隐丹参酮抗静脉血栓栓塞症的网络药理学研究

Network pharmacology study of cryptotanshinone against venous thromboembolism

目的探讨隐丹参酮治疗静脉血栓栓塞症(VTE)的分子机制。方法从网络数据库中分别获得疾病和药物的靶点,并得到所收集靶点的交集,使用R语言包对交集靶点进行基因本体论(GO)分析,探索其生物学功能,使用京都基因和基因组百科全书(KEGG)富集分析探索主要信号途径。通过STRING在线数据库分析疾病与药物交叉靶点之间的蛋白质相互作用,应用Cytoscape的插件获得隐丹参酮抗VTE的核心靶点,使用分子对接技术验证药物与核心靶点之间的相互作用,通过Cytoscape构建药物-疾病-GO-KEGG-靶点的可视化网络图。结果经过筛选共获得261个隐丹参酮靶点和1961个无重复的VTE相关基因,87个隐丹参酮治疗VTE疾病的交集靶基因。GO富集分析产生2012个GO项目,1867个为生物过程(BP),18个为细胞成分(CC),127个为分子功能(MF),KEGG信号通路分析示132条KEGG途径被显著富集,表明这些靶基因与多种重要的疾病有关,主要包括癌症、动脉粥样硬化、内分泌和糖尿病并发症等。经CytoNca筛选得到7个核心靶点非受体酪氨酸激酶(SRC)、丝裂原活化蛋白激酶1(MAPK1)、信号转导和转录激活因子3(STAT3)、蛋白质酪氨酸磷酸酶非受体型11(PTPN11)、磷酸肌醇-3-激酶调节亚基1(PIK3R1)、表皮生长因子受体(EGFR)和Janus蛋白酪氨酸激酶(JAK2)。分子对接表明隐丹参酮可以很容易地进入并结合到其核心基因的活性位点。结论网络药理学和分子对接揭示了隐丹参酮抗静脉血栓栓塞症的核心靶点和信号通路,其防治VTE主要作用于靶点SRC、MAPK1、STAT3、PTPN11、PIK3R1、EGFR和JAK2,参与癌症、动脉粥样硬化、内分泌和糖尿病并发症等多种信号通路。

Objective To investigate the molecular mechanism of cryptotanshinone in the treatment of venous thromboembolism(VTE).Method Disease target and drug targets were obtained from the network database,and the intersection of the collected targets was obtained.The gene ontology(GO)analysis of the intersection targets was carried out by using R language package to explore their biological functions.The Kyoto encyclopedia of genes and genomes(KEGG)enrichment analysis was used to explore the major signaling pathways.The protein interaction between disease and drug cross targets was analyzed through STRING online database,the core target of cryptotanshinone anti-VTE was obtained by Cytoscape plug-ins,and the interaction between drug and core target was verified by molecular docking technology.Construct a visual network diagram of drug-disease-go-KEGG-target via Cytoscape.Result A total of 261 cryptotanshinone targets and 1961 unduplicated VTE-related genes were obtained,and 87 overlapping target genes were identified for the treatment of VTE diseases by cryptotanshinone.GO enrichment analysis produced 2012 GO items,of which 1867 were biological processes(BP),18 were cell components(CC),and 127 were molecular functions(MF).KEGG signaling pathway analysis showed that 132 KEGG pathways were significantly enriched,indicating that these target genes were associated with a variety of important diseases.It mainly includes cancer,atherosclerosis,endocrine and diabetes complications.Seven core targets were identified by CytoNca,nonreceptor-tyrosine-kinase-SRC(SRC),mitogen-activated protein kinase 1(MAPK1),signal transducer and activator of transcription 3(STAT3),protein tyrosine phosphatase non-receptor type 11(PTPN11),phosphoinositide-3-kinase,regulatory subunit 1(PIK3R1),epidermal growth factor receptor(EGFR)and Janus kinase 2(JAK2).Molecular docking shows that cryptotanshinone can easily enter and bind to the active site of its core gene.Conclusion Network pharmacology and molecular docking have revealed the core target and signal pathway of cryptotanshinone in the treatment of venous thromboembolism.Its prevention and treatment of VTE mainly act on the target SRC,MAPK1,STAT3,PTPN11,PIK3R1,EGFR and JAK2,and participate in multiple signal pathways such as cancer,atherosclerosis,endocrine and diabetes complications.