Tripterygium wilfordii Hook.f induced kidney injury through mediating inflammation via PI3K-Akt/HIF-1/TNF signaling pathway: A study of network toxicology and molecular docking
Tripterygium wilfordii Hook.f induced kidney injury through mediating inflammation via PI3K-Akt/HIF-1/TNF signaling pathway: A study of network toxicology and molecular docking
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DOI：
10.1097/md.0000000000036968
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发表时间：
2024-02
期刊：
影响因子：
1.6
通讯作者：
Shuo Yang;Mengmeng Wang;Zhongming Li;Xiangjia Luan;Yanan Yu;Junjie Jiang;Yuanyuan Li;Yanming Xie;Lianxin Wang
中科院分区：
文献类型：
--
作者：
Shuo Yang;Mengmeng Wang;Zhongming Li;Xiangjia Luan;Yanan Yu;Junjie Jiang;Yuanyuan Li;Yanming Xie;Lianxin Wang
本研究拟采用网络毒理学和分子对接的方法探讨雷公藤多甙（Tripterygium wilfordii Hook.f，TwHF）致肾损伤的可能机制。我们确定了TwHF潜在化合物及其靶点和KI靶点，并将TwHF和KI靶点交叉后获得了TwHF诱导的KI靶点。通过蛋白质-蛋白质相互作用（PPI）网络、基因表达分析、基因本体（GO）功能和京都基因与基因组百科全书（KEGG）途径富集分析，探讨了TwHF诱导KI的机制。最后通过分子对接验证了核心毒性化合物和靶点。我们获得了12个雷公藤毒性化合物和62个雷公藤诱导KI靶点。PPI网络、基因表达分析和GO功能富集分析揭示了关键的生物学过程，并提示TwHF诱导KI的机制可能与炎症、免疫反应、缺氧以及氧化应激有关。KEGG信号通路富集分析表明PI 3 K-Akt信号通路、HIF-1信号通路和TNF信号通路是雷公藤红素诱导KI的关键信号通路。分子对接结果表明，核心靶点与毒性化合物的结合能均小于−6.5 kcal/mol，验证了网络药理学的筛选能力，为TwHF毒性化合物的结构修饰提供了依据。本研究揭示了雷公藤多甙诱导KI的机制，即雷公藤多甙可能通过激活PI 3 K-Akt信号通路和TNF信号通路促进肾脏炎症，通过HIF-1信号通路介导缺氧加速炎症过程，为雷公藤多甙毒性化合物的结构修饰提供理论依据，并为后续研究提供支持。
We intend to explore potential mechanisms of Tripterygium wilfordii Hook.f (TwHF) induced kidney injury (KI) using the methods of network toxicology and molecular docking. We determined TwHF potential compounds with its targets and KI targets, obtained the TwHF induced KI targets after intersecting targets of TwHF and KI. Then we conducted protein-protein interaction (PPI) network, gene expression analysis, gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis to explore the mechanism of TwHF-induced KI. Finally we conducted molecular docking to verify the core toxic compounds and the targets. We obtained 12 TwHF toxic compounds and 62 TwHF-induced KI targets. PPI network, gene expression analysis and GO function enrichment analysis unveiled the key biological process and suggested the mechanism of TwHF-induced KI might be associated with inflammation, immune response, hypoxia as well as oxidative stress. KEGG pathway enrichment analysis indicated PI3K-Akt signaling pathway, HIF-1 signaling pathway and TNF signaling pathway were key signaling pathways of TwHF induced KI. Molecular docking showed that the binding energy of core targets and toxic compounds was all less than −6.5 kcal/mol that verified the screening ability of network pharmacology and provided evidence for modifying TwHF toxic compounds structure. Through the study, we unveiled the mechanism of TwHF induce KI that TwHF might activate PI3K-Akt signaling pathway as well as TNF signaling pathway to progress renal inflammation, mediate hypoxia via HIF-1 signaling pathway to accelerate inflammatory processes, and also provided a theoretical basis for modifying TwHF toxic compounds structure as well as supported the follow-up research.