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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 | Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: Impact of dietary fat source显示文摘BACKGROUND The trans-fat containing AMLN(amylin liver non-alcoholic steatohepatitis,NASH)diet has been extensively validated in C57BL/6J mice with or without the Lep^ob/Lep^ob(ob/ob)mutation in the leptin gene for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH.Due to a recent ban on trans-fats as food additive,there is a marked need for developing a new diet capable of promoting a compatible level of disease in ob/ob and C57BL/6J mice.AIM To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated fat.METHODS Male ob/ob mice were fed AMLN diet or a modified AMLN diet with trans-fat(Primex shortening)substituted by equivalent amounts of palm oil[Gubra amylin NASH,(GAN)diet]for 8,12 and 16 wk.C57BL/6J mice were fed the same diets for 28 wk.AMLN and GAN diets had similar caloric content(40%fat kcal),fructose(22%)and cholesterol(2%)level.RESULTS The GAN diet was more obesogenic compared to the AMLN diet and impaired glucose tolerance.Biopsy-confirmed steatosis,lobular inflammation,hepatocyte ballooning,fibrotic liver lesions and hepatic transcriptome changes were similar in ob/ob mice fed the GAN or AMLN diet.C57BL/6J mice developed a mild to moderate fibrotic NASH phenotype when fed the same diets.CONCLUSION Substitution of Primex with palm oil promotes a similar phenotype of biopsyconfirmed NASH in ob/ob and C57BL/6J mice,making GAN diet-induced obese mouse models suitable for characterizing novel NASH treatments. | Michelle L Boland Denise Oro Kirstine S T■lb■l Sebastian T Thrane Jens Christian Nielsen Taylor S Cohen David E Tabor Fiona Fernandes Andrey Tovchigrechko Sanne S Veidal Paul Warrener Bret R Sellman Jacob Jelsing Michael Feigh Niels Vrang James L Trevaskis Henrik H Hansen | 2019 | World Journal of Gastroenterology2019，25，33： | 3 |
| 3 | Pre-processing EO-1 Hyperion hyperspectral data to support the application of agricultural indices 显示文摘 | DATT B MCVICAR T R VAN NIEL T G | 2003 | IEEE Transactions on Geoscience and Remote Sensing2003，41，6： | 1 |
| 4 | Preprocessing EO-1 hyperion hyperspectral data to support the application of agricultural indexes显示文摘 | Datt B McVicar T R Van Niel | 2003 | IEEE Transactions on Geosciences and Remote Sensing2003，41，6： | 1 |
| 5 | Variability of global left ventricular deformation analysis using vendor dependent and independent two-dimensional speckle-tracking software in adults显示文摘 | Niels R Sophia A Niels T | 2012 | Journal of the American Society of Echocardiography2012，25，11： | 1 |
| 6 | Moths produce extremely quietultrasonic courtship songs by rubbing specialized scales显示文摘 | Ryo N Niels S Takuma T | 2008 | ProcNatl Acad Sci USA2008，105，11： | 1 |
| 7 | Fuzzy Logic Control for Parallel Hybrid Vehicles 显示文摘 | Schouten Niels T Salman Mutasim A Kheir Naim A | 2002 | IEEE Transactions on Control Systems Technology2002，10，3： | 1 |
| 8 | A simple method to improve field- level rice identification : toward operational monitoring with satel- lite remote sensing显示文摘 | Van Niel T G Me Vicar T R | 2003 | Aust J Exp Agr2003，43，： | 1 |
| 9 | Pancreatic cancer: cause and result of diabetes mellitus显示文摘 | Niels T | 2008 | Gastroenterology2008，134，1： | 1 |
| 10 | Mechanism of thaumasite formation in concrete slabs on grade in southern califomia显示文摘 | SADANAND S STEVE B NIELS T | 2003 | Cement & Concrete Composites2003，25，8： | 1 |
| 11 | Production of phycocyanin:a pigment with applications in biology,biotechnology,foods and medicine显示文摘 | Niels T E | 2008 | Microbilol Biotechnol2008，80，： | 1 |
| 12 | Calculating environmental moisture for per-field discrimination of rice crops显示文摘 | Van Niel T G McVicar T R Fang H | | 0，，04： | 1 |
| 13 | Stability likelihood of coalitions in a twostage cartel game:An estimation method显示文摘 | Niels J O Eligius M T H | 2006 | European Journal of Operational Research2006，174，1： | 1 |
| 14 | Developing a decision support tool for China's re-vegetation program:Simulating regional impacts of afforestation on average streamflow in the Loess Plateau 显示文摘 | McVicar T R Li L Niel T | 2007 | Forest Ecol Manage2007，251，： | 1 |
| 15 | Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: Systematic review and meta-analysis显示文摘 | Dániel Aradi András Komócsi András Vorobcsuk Orsolya Rideg Margit T?kés-Füzesi Tamás Magyarlaki Iván Gábor Horváth Victor L. Serebruany | 2010 | American Heart Journal2010，，3： | 1 |
| 16 | An international system for human cytogenetic nomenclature显示文摘 | LISA G S NIELS T | 2005 | Basel:ISCN2005，，： | 1 |
| 17 | Response to treatment in Brazilian patients with chronic hepatitis C is associated with a single-nucleotide polymorphism near the interleukin-28B gene显示文摘 | Grandi T da Silva CM Amaral KM Picon PD Costi C da Fre NN Fiegenbaum M Niel C Rossetti ML | 2013 | Mem Inst Oswaldo Cruz2013，108，1： | 1 |
| 18 | Mechanism of concrete deterioration due to salt crystallization显示文摘 | NIELS T SADANANDA S | 2004 | Materials Characterization2004，，53： | 1 |
| 19 | Mechanism of thaumasite formation in concrete slabs on grade in Southern California显示文摘 | SADANAND S STEVE B NIELS T | 2003 | Cem & Concr Compo2003，25，8： | 1 |
| 20 | Phosphorus fertilizer effects on soil phosphorus pools in acid upland soils 显示文摘 | Achim D Thomas G Niels T | 2002 | Soil Science Society of America Journal2002，66，： | 1 |
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