基于网络药理学探讨大黄治疗脊髓损伤的作用机制

The mechanism of treating spinal cord injury with rhubarb based on network pharmacology

目的:基于网络药理学研究探讨大黄在脊髓损伤(Spinal Cord Injury,SCI)治疗中的潜在作用机制。方法:基于所得化合物的口服药物生物利用度(Oral bioavailability,OB)和类药性(Drug-likeness,DL),在中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)预测并筛选大黄的活性成分及其对应的靶标蛋白,利用GeneCards数据库、OMIM数据库筛选并整理SCI相关的基因和蛋白靶点,进而筛选大黄与SCI的核心交集靶点。在Cytoscape 3.7.1软件上构建“药物-成分-靶点-疾病”网络,使用STRING数据库构建靶点蛋白相互作用(Protein-protein Interaction,PPI)网络,并用Cytoscape 3.7.1进行拓扑结构分析,获得PPI核心分子网络,最后利用R软件进行关键靶点基因的基因功能(The Gene Ontology,GO)功能富集分析与京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析。结果:从大黄中筛选出16个活性成分,对应靶点110个,筛选出大黄与SCI的核心交集靶点为28个,PPI核心分子网络分析显示半胱氨酸蛋白酶3(CASP3)、MYC原癌基因蛋白质(MYC Proto-Oncogene Proteins)、雌激素受体1(Estrogen Receptor 1,ESR1)、雄激素受体(Androgen Receptor,AR)等可能是大黄治疗SCI的关键靶点。GO功能富集分析得到条目105个,主要涉及有受体配体活性(Receptor ligand activity)、细胞因子受体结合(Cytokine receptor binding)、辅因子结合(Cofactor binding)、细胞因子活性(Cytokine activity)等方面;KEGG通路富集分析得出条目38个,主要包括p53信号通路(p53 signaling pathway)、凋亡-多物种(Apoptosis-multiple species)、人类免疫缺陷病毒1型感染(Human immunodeficiency virus 1 infection)、胆碱能突触(Cholinergic synapse)等。结论:大黄中的芦荟大黄素(aloe-emodin)、番泻苷D(Sennoside D_qt)、番泻苷E(Sennoside E_qt)、大黄素-1-O-β-D-吡喃葡萄糖苷(Emodin-1-O-beta-D-glucopyranoside)等有效成分可能通过CASP3、MYC、ESR1、AR等靶点作用于p53信号通路、凋亡-多物种等多条信号通路,从而起到治疗SCI的作用。

Objective:To explore the potential mechanism of rhubarb on SCI based on network pharmacology.Methods:Based on the OB and DL of the obtained compounds,the active components of rhubarb and their corresponding target proteins were predicted and screened in TCMSP.The related gene and protein targets of SCI were screened and collated in GeneCards and OMIM database,and then the core intersecting targets of rhubarb and SCI were selected.The“medicine-component-target-disease”networks were built by Cytoscape 3.7.1 software.Moreover,the PPI network was constructed by STRING database.Cytoscape 3.7.1 was used for topological analysis,and then the PPI core molecular network was obtained.Finally,GO functional enrichment analysis and KEGG pathway enrichment analysis of key target genes was executed by R software.Results:16 active components were selected from rhubarb,with 110 corresponding targets,and 28 core intersection targets between rhubarb and SCI were selected.The results of PPI core molecular network analysis showed than CASP3,MYC,ESR1,and AR may be the key targets for rhubarb in the treatment of SCI.GO functional enrichment analysis produced 105 items,mainly involving receptor ligand activity,cytokine receptor binding,cofactor binding,cytokine activity,protein heterodimerization activity,heme binding and other aspects.The KEGG pathway enrichment analysis produced 38 items,including p53 signaling pathway,Apoptosis-multiple species,Human immunodeficiency virus 1 infection,Cholinergic synapse,etc..Conclusion:The active components of rhubarb,such as aloe-emodin,Sennoside D_qt,Sennoside E_qt,Emodin-1-O-beta-D-glucopyranoside,may act on p53 signal pathway,apoptosis-multiple species and other signal pathways through CASP3,MYC,ESR1,AR and other targets,thus play a therapeutic role on SCI.