基于网络药理学探讨雷公藤红素改善奥沙利铂引起的外周神经病变的作用机制  

Analysis of the mechanism of celastrol against oxaliplatin-inducedperipheral neuropathy on network pharmacology

作　　者：许嘉越 张庚弋 江诗琴 秦之焱 黄民[1] 金晶[1] XU Jiayue;ZHANG Gengyi;JIANG Shiqin;QIN Zhiyan;HUANG Min;JIN Jing(School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China)

机构地区：[1]中山大学药学院,广东广州510006

出　　处：《药学研究》2024年第4期319-326,341,共9页Journal of Pharmaceutical Research

基　　金：广东省自然科学基金面上项目(No.2021A1515010580)。

摘　　要：目的结合实验与网络药理学探讨雷公藤红素改善奥沙利铂引起的外周神经病变(OIPN)的作用与机制。方法对大鼠进行奥沙利铂与雷公藤红素的合用给药考察雷公藤红素对OIPN的改善作用。使用中药系统药理学数据库与分析平台(TCMSP)、SwissTargetPrediction和PharmMapper数据库收集雷公藤红素靶点,并从GeneCards和OMIM数据库中获取奥沙利铂引起的外周神经病变的靶点,取两者交集,利用Cytoscape软件构建“雷公藤红素-靶点-OIPN”网络图;采用STRING数据库构建雷公藤红素改善OIPN靶点的蛋白-蛋白相互作用(PPI)网络图;应用DAVID数据库对交集靶点进行GO功能富集分析和KEGG通路富集分析,以及运用MOE软件对核心靶点进行分子对接验证。结果雷公藤红素能明显改善奥沙利铂引起的大鼠机械和冷刺激痛敏症状,减轻背根神经节神经元和坐骨神经的病理损伤,且在体外水平上不影响奥沙利铂对结肠癌细胞的杀伤作用。网络药理学分析获得雷公藤红素靶点309个,OIPN疾病靶点1318个,两者交集靶点80个;PPI相互作用网络分析得到HSP90AA1、CASP3、PTGS2等核心靶点;GO富集分析得到193个条目,KEGG结果表明,雷公藤红素可能作用于白细胞介素-17(IL-17)信号通路和PI3K/Akt信号通路起到对OIPN的改善作用;分子对接结果进一步表明,雷公藤红素与核心靶点CASP3、PTGS2的结合能力良好。结论雷公藤红素具有改善奥沙利铂引起的外周神经病变的作用,网络药理学揭示该机制可能涉及多靶点、多通路的调节。Objective To investigate the effects and mechanisms of celastrol on oxaliplatin-induced peripheral neuropathy(OIPN)by experiments and network pharmacology.Methods Oxaliplatin and celastrol were administered to rats and colon cancer cells to investigate the effect of celastrol on OIPN.The targets of celastrol were collected using TCMSP,SwissTargetPrediction and PharmMapper databases,and the targets of oxaliplatin-induced peripheral neuropathy were obtained from GeneCards and OMIM databases.Both of the intersected targets were taken and the network diagram of celastrol-targets-OIPN was constructed by Cytoscape software.The protein-protein interaction(PPI)network diagram of the targets was constructed using STRING database.DAVID database was used for GO functional enrichment analysis and KEGG pathway enrichment analysis of those intersection targets,and MOE software was used for molecular docking verification of core targets.Results Celastrol could significantly improve the mechanical and cold stimulation pain sensitivity symptoms induced by oxaliplatin in rats,reduce the pathological injury of dorsal root ganglion neurons and sciatic nerve,and do no harm on the killing effect of oxaliplatin on colon cancer cells in vitro.Network pharmacological analysis obtained 309 targets of celastrol,1318 targets of OIPN and 80 targets of their intersection.The core targets such as HSP90AA1,CASP3 and PTGS2 were obtained by PPI interaction network analysis.GO enrichment analysis obtained 193 items and KEGG results showed that celastrol might alleviate OIPN by regulating IL-17 signaling pathway and PI3K/Akt signaling pathway.The molecular docking results further indicated that celastrol had good binding ability with core targets CASP3 and PTGS2.Conclusion Celastrol could ameliorate oxaliplatin-induced peripheral neuropathy,with network pharmacology revealing that the mechanism might involve multi-targets and multi-pathways regulation.

关 键 词：雷公藤红素 奥沙利铂 外周神经病变 网络药理学 分子对接 作用机制 

分 类 号：R285[医药卫生—中药学]