Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii

doi:10.1016/j.phymed.2023.155054

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	Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii
	Dai,Manyun; Peng,Wan; Lin,Lisha; Wu,Zhanxuan; Zhang,Ting; Zhao,Qi; Cheng,Yan; Lin,Qiuxia; Zhang,Binbin; Liu,Aiming; Rao,Qianru; Huang,Jianfeng; Zhao,Jinhua; Gonzalez,Frank J.; Li,Fei
	2023
发表期刊	PHYTOMEDICINE
ISSN	1618-095X
卷号	121 页码:155054
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.
关键词	Intestinal bleeding Triptolide Celastrol Intestinal FXR Tripterygium wilfordii FARNESOID-X-RECEPTOR BACTERIAL TRANSLOCATION ACTIVATION INFLAMMATION DYSFUNCTION TRIPTOLIDE MICROBIOTA PREVENTS OBESITY MICE
DOI	10.1016/j.phymed.2023.155054
收录类别	SCI
WOS记录号	WOS:001083436600001
引用统计
文献类型	期刊论文
条目标识符	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.

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