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W2476 ameliorates beta-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway

文献类型：期刊论文

作者Li, Ting2,5,6; Lin, Guang-yao4,5; Zhong, Li2,5,6; Zhou, Yan2,6; Wang, Jia2,6; Zhu, Yue2,5,6; Feng, Yang2,6; Cai, Xiao-qing2,6; Liu, Qing2,6; Nosjean, Olivier3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2017-07
卷号38期号:7页码:1024-1037
关键词diabetes glucose TXNIP beta-cells W2476 high-throughput screening
ISSN号1671-4083
DOI10.1038/aps.2017.15
文献子类Article
英文摘要Recent evidence shows that high glucose levels recruit carbohydrate response element-binding protein, which binds the promoter of thioredoxin-interacting protein (txnip), thereby regulating its expression in beta-cells. Overexpression of txnip not only induces beta-cell apoptosis but also reduces insulin production. Thus, the discovery of compounds that either inhibit TXNIP activity or suppress its expression was the focus of the present study. INS-1E cells stably transfected with either a txnip proximal glucose response element connected to a luciferase reporter plasmid (BG73) or full-length txnip promoter connected to a luciferase reporter plasmid (CL108) were used in primary and secondary high-throughput screening campaigns, respectively. From 256 000 synthetic compounds, a small molecule compound, W2476 [9-((1-(4-acetyl-phenyloxy)-ethyl)-2-)denine], was identified as a modulator of the TXNIP-regulated signaling pathway following the screening and characterized using a battery of bioassays. The preventive and therapeutic properties of W2476 were further examined in streptozotocin-induced diabetic and diet-induced obese mice. Treatment with W2476 (1, 5, and 15 mu mol/L) dose-dependently inhibited high glucose-induced TXNIP expression at the mRNA and protein levels in INS-1E cells and rat pancreatic islets. Furthermore, W2476 treatment prevented INS-1E cells from apoptosis induced by chronic exposure of high glucose and enhanced insulin production in vitro. Oral administration of W2476 (200 mg.kg(-1).d(-1)) rescued streptozotocin-induced diabetic mice by promoting beta-cell survival and enhancing insulin secretion. This therapeutic property of W2476 was further demonstrated by its ability to improve glucose homeostasis and insulin sensitivity in diet-induced obese mice. Thus, chemical intervention of the TXNIP-regulated signaling pathway might present a viable approach to manage diabetes.
WOS关键词UP-REGULATED PROTEIN-1 ; CARBOHYDRATE RESPONSE ELEMENT ; CALCIUM-CHANNEL BLOCKERS ; OXIDATIVE STRESS ; GLUCOSE TOXICITY ; MIXED DISULFIDE ; EXPRESSION ; TXNIP ; IDENTIFICATION ; APOPTOSIS
资助项目National Health and Family Planning Commission[2012ZX09304-011] ; National Health and Family Planning Commission[2013ZX09401003-005] ; National Health and Family Planning Commission[2013ZX09507001] ; National Health and Family Planning Commission[2013ZX09507002] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Shanghai Science and Technology Development Fund[14431901200] ; Ministry of Science and Technology International Cooperation Program[2014DFG32200] ; Les Laboratories Servier (France)[00000000] ; Thousand Talents Program in China[00000000]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000404918600006
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/272585]  
专题国家新药筛选中心
通讯作者Wang, Ming-wei
作者单位1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
3.Inst Rech SERVIER, Pole Expertise Biotechnol Chim & Biol, F-78290 Croissy Sur Seine, France;
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
6.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Li, Ting,Lin, Guang-yao,Zhong, Li,et al. W2476 ameliorates beta-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway[J]. ACTA PHARMACOLOGICA SINICA,2017,38(7):1024-1037.
APA Li, Ting.,Lin, Guang-yao.,Zhong, Li.,Zhou, Yan.,Wang, Jia.,...&Wang, Ming-wei.(2017).W2476 ameliorates beta-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway.ACTA PHARMACOLOGICA SINICA,38(7),1024-1037.
MLA Li, Ting,et al."W2476 ameliorates beta-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway".ACTA PHARMACOLOGICA SINICA 38.7(2017):1024-1037.

入库方式： OAI收割

来源：上海药物研究所

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