Integrated network pharmacology and targeted metabolomics to reveal the mechanism of nephrotoxicity of triptolide
Integrated network pharmacology and targeted metabolomics to reveal the mechanism of nephrotoxicity of triptolide
复制标题
整合网络药理学和靶向代谢组学揭示雷公藤甲素的肾毒性机制
DOI：
10.1039/c9tx00067d
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发表时间：
2019-11-01
影响因子：
2.1
通讯作者：
Li, Yubo
中科院分区：
文献类型：
--
作者：
Huang, Wei;Liu, Chuanxin;Li, Yubo
雷公藤甲素(Triptolide，TP)是雷公藤的重要活性成分。具有较强的抗炎和免疫调节作用。然而，大量文献研究表明，茶多酚是引起肾毒性的主要成分，其作用机制尚不清楚。因此，阐明茶多酚的毒性机制具有重要的现实意义。本研究将网络药理学与靶向代谢组学相结合，揭示茶多酚的肾毒性机制。首先，对与茶多酚肾毒性相关的61个作用靶点进行了网络药理学筛选，其中直接靶点39个，间接靶点22个。随后，基于大规模蛋白质-蛋白质相互作用(PPI)和分子对接验证，确定了核心靶点。基于以上指标和浓缩分析，发现嘌呤代谢、Toll样受体信号通路和核因子-kappaB信号通路在TP诱导的肾毒性中起关键作用。文献研究表明，嘌呤和嘧啶代谢途径与肾脏疾病密切相关。因此，利用实验室建立的内源性嘌呤和嘧啶的定量测定方法，对茶多酚进行了靶向代谢组学分析。最终发现了六种肾毒性生物标志物：二氢核苷、胸腺嘧啶核苷、2-脱氧肌苷、尿酸、腺苷和黄嘌呤。综合以上结果，推测茶多酚肾毒性的机制可能是由于体内过量摄入黄嘌呤和尿酸，导致体内氧化应激释放大量ROS所致。此外，Toll样受体信号通路的激活可以促进下游蛋白NF-kappa B的磷酸化，引起炎症反应，最终导致肾毒性。
Triptolide (TP) is one of the important active components in Tripterygium wilfordii Hook. F., which shows strong anti-inflammatory and immunomodulatory effects. However, a large number of literature studies have reported that TP is the main component causing nephrotoxicity, and the mechanism of nephrotoxicity has not yet been revealed. Therefore, it is of great practical significance to clarify the toxicity mechanism of TP. This study integrated network pharmacology and targeted metabolomics to reveal the nephrotoxicity mechanism of TP. Firstly, network pharmacology screening of 61 action targets related to TP induced nephrotoxicity, with 39 direct targets and 22 indirect targets, was performed. Subsequently, based on a large-scale protein-protein interaction (PPI) and molecular docking validation, the core targets were identified. Based on the above targets and enrichment analysis, the purine metabolism, Toll-like receptor signaling pathway and NF-kappa B signaling pathway were found play a pivotal role in TP-induced nephrotoxicity. Literature investigation showed that purine and pyrimidine metabolism pathways were closely related to kidney diseases. Therefore, by using the quantitative method of determining endogenous purine and pyrimidine previously established in the laboratory, a targeted metabolomic analysis of TP was carried out. Finally, six nephrotoxicity biomarkers, dihydroorotate, thymidine, 2-deoxyinosine, uric acid, adenosine and xanthine, were found. Combining the above results, the mechanisms underlying the nephrotoxicity of TP were speculated to be due to the over-consumption of xanthine and uric acid, which would result in enormous ROS being released in response to oxidative stress in the body. Furthermore, activation of the Toll-like receptor signalling pathway can promotes the phosphorylation of the downstream protein NF-kappa B and causes an inflammatory response that ultimately leads to nephrotoxicity.