Proteomics analysis reveals novel insights into the mechanism of hepatotoxicity induced by Tripterygium wilfordii multiglycoside in mice.
Proteomics analysis reveals novel insights into the mechanism of hepatotoxicity induced by Tripterygium wilfordii multiglycoside in mice.
复制标题
DOI：
10.3389/fphar.2022.1032741
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
Jiang, Zhenzhou
中科院分区：
文献类型：
--
作者：
Miao, Yingying;Zhang, Qin;Yuan, Zihang;Wang, Jie;Xu, Yunxia;Chai, Yuanyuan;Du, Min;Yu, Qinwei;Zhang, Luyong;Jiang, Zhenzhou
关键词：
雷公藤多苷（GTW）是从雷公藤（Tripterygiumwilfordii）的去皮根中提取纯化得到的一种有效成分。雷公藤雷公藤多甙（TwHF）是一种著名的传统中药，临床上应用于多种自身免疫性疾病。然而，据报道，它会导致严重的肝损伤。目前，GTW诱导肝毒性的机制仍不清楚。本研究采用无标记蛋白质组学技术结合生物信息学分析方法，评价雷公藤多甙对小鼠肝脏的影响，并阐明其作用机制。雄性C57 BL/6J小鼠随机分为正常组、雷公藤多甙低剂量组（70 mg/kg）和雷公藤多甙高剂量组（140 mg/kg）。给药1周后，GTW剂量依赖性地诱导肝毒性。进一步分析表明，GTW可作用于肠道免疫网络中的IgA生成途径，在维持肠道内环境稳定中发挥重要作用，并影响肠道与肝脏之间的相互作用。Western blot证实GTW可降低肝脏和回肠中pIgR蛋白的表达，从而减少IgA向肠腔的分泌。进一步验证表明，GTW处理的小鼠肠道屏障完整性受损，促进细菌转移到肝脏并引发促炎反应。我们的研究结果表明，肝-肠轴可能在雷公藤多甙肝毒性的发展过程中起着重要作用，这为雷公藤多甙的基础研究和临床应用提供了指导。
Tripterygium wilfordii multiglycoside (GTW), extracted and purified from the peeled roots of T. wilfordii Hook.f. (TwHF), is a well-known traditional Chinese medicine and applied to various autoimmune diseases clinically. However, it has been reported to cause severe liver injury. At present, the mechanism underlying GTW-induced hepatotoxicity remain poorly defined. Here, we evaluated the effects of GTW on mouse liver and elucidated the associated mechanisms via label-free proteomics combined with bioinformatics analysis. Male C57BL/6J mice were randomly divided into normal group, a low-dose GTW (70 mg/kg) group and a high-dose GTW (140 mg/kg) group. After 1-week administration, GTW dose-dependently induced hepatotoxicity. Further analysis showed that GTW could act on the intestinal immune network for IgA production pathway, which plays an important role in maintaining intestinal homeostasis and influences the crosstalk between gut and liver. Western blots confirmed that GTW could decrease pIgR protein expression in the liver and ileum, and, as a result, the secretion of IgA into gut lumen was reduced. Further validation showed that intestinal barrier integrity was impaired in GTW-treated mice, promoting bacteria transferring to the liver and triggering proinflammatory response. Our study demonstrated that gut-liver axis may play a vital part in the progression of GTW-induced hepatotoxicity, which provides guidance for basic research and clinical application of GTW.
登录
查看更多内容
影响因子：
5.6
作者：
Dragoi, Diana;Benesic, Andreas;Gerbes, Alexander L.
通讯作者：
Gerbes, Alexander L.
Nrf2 的激活可防止雷公藤甲素诱发的肝毒性
影响因子：
3.7
作者：
Li J;Shen F;Guan C;Wang W;Sun X;Fu X;Huang M;Jin J;Huang Z
通讯作者：
Huang Z
影响因子：
7.3
作者：
Kawasaki T;Kawai T
通讯作者：
Kawai T
影响因子：
1.6
作者：
Gong, Liang;Wang, Lun;Li, Chen
通讯作者：
Li, Chen
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J