基于网络药理学研究茵陈治疗良性前列腺增生症的作用机制

Study of the mechanism of oriental wormwood in the treatment of benign prostatic hyperplasia based on network pharmacology

目的:探索使用网络药理学方法和动物实验研究中药茵陈治疗良性前列腺增生症(BPH)的作用机制。方法:通过TCMSP数据库筛选出茵陈有效成分及其靶点,经uniprot统一靶点简写;GeneCards、OMIM及GisGeNET数据库在线检索BPH的疾病靶点。在venny 2.1网站筛选出交集靶点并将交集靶点在线做“蛋白-蛋白”网络分析和GO、京都基因与基因组百科全书(KEGG)富集分析。使用Cytoscape制作“成分-靶点-通路”网络图。建立BPH大鼠模型,使用茵陈药液灌胃治疗,采用酶联免疫方法检测靶蛋白表达。结果:茵陈中有12个有效成分,这些有效成分通过干预67个靶点调节多个分子通路,从而治疗BPH。槲皮素、茵陈色酮、β-谷甾醇、芫花素、茵陈黄酮、异鼠李素等是核心成分,肿瘤蛋白p53(TP53)、丝/苏氨酸蛋白激酶(AKT)1、表皮生长因子受体(EGFR)、JUN、白细胞介素-6(IL-6)、肿瘤坏死因子(TNF)、血管内皮生长因子A(VEGFA)是核心靶点。GO分析结果显示,生物过程主要涉及细胞对激素反应和对脂质的反应等,细胞组分包含转录调节复合物、膜筏、质膜筏等,分子功能包含DNA结合转录因子结合、核受体活性和激酶调节活性等。KEGG分析结果显示磷脂酰肌醇3激酶(PI3K)-AKT、缺氧诱导因子-1(HIF-1)、IL-17、TNF、丝裂原活化蛋白激酶(MAPK)、EGFR、P53等信号通路与茵陈治疗BPH相关。动物实验结果显示,经茵陈治疗后前列腺重量减轻,血清TP53蛋白表达增加,血清AKT1、EGFR、JUN、IL-6、TNF、VEGFA等蛋白表达减少(均P<0.0001)。结论:茵陈作为治疗BPH的中药可以通过多种通路参与调控疾病靶点,具有良好的治疗效果和广泛的作用机制。

Objective:To study the mechanism of the oriental wormwood treating benign prostatic hyperplasia(BPH)by using network pharmacology and animal experiments.Methods:First,the active constituents and targets were screened out by TCMSP database,and then uniprot was used to simplify the target.GeneCards,OMIM and GisGeNET databases were used to search disease targets of BPH online.The intersection targets were screened on venny 2.1 website,and the intersection targets were analyzed online for"protein-protein"network analysis and GO and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.Then,the Cytoscape was used to create a Composition-Target-Pathway network diagram.Finally,the rat models of BPH were established and treated by intragastric administration with oriental wormwood.The expression of targets protein was detected by ELISA.Results:There were 12 active components of oriental wormwood in the treatment of BPH by intervening 67 targets and regulating multiple molecular pathways.The core components were Quercetin,Capillarisin,β-sitosterol,genkwanin,wormwood flavone,isorhamnetin and so on.Tumor protein p53(TP53),silk/threonine protein kinase(AKT)1,epidermal growth factor receptor(EGFR),JUN,interleukin-6(IL-6),tumor necrosis factor(TNF),vascular endothelial growth factor A(VEGFA)were the core targets.GO analysis results showed that biological processes mainly involved cell responses to hormones and lipids.Cellular components included transcriptional regulatory complexes,membrane rafts,plasma membrane rafts.Molecular functions included DNA binding,transcription factor binding,nuclear receptor activity and kinase regulatory activity.The results of the KEGG analysis showed that phosphatidylinositol 3 kinase(PI3K)-AKT,hypoxia-inducible factor-1(HIF-1),IL-17,TNF,mitogen-activated protein kinase(MAPK),EGFR,P53 and other signaling pathways are related to the treatment of BPH by oriental wormwood.The results of animal experiments showed that the weight of the prostate decreased,the expression of serum TP53 protein increased and the protein expression of serum AKT1,EGFR,JUN,IL6,TNF and VEGFA decreased after the treatment of oriental wormwood(all P<0.0001).Conclusion:As a traditional Chinese medicine for the treatment of BPH oriental wormwood can participate in the regulation of disease targets through various pathways,and has good therapeutic effect and extensive mechanisms.