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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 | Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial显示文摘 | JY Douillard D Cunningham AD Roth M Navarro RD James P Karasek P Jandik T Iveson J Carmichael M Alakl G Gruia L Awad P Rougier | 2000 | The Lancet2000，，9209： | 4 |
| 3 | Geometric primitive extraction using a genetic algorithm显示文摘 | Roth G Levin M D | 1994 | IEEE Trans on PAMI1994，16，9： | 2 |
| 4 | The cost of hospitalization in Crohn’s disease显示文摘 | Russell D Cohen Leanne R Larson Joel M Roth Russell V Becker Lisa L Mummert | 2000 | The American Journal of Gastroenterology2000，，2： | 2 |
| 5 | Role for dopamine in the behavioral functions of the prefrontal corticostriatal system: implications for mental disorders and psychotropic drag action显示文摘 | Jentsch J D Roth R H Taylor J R | 2000 | Prog Brain Res2000，126，： | 2 |
| 6 | Reasoning with models显示文摘 | MADISO WI KHARDON R ROTH D | 1996 | Artificial Intelligence1996，87，： | 1 |
| 7 | CAP(cyclophosphamide,adriamycin,platinum) vs CMFVP(cyclophosphamide,methorrexate,5-florouracil,Vincristin,prednisone) combination chemotherapy in untreated metastatic breast cancer显示文摘 | Kolaric K Roth A Vukas D | 1984 | Cancer Chemother Pharmacol1984，13，1： | 1 |
| 8 | Expression of cyclooxygenase-2 in human squamous cell carcinoma of the esophagus: an immunohistochemical survey 显示文摘 | Ratnasinghe D Tangrea J Roth MJ | 1999 | Anticancer Res1999，19，1： | 1 |
| 9 | 5-Fluorouracil as protracted continuous intravenous infusion can be added to full-dose docetaxel (Taxotere)-cisplatin in advanced gastric carcinoma:a phase Ⅰ-Ⅱ trial显示文摘 | Roth A D Maibach R Fazio N | 2004 | Ann Oncol2004，15，5： | 1 |
| 10 | Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer:a multicentre randomized trial显示文摘 | Douillard JY Cunningham D Roth AD | | 0，，： | 1 |
| 11 | Self-assembly and phase behavior of germanium oxide nanoparticles in basic aqueous solutions显示文摘 | Rimer J D Roth D D Vlachos D G | | 0，，5： | 1 |
| 12 | Stimulation of catecholamine secretion from adrenal chromaffin cells by 14-3-3 proteins is due to reorganisation of the cortical actin network显示文摘 | Roth D Burgoyne RD | 1995 | FEBS Lett1995，374，1： | 1 |
| 13 | Role of temperature gradient in bulk crystal growth of SiC 显示文摘 | BALKAS C M MALTSEV A A ROTH M D | 2000 | Materials Science Forum2000，33，833934034： | 1 |
| 14 | Learning to detect objects in images via a sparse, part-based representation显示文摘 | Agarwal S Awan A Roth D | 2004 | Pattern Anal- ysis and Machine Intelligence IEEE Transactions on2004，26，11： | 1 |
| 15 | On the hardness of approximate reasoning显示文摘 | Roth D | 1996 | Artificial Intelligence1996，82，12： | 1 |
| 16 | Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer:a multicentre randomised trial显示文摘 | Douillard JY Cunningham D Roth AD | 2000 | Lancet2000，355，9209： | 1 |
| 17 | NAT for HBV and anti- HBe testing increase blood safety 显示文摘 | Roth WK Weber M Petersen D | 2002 | Transfusion2002，42，7： | 1 |
| 18 | Aspirin, platelets, and thrombo-sis: theory and practice显示文摘 | ROTH G J CALVERLEY D C | 1994 | Blood1994，83，4： | 1 |
| 19 | Primary CNS lymphoma in the elderly:temozolomide therapy and MGMT status显示文摘 | Kurzwelly D Glas M Roth P | 2010 | J Neurooncol2010，97，3： | 1 |
| 20 | Cross-reactivity of Epstein-Barr Virus specific immunoglobulin M antibodies with cytomegalovirus antigens containing glycine homoplymers显示文摘 | Lang D Vornhagen R Rothe M | 2001 | Clin Diagh Lab immunol2001，8，4： | 1 |
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