohgaki H Wiestler OD | | 0，，02： | 1 |
| 4 | 查看详情显示文摘 | Louis B Ocampo F Yun H S Twssonnier J P Pereira M M | | 0，，： | 1 |
| 5 | The 2007 WHO classification of tumours of the central nervous system显示文摘 | Louis DN Ohgaki H Wiestler OD | | 0，，07： | 1 |
| 6 | Citrate anticoagulation versus systemic heparinisation in continuous veno- venous hemofiltration in critically ill patients with acute kidney inju- ry:a multi-center randomized clinical trial 显示文摘 | Louise Schilder S Azam Nurmohamed Frank H Bosch | 2014 | Crit Care2014，18，4： | 1 |
| 7 | Accurate quantitation of Leishmania infection in cultured cells by flow cytometry 显示文摘 | Guinet F Louise A Jouin H | 2000 | Cytometry2000，39，3： | 1 |
| 8 | Centennial review of corneal transplantation显示文摘 | S Louise Moffatt BSc Victoria A Cartwright BA Thomas H Stumpf | 2005 | Clinical and Experimental Ophthalmology2005，33，： | 1 |
| 9 | Intrahepatic IL-8 producing Foxp3 + CD4 + regulatory T cells and fibrogenesis in chronic hepatitis C<!-- Doctopic: VH -->显示文摘 | Bettina Langhans Benjamin Kr?mer Marcell Louis Hans Dieter Nischalke Robert Hüneburg Andrea Staratschek-Jox Margarethe Odenthal Steffen Manekeller Michael Schepke J?rg Kalff Hans-Peter Fischer Joachim L. Schultze Ulrich Spengler | 2013 | Journal of Hepatology2013，，2： | 1 |
| 10 | The 2007 WHO classification of tumours of the central nervous system显示文摘 | Louis DN Ohgaki H Wiestler OD | | 0，，02： | 1 |
| 11 | Increasing incidence of thyroid cancer in the United States, 1973-2002显示文摘 | Louise D H Gilbert W | 2006 | Jama the Journal of the American Medical Association2006，295，18： | 1 |
| 12 | Synthesis and processing of the trasmembrane envelope protein of equine infectious anemia virus显示文摘 | Nancy R Louise H Raymond C S | 1990 | J Virol1990，64，： | 1 |
| 13 | The 2007 WHO classification of tumours of the central nervous system显示文摘 | Louis DN Ohgaki H Wiestler OD | | 0，，： | 1 |
| 14 | The Ten-year Single-center Experience With 6-Mercaptopurine in the Treatment of Inflammatory Bowel Disease显示文摘 | Kenneth D Glazier Adam L Palance Louis H Griffel Kiron M Das | 2005 | Journal of Clinical Gastroenterology2005，，1： | 1 |
| 15 | Profiling the Senior Traveler: An Australian Perspective显示文摘 | Louise H Carter R W Sherrie W Hein R | 2002 | Journal of Travel Research2002，41，8： | 1 |
| 16 | The 2007 WHO classifcation of tumours of the central nervous system显示文摘 | Louis DN Ohgaki H Wiestler OD | | 0，，02： | 1 |
| 17 | Agro-forestry practice and policy in the United States of America显示文摘 | H E Gene Garrett Louise Buck | 1997 | Forest Ecology and Management1997，91，1： | 1 |
| 18 | Diversity,metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine显示文摘 | Louis P Flint H J | | 0，，： | 1 |
| 19 | A conceptual approach for integrating phosphorus and nitrogen management at watershed scale 显示文摘 | LOUISE H ANDREW S WILLIAM G | 2000 | Environment Quality2000，29，1： | 1 |
| 20 | Managers and Investors Responses to Media Exposure of Board Ineffectiveness显示文摘 | Jennifer J Louis H Dahlia R | | 0，，03： | 1 |
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