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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 | Effects of liraglutide and sibutramine on food intake, palatability, body weight and glucose tolerance in the gubra DlO-rats显示文摘 | Gitte HANSEN Jacob JELSlNG Niels VRANG | 2012 | Acta Pharmacologica Sinica2012，33，2： | 6 |
| 3 | Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis显示文摘AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH. | Kirstine S Tolbol Maria NB Kristiansen Henrik H Hansen Sanne S Veidal Kristoffer TG Rigbolt Matthew P Gillum Jacob Jelsing Niels Vrang Michael Feigh | 2018 | World Journal of Gastroenterology2018，24，2： | 5 |
| 4 | Laminated Fe-34.5 Mn-0.04C composite with high strength and ductility显示文摘To obtain a good combination of strength and ductility, a laminated composite structure composed of recovered hard lamellae and soft recrystallized lamellae has been produced in a single phase austenitic Fe-34.5 Mn-0.04 C steel by cold rolling and partial recrystallization. Enhanced mechanical properties in both strength and ductility have been obtained in the composite structure compared to a fully recrystallized coarse grain structure. A further increase in strength with only minor loss in total elongation has been achieved by a slight cold rolling of the composite structure, which also removes the small yield drop and Lüders elongation observed in the composite structure. | Yuhui Wang Jianmei Kang Yan Peng Tiansheng Wang Niels Hansen Xiaoxu Huang | 2018 | Journal of Materials Science & Technology2018，34，10： | 4 |
| 5 | 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 |
| 6 | Phenology of high-arctic butterflies and their floral resources: Species-specific responses to climate change显示文摘 | Toke T.HФYE Anne ESKILDSEN Rikke R. HANSEN Joseph J.BOWDEN Niels M.SCHMIDT W.Daniel KISSLING | 2014 | Current Zoology2014，60，2： | 2 |
| 7 | High expression of microRNA-625-3p is associated with poor response to first-line oxaliplatin based treatment of metastatic colorectal cancer显示文摘 | Mads H. Rasmussen Niels F. Jensen Line S. Tarpgaard Camilla Qvortrup Maria U. R?mer Jan Stenvang Tine P. Hansen Lise L. Christensen Jan Lindebjerg Flemming Hansen Benny V. Jensen Torben F. Hansen Per Pfeiffer Nils Brünner Torben F. ?rntoft Claus L. Anders | 2013 | Molecular Oncology2013，，3： | 2 |
| 8 | Hall–Petch relation and boundary strengthening显示文摘 | Niels Hansen | 2004 | Scripta Materialia2004，，： | 2 |
| 9 | Hardening by annealing and softening by deformation in nanostructured metals 显示文摘 | Xiaoxu Huang Niels Hansen Nobuhiro Tsuji | 2006 | Science2006，312，： | 1 |
| 10 | Hall-Petch relation and boundary strengthening显示文摘 | Niels Hansen | 2004 | ScriptaMaterialia2004，51，8： | 1 |
| 11 | Subclinical Coronary and Aortic Atherosclerosis Detected by Magnetic Resonance Imaging in Type 1 Diabetes With and Without Diabetic Nephropathy显示文摘 | Won Yong Kim Anne Sofie Astrup Matthias Stuber Lise Tarnow Erling Falk René M. Botnar Cheryl Simonsen Lotte Pietraszek Peter R. Hansen Warren J. Manning Niels T. Andersen Hans-Henrik Parving | 2007 | Circulation2007，，2： | 1 |
| 12 | Detection of Enterotoxic Bacillus cereus and Bacillus thuringiensis Strains by PCR Analysis显示文摘 | Munk Bjarne Hansen Bohse Niels Hendriksen | 2001 | Applied and Environmental Microbiology2001，67，1： | 1 |
| 13 | HalI-Petch relation and boundary strengthening显示文摘 | Niels Hansen | 2004 | Scripta Materialia2004，10，51： | 1 |
| 14 | Precipitation strengthening显示文摘 | Hansen Niels | 1985 | Metallurgical Transactions A1985，16，12： | 1 |
| 15 | Macroscopic and microscopic subdivision of a cold-rolled aluminium single crystal of cubic orientation 显示文摘 | Niels Hansen | 1998 | The Royal Society1998，454，： | 1 |
| 16 | Strengthening mechanisms in nanostructured high-purity aluminium deformed to high strain and annealed显示文摘 | Naoya Kamikawa Xiaoxu Huang Nobuhiro Tsuji Niels Hansen | 2009 | Acta Materialia2009，，14： | 1 |
| 17 | Recent advances in the nutrition of fur animals显示文摘 | Hansen Niels Enggaard | 1992 | Norwegian Journal of Agricultural Sciences1992，，9： | 1 |
| 18 | Hierarchical structures in cold-drawn pearlitic steel wire显示文摘 | Xiaodan Zhang Andrew Godfrey Niels Hansen Xiaoxu Huang | 2013 | Acta Materialia2013，，13： | 1 |
| 19 | Microstructure and strengthening mechanisms in cold-drawn pearlitic steel wire显示文摘 | Xiaodan Zhang Andy Godfrey Xiaoxu Huang Niels Hansen Qing Liu | 2011 | Acta Materialia2011，，9： | 1 |
| 20 | Microstructure evolution during plastic deformation of metals显示文摘 | Xiaoxu HUANG Niels HANSEN | 2003 | CA MP-ISIJ2003，16，： | 1 |
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