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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 | Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 2: Current management显示文摘 | Axel Dignass James O. Lindsay Andreas Sturm Alastair Windsor Jean-Frederic Colombel Mathieu Allez Gert D’Haens André D’Hoore Gerassimos Mantzaris Gottfried Novacek Tom ?resland Walter Reinisch Miquel Sans Eduard Stange Severine Vermeire Simon Travis Gert | 2012 | Journal of Crohn’s and Colitis2012，，10： | 4 |
| 3 | Treatment of small-bowel fistulae in the open abdomen with topical negative-pressure therapy显示文摘 | Mathieu D’Hondt Dirk Devriendt Frank Van Rooy Franky Vansteenkiste André D’Hoore Freddy Penninckx Marc Miserez | 2011 | The American Journal of Surgery2011，，： | 2 |
| 4 | Development of 5-iodo-2'-deoxyuridine milling process to reduce initial burst release from PLGA microparticles显示文摘 | Geze A Venier-Julienne M C Mathieu D | 1999 | Int J Pharm1999，178，2： | 1 |
| 5 | Carbon monoxide poisoning:Interpretation of randomized clinical trials and unresolved treatment issues显示文摘 | Hampson NB Mathieu D Piantadosi CA | 2001 | Undersea Hyperbar M2001，28，3： | 1 |
| 6 | Possibleconfigurations for the thorium molten salt reactor andadvantages of the fast non-moderated version显示文摘 | Mathieu L Heuer D Merle-lucott E | 2009 | NuclearScience and Engineering2009，161，1： | 1 |
| 7 | Les pseudolsions hpatiques 显示文摘 | Mathieu D Luciani A Achab A | 2001 | Gastroenterol Clin Biol2001，25，4： | 1 |
| 8 | A review and meta - analy- sis of the antecedents, correlates, and consequences of organizational commitment 显示文摘 | MATHIEU J E ZAJAC D M | 1990 | Psychological bulletin1990，108，2： | 1 |
| 9 | Controversial issue in hyperbaric oxygen therapy:a European Committee for Hyperbaric Medicine Workshop显示文摘 | Kot J Mathieu D | 2011 | Diving Hyperb Med2011，41，2： | 1 |
| 10 | Internal abdominal herniations显示文摘 | Mathieu D Luciaani A | 2004 | AJR2004，183，2： | 1 |
| 11 | Castleman disease mimicking liver tumor: CT and MR features 显示文摘 | Rahmouni A Golli M Mathieu D | 1992 | J Comput Assist Tomogr1992，16，5： | 1 |
| 12 | Complications of Gamma Knife surgery:an early report from 2 Canadian centers显示文摘 | Vachhrajani S Fawaz C Mathieu D | 2008 | J Neurosurg2008，109，6： | 1 |
| 13 | The more you have, the less you get : the functional role of inflammation on neuronal differentiation of endogenous and transplanted neural stem cells in the adult brain 显示文摘 | Mathieu P Battista D Depino A | 2009 | J Neurochem2009，29，87： | 1 |
| 14 | Focal nodular hyperplasia of liver:assessment with contrast-enhanced turbo FLASH MR imaging显示文摘 | Mathieu D Rahmouni A Anglade MC | 1991 | Radiology1991，180，1： | 1 |
| 15 | Computed tomography of thoracic dissection:accuracy and pitfalls显示文摘 | Vasile N Mathieu D Keita K | 1986 | JCAT1986，10，1： | 1 |
| 16 | Dynamic CT Features of Hepatic Abscesses显示文摘 | Mathieu D Vasile N Fagniez PL | 1985 | Radiology1985，154，3： | 1 |
| 17 | Electromyography of sco- liotic patients treated with a brace显示文摘 | Odermatt D Mathieu PA Beausejour M | 2003 | J Orthop Res2003，21，5： | 1 |
| 18 | Diagnosis of pneumonia in mechanicall Ventilated patients显示文摘 | Maquette CH Herengt F Mathieu D | 1993 | Am Rev Respir Dis1993，147，1： | 1 |
| 19 | In Search of a Cytostatic Agent Derived from the Alkaloid Lycorine:Synthesis and Growth Inhibitory Properties of Lycorine Derivatives显示文摘 | EVDOKIMOVA N M LAMORAL-THEYSB D MATHIEU V | 2011 | Bioorganic&Medicinal Chemistry2011，19，23： | 1 |
| 20 | Oral Contraceptive use and focal nodular hy-Perplasia of the liver显示文摘 | Mathieu D Kobeiter H Maison P | 2000 | Gastroenterology2000，118，： | 1 |
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