雷公藤红素作为肠道 FXR 抑制剂引发雷公藤内酯诱导的肠道出血：雷公藤诱导胃肠道损伤的潜在机制,Phytomedicine

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雷公藤红素作为肠道 FXR 抑制剂引发雷公藤内酯诱导的肠道出血：雷公藤诱导胃肠道损伤的潜在机制
Phytomedicine ( IF 6.7 ) Pub Date : 2023-09-02 , DOI: 10.1016/j.phymed.2023.155054
Manyun Dai ₁ , Wan Peng ₂ , Lisha Lin ₃ , Zhanxuan E Wu ₄ , Ting Zhang ₅ , Qi Zhao ₄ , Yan Cheng ₄ , Qiuxia Lin ₄ , Binbin Zhang ₄ , Aiming Liu ₆ , Qianru Rao ₄ , Jianfeng Huang ₃ , Jinhua Zhao ₇ , Frank J Gonzalez ₈ , Fei Li ₉

Affiliation

Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; School of Public Health, Ningbo University Health Science Center, Ningbo 315211, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu 610041, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
School of Public Health, Ningbo University Health Science Center, Ningbo 315211, China.
School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, China.
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

背景

雷公藤已广泛用于治疗类风湿性关节炎，这种关节炎常常伴有严重的胃肠道损伤。雷公藤损伤胃肠道的分子机制尚未阐明。

方法

应用透射电子显微镜、病理学和生化分析来评估肠道出血。通过代谢组学测定血清和肠道的代谢变化。通过体内（时间依赖性效应和剂量反应）和体外（双荧光素酶报告基因系统、DRAT、分子对接、HepG2细胞和小肠类器官）研究来鉴定雷公藤红素对肠法尼醇X受体的抑制作用。 FXR）信令。采用FXR基因敲除小鼠以及FXR抑制剂和激动剂来评价FXR在雷公藤诱导的肠道出血中的作用。

结果

雷公藤甲素 + 雷公藤红醇（来自雷公藤）的联合治疗可诱导小鼠肠道出血。代谢组学分析表明雷公藤红醇抑制肠道 FXR 信号传导，进一步的分子研究表明雷公藤红醇是一种新型肠道 FXR 拮抗剂。在Fxr基因敲除小鼠或经FXR药物抑制剂预处理的野生型小鼠中，单独使用雷公藤甲素即可激活十二指肠JNK通路并诱导肠道出血，这再现了雷公藤甲素和雷公藤红素联合治疗所获得的致病特征。最后，FXR 或肠道限制性 FXR 激动剂通过下调十二指肠 JNK 通路，可以有效减轻雷公藤甲素和雷公藤红素联合治疗引起的肠道出血。

结论

雷公藤内酯醇和雷公藤红醇之间的协同作用通过FXR-JNK轴失调导致雷公藤所致胃肠道损伤，提示雷公藤红醇应纳入雷公藤制剂评价的质量标准体系。确定 FXR-JNK 轴在肠道出血中的机制有助于确定治疗胃肠道出血疾病的其他治疗靶点。该研究还为雷公藤用于治疗胃肠道疾病的质量评估提供了新的标准。

"点击查看英文标题和摘要"

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

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 gastrointestinal 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, molecular 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.

更新日期：2023-09-02

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