基于网络药理学研究覆盆子活性成分抗肿瘤作用机制

Mechanism of Anti-tumor Effects Exhibited by Rubi Fructus Based on Network Pharmacology

目的采用网络药理学挖掘覆盆子抗肿瘤主要活性成分的作用靶点,探讨其多成分、多靶点、多通路的作用机制。方法通过TCMSP数据库,结合口服生物利用度(OB≥30%)和类药性(DL≥0.18)参数,筛选覆盆子的活性成分;登录PharmMapper服务器反向预测,利用Uniprot数据库进行校正与转化,获得潜在作用靶点;比对CTD数据库筛选并整合得覆盆子抗肿瘤的潜在靶点;通过DAVID v6.8数据库进行GO富集和KEGG通路注释分析;采用Cytoscape 3.6.1软件构建“活性成分-靶点”网络图、“核心成分-核心靶点-核心通路”网络图。结果经筛选后得到覆盆子7个活性成分,63个潜在靶点,其中26条重要信号通路关联32个核心靶点,聚焦在5个核心成分,即谷甾醇、β-谷甾醇、覆盆子酸、鞣花酸、欧前胡素可能是覆盆子抗肿瘤的主要活性成分,而PI3K-Akt信号通路、癌症的途径、癌症中的蛋白多糖、原癌基因蛋白信号通路、胰岛素抵抗、Rap1信号通路可能是重要的通路。结论覆盆子中富含的甾醇类、酚酸类、香豆素类等活性成分可能作用于PPP1CC、SHBG、MAP2K1、MAPK14、RXRB、ABL1、FABP7、SULT2B1、HPGDS等关键靶点,通过抑制肿瘤细胞增殖和分化、诱导肿瘤细胞凋亡,调节糖脂代谢、激素水平、炎症反应等发挥多成分-多靶点-多通路的抗肿瘤作用机制。

Objective To excavate the action targets of the anti-tumor active ingredients of Rubi Fructus,and to explore the“multi-components-multi-targets-multi-pathways”mechanism by network pharmacology.Methods The active ingredients of Rubi Fructus were screened by combining the parameters of oral bioavailability(OB≥30%)and drug-like properties(DL≥0.18)through the TCMSP database.The potential targets of the main active ingredients were further screened by the Pharm Mapper method,which were then corrected and transformed by the UniProt database.The potential targets of anti-tumor qualities from Rubi Fructus were screened and integrated by comparing with the CTD database.Gene Ontology enrichment and KEGG path annotation were analyzed by the DAVID database v6.8.The Cytoscape 3.6.1 software was used to construct the active components-targets network and the core compounds-targets-pathways network.Results After screening,7 active ingredients and 63 potential targets were obtained,of which 26 important signal pathways were associated with 32 core targets,focusing on 5 core ingredients,namely sitosterol,β-sitosterol,fupenzic acid,ellagic acid and ammidin may be the main anti-tumor active components of Rubi Fructus PI3K-Akt signaling pathway,pathways in cancer,proteoglycans in cancer,Ras signaling pathway,insulin resistance,and Rap1 signaling pathway might be important pathways.Conclusion Active ingredients such as sterols,phenolic acids,and coumarins rich in raspberries may act on key targets such as PPP1CC,SHBG,MAP2K1,MAPK14,RXRB,ABL1,FABP7,SULT2B1,HPGDS,etc.,which play a multi-component-multi-target-multi-path anti-tumor mechanism by inhibiting tumor cell proliferation and differentiation,inducing tumor cell apoptosis,regulating glucose and lipid metabolism,hormone levels,inflammation,etc.