桑叶-菊花药对治疗糖尿病视网膜病变的网络药理和分子对接研究

Network pharmacology research of treating diabetic retinopathy with Sangye-Juhua

目的:运用网络药理学的研究方法预测桑叶-菊花药对治疗糖尿病视网膜病变(Diabetic Retionpathy,DR)的有效成分、作用靶点及分子机制。方法:在中药系统药理学数据库与分析平台(TCMSP)数据库中以“桑叶”“菊花”作为检索对象,筛选出其有效成分及作用靶点,然后应用GeneCards、OMIM数据库以“Diabetic retionpathy”为关键词寻找疾病的相关靶点,利用Cytoscape构建靶点关系网络,录入STRING平台构建蛋白质-蛋白质相互作用网络,应用R语言软件对共同靶点进行基因本体论(GO)功能富集分析与京都基因与基因组百科全书(KEGG)通路富集分析,得到桑叶-菊花治疗DR核心基因的生物功能和信号通路。最后使用PubChem、AutoDock Tools、Vina和PyMol等工具对小分子配体和蛋白受体进行分子对接。结果:经筛选得到桑叶-菊花的有效成分共117个,与DR相关基因共438个,桑叶-菊花作用靶点294个,而桑叶-菊花作用于DR的靶点共72个。蛋白质-蛋白质相互作用网络核心靶点为周期蛋白D1(Cyclin D1,CCND1)、Jun原癌基因(Jun ProtoOncogene,JUN)、表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)、酪氨酸激酶受体2(Receptor Tyrosine Kinases 2,ERBB2)、一氧化氮合酶2(Nitric Oxide Synthase 2,NOS2)、表皮生长因子(Epidermal Growth Factor,EGF)、肿瘤坏死因子(Tumor Necrosis Factor,TNF)、B细胞κ轻肽基因增强子核因子抑制因子α(NF-κB Inhibitor Alpha,NFKBIA)、MYC原癌基因(MYC Proto-Oncogene,MYC)、连环蛋白β1(Catenin beta 1,CTNNB1)。GO功能富集分析得到生物过程1927项、分子功能89项、细胞组成58项。KEGG通路富集分析得到134条信号通路。结论:桑叶-菊花主要通过青蒿素、柚皮素、莫拉辛、司鞘林、阿尔巴诺尔等活性成分作用于JUN、NFKBIA、MYC、TNF、CTNNB1等靶基因,经过对氧化应激的反应、凋亡信号通路的调节、脂多糖的反应、细胞对化学压力的反应等生物过程,以脂质-动脉硬化信号通路、流体剪切应力-动脉硬化信号通路为主要通路发挥对DR的治疗作用。

Objective:To predict the active ingredients,targets of action and molecular mechanisms of Sangye(Folium Mori)-Juhua(Flos Chrysanthemi)for the treatment of diabetic retinopathy using a network pharmacology study.Methods:In TCMSP database,Sangye and Juhua were used as search objects to screen out their active ingredients and targets;then in GeneCards and OMIM database,“Diabetic retionpathy”was used as keywords to find the relevant targets of the disease.Cytoscape was used to build the target relationship network,and STRING platform was used to build the protein-protein interaction network.R language software was applied to enrich the GO function analysis and KEGG pathway analysis of common targets to obtain the biological functions and signaling pathways of the core genes of Sangye-Juhua for DR treatment.Molecular docking of the screened core active ingredients of Sangye-Juhuu with the core disease targets was performed by PubChem,AutoDock Tools,Vina and PyMol.Results:A total of 117 active ingredients and 1293 predicted targets of Sangye-Juhua were obtained by screening,with 438 genes related to DR,294 targets of Sangye-Juhua action,and 72 targets of Sangye-Juhua action on DR.Core targets of PPI network were CCND1,JUN,EGFR,ERBB2,NOS2,EGF,TNF,NFKBIA,MYC,CTNNB1.The GO functional enrichment analysis yielded 1927 biological processes,89 molecular functions and 58 cellular compositions.A total of 134 signaling pathways were analyzed by KEGG pathway enrichment.Conclusion:Sangye-Juhua mainly acts on target genes such as JUN,NFKBIA,MYC,TNF and CTNNB1 through active ingredients such as artemisinin,naringenin,moraxin,spermidine and albanol,and through biological processes such as response to oxidative stress,regulation of apoptotic signaling pathway,response of lipopolysaccharide,and cellular response to chemical stress,by taking lipid-atherosclerosis signaling pathway,fluid shear stress-atherosclerosis signaling pathway as the main pathways to play a therapeutic role in treating DR.