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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 | Noninvasive In Vivo Liver Fibrosis Evaluation Using Supersonic Shear Imaging: A Clinical Study on 113 Hepatitis C Virus Patients显示文摘 | éric Bavu Jean-Luc Gennisson Mathieu Couade Jeremy Bercoff Vincent Mallet Mathias Fink Anne Badel Ana?s Vallet-Pichard Bertrand Nalpas Micka?l Tanter Stanislas Pol | 2011 | Ultrasound in Medicine & Biology2011，，9： | 3 |
| 3 | Radiation dose reduction for CT lung cancer screening using ASIR and MBIR: a phantom study显示文摘 | Mathieu K B Ai H Fox P S | 2014 | J Appl Clin Med Phys2014，15，2： | 1 |
| 4 | A corrosion study of the main constituent phases of AZ91 magnesium alloys 显示文摘 | MATHIEU S RAPIN C STEINMETZ J STEINMETZ P | 2003 | Corrosion Science2003，45，12： | 1 |
| 5 | Acorrosion study of the main constituent phases of AZ91 magnesiumalloys 显示文摘 | MATHIEU S RAPIN C STEINMETZ J STEINMETZ P | 2003 | Corrosion Science2003，45，： | 1 |
| 6 | An examination of the relationships between affeetive reactions, work perceptions, individual resource characteristics, and multiple absence criteria 显示文摘 | Kohler S S Mathieu J E | 1993 | Journal of Organizational Behavior1993，14，： | 1 |
| 7 | A temporally based framework and taxonomy of team processes显示文摘 | MARKS M A MATHIEU J E ZACCARO S J | 2001 | Academy of Management Review2001，26，3： | 1 |
| 8 | The influence of shared mental models on team process and performance显示文摘 | Mathieu J E Heffner T S Goodwin G F | 2000 | Journal of Applied Psychology2000，85，2： | 1 |
| 9 | Increased Expression of LP-PLA2 in Aortic Stenosis Is Associated With Mineralization and Tissue Remodelling显示文摘 | M. Abulajiang M. Boulanger D.E. Husseini D. Fournier R. Bouchareb J. Després P. Pibarot Y. Bossé P. Mathieu | 2013 | Canadian Journal of Cardiology2013，，10： | 1 |
| 10 | A framework for testing meso-mediational relationship in organizational behavior显示文摘 | Mathieu J E Taylor S R | 2007 | Journal of Organizational Behavior2007，28，2： | 1 |
| 11 | A temporally based framework and taxonomy of team processes 显示文摘 | Marks M A Mathieu J E Zaccaro S J | 2001 | Academy ofManagement Review2001，26，： | 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 | Defense mechanisms of Pseudomonas aeruginosa PAO1 against quantum dots and their released heavy metals显示文摘 | Yang Y Mathieu J M Chattopadhyay S | 2012 | ACS Nano2012，6，7： | 1 |
| 14 | Laser brazing of a steel/aluminium assembly with hot filler wire (88%Al,12%Si)显示文摘 | MATHIEU A PONTEVICCI S VIALA J C CICALA E MATTE S GREVEY D | 2006 | Mater Sci Eng A2006，，5： | 1 |
| 15 | Intensive care unit-acquired infection as a side effect of sedation 显示文摘 | Nseir S Makris D Mathieu D | 2010 | Crit Care2010，14，2： | 1 |
| 16 | Performance implications of leader briefings and team - interaction training for team adaptation to novel environments 显示文摘 | Marks M A Zaccaro S J Mathieu J E | 2000 | Journal of Applied Psychology2000，85，6： | 1 |
| 17 | Galectins and gli- omas显示文摘 | Le MM Fortin S Mathieu V et aI | 2010 | BrainPathol2010，20，1： | 1 |
| 18 | Intergenic splicing of MDSI and EVIl occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family 显示文摘 | Fears S Mathieu C Zeleznik-Le N | 1996 | Proc Nat! Acad Sci U S A1996，93，4： | 1 |
| 19 | A tempo- rally based frame work and taxonomy of team processes显示文摘 | MARKS M A MATHIEU J E ZACCARO S J | 2001 | Academy of Management Review2001，26，： | 1 |
| 20 | Defensemechanisms of Pseudomonas aeruginosa PAOl againstquantum dots and their released heavy metals显示文摘 | Yang Y Mathieu J M Chattopadhyay S | 2012 | ACSNano2012，6，7： | 1 |
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