肠血管屏障介导雷公藤致肝损伤：雷公藤甲素与雷公藤红素通过肠道FXR-ET-1途径的协同作用
Gut-vascular barrier mediated Tripterygium wilfordii-induced liver injury: the synergism between triptolide and celastrol via intestinal FXR-ET-1 pathway.
作者信息
Dai Manyun, Peng Wan, Zhang Binbin, Lin Qiuxia, Zhang Ting, Liu Aiming, Li Fei
机构信息
Laboratory of Hepato-intestinal Diseases and Metabolism, 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, 315211, Ningbo, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
Laboratory of Hepato-intestinal Diseases and Metabolism, 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.
出版信息
J Ethnopharmacol. 2025 Jun 12;349:119900. doi: 10.1016/j.jep.2025.119900. Epub 2025 Apr 28.
ETHNOPHARMACOLOGICAL RELEVANCE
Therapy based on Tripterygium wilfordii Hook F (TWHF) is considered as one of the most effective and vital treatments for managing rheumatoid arthritis. It induces significant liver toxicities in 11.4 % of the patients, but the mechanisms not well known.
AIM OF THE STUDY
This study examined the mechanisms of the drug interaction between Cela and Trip which mediate the hepatotoxicity of TWHF.
METHODS
Pathological and biochemical methods were utilized to evaluated liver damage. The metabolic alterations occurring in the serum and liver were assessed via metabolism. Transmission electron microscope, Evans blue infiltrating, LPS and DAO activity were used to evaluate GVB. Fxr-knockout mice, intestinal FXR agonists and inhibitors were used to reveal the critical role of intestinal FXR in liver injury. Endothelin-1 (ET-1) inhibitors and over-expression vector were applied to evaluate the regulatory role of FXR-ET-1 in GVB.
RESULTS
The synergistic actions of triptolide (Trip) and celastrol (Cela), two major components in TWHF, led to liver injury, which involved sequential events of FXR inhibition, ET-1 up-regulation, and then GVB disruption. The intestinal FXR inhibition by Cela and probe inhibitor, and FXR knockout significantly aggravated liver injury induced by Trip. Activation of intestinal FXR alleviated liver injury via down-regulating ET-1 and improving GVB integrity. And ET-1 was found to mediate the normal structure and function of GVB. In HUVECs, FXR inhibition by Cela potentiated the ET-1 increase and activation of JNK-Caspase3-GSDME by Trip.
CONCLUSIONS
Thus, Cela as an identified intestinal FXR antagonist up-regulated ET-1 expression, thereby disrupted GVB. This interaction between Cela and Trip mediated TWHF-induced liver injury. Activation of intestinal FXR and protection of GVB were suggested to be strategies for the treatment of DILI.
民族药理学相关性
基于雷公藤（Tripterygium wilfordii Hook F，TWHF）的疗法被认为是治疗类风湿性关节炎最有效且至关重要的治疗方法之一。它在11.4%的患者中会引发显著的肝脏毒性，但其机制尚不清楚。
研究目的
本研究探讨了塞来昔布（Cela）与雷公藤多苷（Trip）之间药物相互作用介导TWHF肝毒性的机制。
方法
采用病理和生化方法评估肝损伤。通过代谢评估血清和肝脏中发生的代谢变化。利用透射电子显微镜、伊文思蓝浸润、脂多糖（LPS）和二胺氧化酶（DAO）活性评估肠道屏障功能（GVB）。使用法尼酯X受体（Fxr）基因敲除小鼠、肠道FXR激动剂和抑制剂来揭示肠道FXR在肝损伤中的关键作用。应用内皮素-1（ET-1）抑制剂和过表达载体评估FXR-ET-1在GVB中的调节作用。
结果
TWHF中的两种主要成分雷公藤甲素（Trip）和雷公藤红素（Cela）的协同作用导致肝损伤，这涉及FXR抑制、ET-1上调以及随后的GVB破坏的连续事件。Cela和探针抑制剂对肠道FXR的抑制以及FXR基因敲除显著加重了Trip诱导的肝损伤。肠道FXR的激活通过下调ET-1和改善GVB完整性减轻肝损伤。并且发现ET-1介导GVB的正常结构和功能。在人脐静脉内皮细胞（HUVECs）中，Cela对FXR的抑制增强了Trip诱导的ET-1增加以及JNK-半胱天冬酶3- Gasdermin E（JNK-Caspase3-GSDME）的激活。
结论
因此，作为已确定的肠道FXR拮抗剂，Cela上调ET-1表达，从而破坏GVB。Cela与Trip之间的这种相互作用介导了TWHF诱导的肝损伤。肠道FXR的激活和GVB的保护被认为是治疗药物性肝损伤（DILI）的策略。
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