FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach

doi:10.1038/srep08114

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach
	Lu, Weiqiang 1,2,5; Cheng, Feixiong 1; Jiang, Jing 1; Zhang, Chen 1; Deng, Xiaokang 1; Xu, Zhongyu 1; Zou, Shien 3; Shen, Xu1,4 ; Tang, Yun 1; Huang, Jin 1
刊名	SCIENTIFIC REPORTS
	2015-01-29
卷号	5
ISSN号	2045-2322
DOI	10.1038/srep08114
文献子类	Article
英文摘要	Non-steroidal anti-inflammatory drugs (NSAIDs) are worldwide used drugs for analgesic, antipyretic, and anti-inflammatory therapeutics. However, NSAIDs often cause several serious liver injuries, such as drug-induced liver injury (DILI), and the molecular mechanisms of DILI have not been clearly elucidated. In this study, we developed a systems pharmacology approach to explore the mechanism-of-action of NSAIDs. We found that the Farnesoid X Receptor (FXR) antagonism of NSAIDs is a potential molecular mechanism of DILI through systematic network analysis and in vitro assays. Specially, the quantitative real-time PCR assay reveals that indomethacin and ibuprofen regulate FXR downstream target gene expression in HepG2 cells. Furthermore, the western blot shows that FXR antagonism by indomethacin induces the phosphorylation of STAT3 (signal transducer and activator of transcription 3), promotes the activation of caspase9, and finally causes DILI. In summary, our systems pharmacology approach provided novel insights into molecular mechanisms of DILI for NSAIDs, which may propel the ways toward the design of novel anti-inflammatory pharmacotherapeutics.
资助项目	National Natural Science Foundation of China[81102420] ; National Natural Science Foundation of China[81200415] ; National Natural Science Foundation of China[81373329] ; National Natural Science Foundation of China[81402482] ; Shanghai Committee of Science and Technology[11DZ2260600] ; Shanghai Committee of Science and Technology[14ZR1411100] ; China Postdoctoral Science Foundation grant[2014M551361] ; Shanghai Municipal Commission of Health and Family Planning[20124468] ; Fudan University[20520133421] ; Fundamental Research Funds for the Central Universities[WY1113007]
WOS关键词	FARNESOID-X-RECEPTOR ; NONSTEROIDAL ANTIINFLAMMATORY DRUGS ; HEPATOCELLULAR-CARCINOMA ; CLINICAL-PRACTICE ; ACID RECEPTOR ; MURINE MODEL ; HUMAN GENES ; PREDICTION ; HEPATOTOXICITY ; INFLAMMATION
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000348501100005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276663]
专题	药理学第三研究室
通讯作者	Zou, Shien
作者单位	1.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 2.E China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China; 3.Fudan Univ, Obstet & Gynecol Hosp, Dept Gynecol, Shanghai 200011, Peoples R China; 4.Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 5.E China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China;
推荐引用方式 GB/T 7714	Lu, Weiqiang,Cheng, Feixiong,Jiang, Jing,et al. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach[J]. SCIENTIFIC REPORTS,2015,5.
APA	Lu, Weiqiang.,Cheng, Feixiong.,Jiang, Jing.,Zhang, Chen.,Deng, Xiaokang.,...&Huang, Jin.(2015).FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach.SCIENTIFIC REPORTS,5.
MLA	Lu, Weiqiang,et al."FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach".SCIENTIFIC REPORTS 5(2015).