FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach
文献类型：期刊论文
| 作者 | Lu, Weiqiang1,2,5; Cheng, Feixiong1; Jiang, Jing1; Zhang, Chen1; Deng, Xiaokang1; Xu, Zhongyu1; Zou, Shien3; Shen, Xu1,4 ; Tang, Yun1; Huang, Jin1
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| 刊名 | SCIENTIFIC REPORTS
 |
| 出版日期 | 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. |
| WOS关键词 | FARNESOID-X-RECEPTOR ; NONSTEROIDAL ANTIINFLAMMATORY DRUGS ; HEPATOCELLULAR-CARCINOMA ; CLINICAL-PRACTICE ; ACID RECEPTOR ; MURINE MODEL ; HUMAN GENES ; PREDICTION ; HEPATOTOXICITY ; INFLAMMATION |
| 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研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000348501100005 |
| 出版者 | NATURE PUBLISHING GROUP |
| 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). |
入库方式： OAI收割
来源：上海药物研究所
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