Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii
文献类型：期刊论文
| 作者 | Dai,Manyun; Peng,Wan ; Lin,Lisha; Wu,Zhanxuan; Zhang,Ting; Zhao,Qi; Cheng,Yan; Lin,Qiuxia; Zhang,Binbin; Liu,Aiming
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| 刊名 | PHYTOMEDICINE
 |
| 出版日期 | 2023 |
| 卷号 | 121页码:155054 |
| 关键词 | Intestinal bleeding Triptolide Celastrol Intestinal FXR Tripterygium wilfordii FARNESOID-X-RECEPTOR BACTERIAL TRANSLOCATION ACTIVATION INFLAMMATION DYSFUNCTION TRIPTOLIDE MICROBIOTA PREVENTS OBESITY MICE |
| ISSN号 | 1618-095X |
| DOI | 10.1016/j.phymed.2023.155054 |
| 英文摘要 | Background: Tripterygium wilfordii has been widely used for the treatment of rheumatoid arthritis, which is frequently accompanied by severe gastrointestinal damage. The molecular mechanism underlying the gastro-intestinal injury of Tripterygium wilfordii are yet to be elucidated. Methods: Transmission electron microscopy, and pathological and biochemical analyses were applied to assess intestinal bleeding. Metabolic changes in the serum and intestine were determined by metabolomics. In vivo (time-dependent effect and dose-response) and in vitro (double luciferase reporter gene system, DRATs, molec-ular docking, HepG2 cells and small intestinal organoids) studies were used to identify the inhibitory role of celastrol on intestinal farnesoid X receptor (FXR) signaling. Fxr-knockout mice and FXR inhibitors and agonists were used to evaluate the role of FXR in the intestinal bleeding induced by Tripterygium wilfordii. Results: Co-treatment with triptolide + celastrol (from Tripterygium wilfordii) induced intestinal bleeding in mice. Metabolomic analysis indicated that celastrol suppressed intestinal FXR signaling, and further molecular studies revealed that celastrol was a novel intestinal FXR antagonist. In Fxr-knockout mice or the wild-type mice pre-treated with pharmacological inhibitors of FXR, triptolide alone could activate the duodenal JNK pathway and induce intestinal bleeding, which recapitulated the pathogenic features obtained by co-treatment with triptolide and celastrol. Lastly, intestinal bleeding induced by co-treatment with triptolide and celastrol could be effectively attenuated by the FXR or gut-restricted FXR agonist through downregulation of the duodenal JNK pathway. Conclusions: The synergistic effect between triptolide and celastrol contributed to the gastrointestinal injury induced by Tripterygium wilfordii via dysregulation of the FXR-JNK axis, suggesting that celastrol should be included in the quality standards system for evaluation of Tripterygium wilfordii preparations. Determining the mechanism of the FXR-JNK axis in intestinal bleeding could aid in the identification of additional therapeutic targets for the treatment of gastrointestinal hemorrhage diseases. This study also provides a new standard for the quality assessment of Tripterygium wilfordii used in the treatment of gastrointestinal disorders. |
| WOS记录号 | WOS:001083436600001 |
| 源URL | [http://ir.kib.ac.cn/handle/151853/75396]  |
| 专题 | 中国科学院昆明植物研究所 |
| 推荐引用方式 GB/T 7714 | Dai,Manyun,Peng,Wan,Lin,Lisha,et al. Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii[J]. PHYTOMEDICINE,2023,121:155054. |
| APA | Dai,Manyun.,Peng,Wan.,Lin,Lisha.,Wu,Zhanxuan.,Zhang,Ting.,...&Li,Fei.(2023).Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii.PHYTOMEDICINE,121,155054. |
| MLA | Dai,Manyun,et al."Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii".PHYTOMEDICINE 121(2023):155054. |
入库方式： OAI收割
来源：昆明植物研究所
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