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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 | Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial显示文摘 | Paul Y Kwo Eric J Lawitz Jonathan McCone Eugene R Schiff John M Vierling David Pound Mitchell N Davis Joseph S Galati Stuart C Gordon Natarajan Ravendhran Lorenzo Rossaro Frank H Anderson Ira M Jacobson Raymond Rubin Kenneth Koury Lisa D Pedicone Clifford | 2010 | The Lancet2010，，9742： | 3 |
| 3 | Chronic overexpression of PNPLA3^sup I148M^ in mouse liver causes hepatic steatosis显示文摘 | Li John Zhong Huang Yongcheng Karaman Ruchan Ivanova Pavlina T Brown H Alex Roddy Thomas Castro-Perez Jose Cohen Jonathan C Hobbs Helen H | 2012 | EN2012，，11： | 3 |
| 4 | Defying gravity显示文摘 | Jonathan H C Stephen F T | 1998 | Civil Engineering1998，68，2： | 1 |
| 5 | Guidelines for Conscious Sedation and Monitoring During Gastrointestinal Endoscopy显示文摘 | J.Patrick Waring Todd H Baron William K Hirota Jay L Goldstein Brian C Jacobson Jonathan A Leighton J.Shawn Mallery Douglas O Faigel | 2003 | Gastrointestinal Endoscopy2003，，3： | 1 |
| 6 | Physical Activity Constrains among Latinos 显示文摘 | Michelle G H Myron F F Jonathan M C | 2013 | Journal of Leisure Re- search2013，45，1： | 1 |
| 7 | NASA's evolutionary xenon thruster long-duration test results显示文摘 | Daniel A H Soulas G C Jonathan L | 2012 | Journal of Propulsion and Power2012，28，3： | 1 |
| 8 | Stress-induced and electromigration voiding in aluminum interconnects passivated with Silicon nitride显示文摘 | Lee S H John C B Jonathan C D | 2002 | Journal of Applied Physics2002，91，6： | 1 |
| 9 | Epigenomic plasticity enables human pancreatic [alpha] to [Beta] cell reprogramming显示文摘 | Bramswig Nuria C Everett Logan J Schug Jonathan Dorrell Craig Liu Chengyang Luo Yanping Streeter Philip R Naji Ali Grompe Markus Kaestner Klaus H | 2013 | Journal of Clinical Investigation2013，，3： | 1 |
| 10 | Constructing con- trollers for physical nmhilegged robots using the ENSO neu- roevolution approach显示文摘 | Vinod K V Jonathan H Rohcrt M c| al | 2012 | Evolutionary Intelligence2012，，5： | 1 |
| 11 | Differentiation of subendocardial and transmural infarction using two-dimensional strain rate imaging to assess short-axis and long-axis myocardial function显示文摘 | Jonathan C Lizelle H Wong C | 2006 | J Am Coll Cardiol2006，48，10： | 1 |
| 12 | Modeling of chaotic DC/DC converters by iterated nonlinear mappings显示文摘 | David C H Jonathan H B D David J | 1992 | Power Electronics1992，7，1： | 1 |
| 13 | Deformable dose accumulation with image guided radiotherapy for final dose evaluation in pelvic cases 显示文摘 | YUNFENG C JONATHAN W P AMY S H | 2012 | J Nucl Ned Radiat Ther2012，2，： | 1 |
| 14 | Instability sub harmonics and chaos in power electronic systems 显示文摘 | JONATHAN H B DEANE Y DAVID C | 1990 | Transaction on Power Electronics1990，5，3： | 1 |
| 15 | Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial显示文摘 | Paul Y Kwo Eric J Lawitz Jonathan McCone Eugene R Schiff John M Vierling David Pound Mitchell N Davis Joseph S Galati Stuart C Gordon Natarajan Ravendhran Lorenzo Rossaro Frank H Anderson Ira M Jacobson Raymond Rubin Kenneth Koury Lisa D Pedicone Clifford | 2010 | The Lancet2010，，9742： | 1 |
| 16 | Determination of furosine in honey显示文摘 | JONATHAN C R BLEN G V EDUARDO G H | 2003 | J Liq Chromatogr Relat Technol2003，26，2： | 1 |
| 17 | A database of annotated tentative orthologs from eropabiotic stress transcripts 显示文摘 | Jayashree B Jonathan H C Presad P | 2006 | Bioinformation2006，6，1： | 1 |
| 18 | Proton and gamma radiation effects in a new firstgeneration SiGe HBT technology显示文摘 | BECCA M H MUSTANSIR M P JONATHAN P C | | Solid-State Electronics0，50，2： | 1 |
| 19 | An HLA-A2-restrieted Tyrosinase Antigen on Melanoma Cells Results from Posttranslational Modification and Suggests a Novel Pathway for Processing of Membrane Proteins显示文摘 | Jonathan C A Skipper Ronald C Hendrickson Pamela H Gulden | 1996 | J Exp Med1996，，183： | 1 |
| 20 | Strand spaces:proving security protocols correct显示文摘 | Fdbrega J T Jonathan C H Joshua D G | 1999 | Journal of Computer Security1999，7，23： | 1 |
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