基于网络药理学方法探究补肾活血汤治疗激素性股骨头坏死的作用机制

A study of mechanism of action of Bushen Huoxue Tang(补肾活血汤)for treatment of steroid-induced osteonecrosis of the femoral head using network pharmacology approach

目的:探讨补肾活血汤治疗激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SONFH)的作用机制。方法:通过中医药整合药理学网络计算研究平台(integrative pharmacology-based network computational research platform of Traditional Chinese Medicine,TCMIP)v2.0预测、筛选补肾活血汤组方中14味中药的作用靶标,通过GeneCards、CTD和OMIM数据库查询SONFH的疾病靶点。根据获取的药物靶标和疾病靶点,进一步利用TCMIP v2.0中医药关联网络分析模块构建"药物靶标-疾病靶点"相互作用网络,根据网络拓扑特征值筛选补肾活血汤治疗SONFH的核心作用靶点。利用GO和KEGG数据库,采用富集算法挖掘上述方剂核心作用靶点的生物学功能和通路信息。结果:共获得891个补肾活血汤药物靶标和365个SONFH疾病靶点。经"药物靶标-疾病靶点"相互作用网络分析,最终筛选出31个补肾活血汤治疗SONFH核心靶点,GO功能分析富集出生物过程532条、分子功能29条,KEGG信号通路富集分析出相关通路共12条,主要涉及炎症免疫调节(chemokine signaling pathway,Toll-like receptor signaling pathway,NOD-like receptor signaling pathway,leukocyte transendothelial migration,Complement and coagulation cascades,cytokine-cytokine receptor interaction)、血管新生及血液循环调节(VEGF signaling pathway)、神经系统调节(neuroactive ligand-receptor interaction)和细胞功能调节(apoptosis,regulation of actin cytoskeleton)等方面。结论:结合SONFH的病理机制,排除缺乏特异性的信号通路,我们推测补肾活血汤可能通过调节TLR4/NF-κB和VEGF信号通路发挥补肾壮骨、活血化瘀的功效,这可能是其治疗SONFH的作用机制之一。

Objective:To explore the mechanism of action of Bushen Huoxue Tang(补肾活血汤,BSHXT)for treatment of steroid-induced osteonecrosis of the femoral head(SONFH).Methods:Fourteen Traditional Chinese Medicines(TCMs)in BSHXT prescription were screened for predicting their therapeutic targets by searching integrative pharmacology-based network computational research platform of Traditional Chinese Medicine(TCMIP)v2.0,and the pathogenic targets of SONFH were searched from GeneCards,CTD and OMIM databases.The network of interaction between drug targets and disease targets was built by using TCM association network analysis module of TCMIP v2.0 according to the obtained drug targets and pathogenic targets,and the core therapeutic targets of BSHXT for treatment of SONFH were selected according to network topology eigenvalues.The biological function and pathway information of core therapeutic targets of BSHXT were found out from Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)databases by using enrichment algorithm.Results:Eight hundred and ninety-one therapeutic targets of BSHXT and 365 pathogenic targets of SONFH were obtained.Thirty-one core targets of BSHXT for treatment of SONFH were selected out finally through analyzing the network of interaction between drug targets and pathogenic targets.The results of GO enrichment analysis demonstrated 532 pieces of information about biological processes and 29 pieces of information about molecular function and the results of KEGG enrichment analysis demonstrated 12 signal pathways,which related to inflammatory-immune regulation(chemokine signaling pathway,Toll-like receptor signaling pathway,NOD-like receptor signaling pathway,leukocyte transendothelial migration,Complement and coagulation cascades,cytokine-cytokine receptor interaction),angiogenesis and blood circulation regulation(VEGF signaling pathway),nervous system regulation(neuroactive ligand-receptor interaction)and cell function regulation(apoptosis,regulation of actin cytoskeleton).Conclusion:After ruling out nonspecific signaling pathways according to the pathological mechanism of SONFH,we can infer that BSHXT may produce the effect of reinforcing kidney and strengthening bone and activating blood and resolving stasis through regulating TLR4/NF-κB and VEGF signal pathways,which may be one of its mechanisms of action in treatment of SONFH.