巴戟天-牛膝治疗骨关节炎的计算机模拟分析研究

A computer simulation analysis of Morinda officinalis-Radix Achyranthis Bidentatae in treatment of osteoarthritis

目的:基于网络药理学技术挖掘及佐证巴戟天-牛膝药对切合骨关节炎(OA)治则的效应机制。方法:在TCMSP数据库中筛选巴戟天-牛膝药对的所有成分,借助UniProt数据库将药对中显效物质成分所靶向关联的效用点进行筛选,对OA的疾病靶点进行联合检索、收集与分析。将筛选出的显效靶标与OA靶点进行交联分析,将其共有靶标作为巴戟天-牛膝药对治疗OA的预测靶基因。将预测靶基因通过蛋白质-蛋白质互作关系(PPI)网络显示,筛选核心基因,构建“药物-成分-疾病-靶点”网络。联合基因本体(GO)功能和京都基因与基因组百科全书(KEGG)通路富集分析,探究巴戟天-牛膝药对切合OA治则的药效基础及效应机制。结果:经筛选分析得出槲皮素可能在巴戟天-牛膝药对治疗OA中发挥主导作用,观察预测靶基因之间的PPI关系,发现网络中转录因子AP-1(JUN)、丝氨酸/苏氨酸蛋白激酶(AKT1)、丝裂原活化蛋白激酶1(MAPK1)、V-Rel网状内皮增生病毒癌基因同源物A(RELA)、白细胞介素-6(IL-6)5个核心基因度值较高。GO功能和KEGG通路富集分析提示巴戟天-牛膝药对治疗OA主要涉及抗炎、抗氧化以及白细胞介素-17(IL-17)、肿瘤坏死因子(TNF)信号通路、细胞凋亡途径。在大鼠体外实验中,模型组与正常组比较,RELA、IL-17、IL-6蛋白表达升高(P<0.01);经过槲皮素治疗后RELA、IL-17、IL-6蛋白表达降低(P<0.01)。结论:巴戟天-牛膝药对治疗OA的潜在机制是通过槲皮素降低RELA、IL-17、IL-6蛋白表达,抑制炎症反应,从而延缓关节软骨退变。

Objective: To investigate the effect mechanism of Morinda officinalis-Radix Achyranthis Bidentatae drug combination in fitting in with the principle of treatment of osteoarthritis(OA) based on network pharmacology.Methods: TCMSP database was used to screen out all components of Morinda officinalis-Radix Achyranthis Bidentatae drug combination, and UniProt database was used to screen out the effect points targeted by the markedly effective components in this drug combination.The disease targets of OA were searched, collected, and analyzed.A cross-linking analysis was performed for the markedly effective targets and the OA targets screened out, and the intersecting targets were used as the predictive target genes for Morinda officinalis-Radix Achyranthis Bidentatae drug combination in the treatment of OA.The predictive target genes were displayed in protein-protein interaction(PPI) network, core genes were screened out, and a “drug-component-disease-target” network was established.Gene ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were performed to investigate the pharmacodynamic material basis and effect mechanism of Morinda officinalis-Radix Achyranthis Bidentatae drug combination in fitting in with the principle of treatment of OA.Results: Screening and analysis showed that quercetin might play a leading role in the treatment of OA by Morinda officinalis-Radix Achyranthis Bidentatae drug combination, and the PPI network of predictive target genes showed that the five core genes of JUN,AKT1,MAPK1,RELA,and IL-6 had a relatively high value.GO functional and KEGG pathway enrichment analyses showed that Morinda officinalis-Radix Achyranthis Bidentatae drug combination mainly involved the anti-inflammatory pathway, the antioxidant pathway, the interleukin-17(IL-17) pathway, the tumor necrosis factor signaling pathway, and the cell apoptosis pathway in the treatment of OA.The in vitro experiment in rats showed that compared with the normal group, the model group had significant increases in the expression of RELA,IL-17,and interleukin-6(IL-6)(P<0.01),and there were significant reductions in the expression of RELA,IL-17,and IL-6 after quercetin treatment(P<0.01).Conclusion: Morinda officinalis-Radix Achyranthis Bidentatae drug combination exerts a therapeutic effect on OA possibly by reducing the protein expression of RELA,IL-17,and IL-6,inhibiting inflammatory response, and delaying articular cartilage degeneration.