基于网络药理学探讨通关藤抗肝细胞癌的作用机制
投稿时间:2022-12-24  修订日期:2023-06-17  点此下载全文
引用本文:董雨龙,娄成,陈熙昀,魏炜,陶晨洁,韩琴,袁振刚.基于网络药理学探讨通关藤抗肝细胞癌的作用机制[J].药学实践杂志,2023,41(10):600~609
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作者单位E-mail
董雨龙 海军军医大学第三附属医院肿瘤科, 上海 201805  
娄成 海军军医大学第三附属医院肿瘤科, 上海 201805  
陈熙昀 海军军医大学第三附属医院肿瘤科, 上海 201805  
魏炜 海军军医大学第三附属医院肿瘤科, 上海 201805  
陶晨洁 海军军医大学第三附属医院肿瘤科, 上海 201805  
韩琴 海军军医大学第三附属医院肿瘤科, 上海 201805  
袁振刚 海军军医大学第三附属医院肿瘤科, 上海 201805 yuanzg@smmu.edu.cn 
基金项目:孟超人才培养计划(SHDC12019X04)
中文摘要:目的 通过生物信息学、网络药理学和分子对接技术研究通关藤治疗肝细胞癌(HCC)的作用机制。方法 通过文献检索和ADME平台筛选通关藤活性成分并利用Swiss Target Prediction预测化合物的作用靶点;从GEO数据库获得HCC数据芯片GSE147888并筛选表达差异显著基因;通过Genecards和OMIM数据库获得HCC疾病相关靶点;Venny在线对上述靶点取交集。利用Cytoscape软件和String数据库构建药物成分-靶点网络图和PPI网络图;利用R软件进行GO功能富集分析和KEGG通路富集分析;利用GEPIA数据库对靶基因进行生存分析,筛选在HCC生存率中显著差异表达的基因,并用Proteinatlas数据库分析基因在HCC组织中免疫组化表达情况;将排名前5的靶蛋白与对应药物活性成分进行分子对接验证。结果 共筛选通关藤活性成分50个,药物与疾病交集靶基因12个。通关藤治疗HCC的重要成分有野黄芩素四甲醚、通关苷元、芥子酸、苦绳苷元、山奈酚等,关键基因有JUN、MMP9、PTGS2等。GO、KEGG分析结果显示,关键靶点主要涉及基因沉默调节、炎症反应调节等过程,主要富集在IL-17、TNF等信号通路。生存分析显示ESR1、MMP1、MMP9、JUN、PPARG在高低风险组之间有显著差异。免疫组化结果显示ESR1和MMP9在正常组织和肝癌组织中差异表达。分子对接结果验证了药物活性成分与靶蛋白可稳定结合。结论 研究体现了中草药通关藤治疗HCC的多成分、多靶点、多通路的特点,为通关藤在HCC的临床应用中提供科学依据。
中文关键词:通关藤  肝细胞癌  生物信息学  网络药理学  分子对接
 
Exploring the mechanism of Marsdenia tenacissima in the treatment of hepatocellular carcinoma based on network pharmacology
Abstract:Objective To investigate the material basis and antitumor mechanism of Marsdenia tenacissima (MT) on hepatocellular carcinoma (HCC) by bioinformatics, network pharmacology and molecular docking technology. Methods Active ingredients of MT were collected by literature search and screened by Swiss ADME website, which targets were predicted by Swiss Target Prediction. The chip data of HCC (GSE147888) were downloaded from the NCBI Gene Expression Omnibus (GEO) database. Differentially expressed genes were screened by R software. HCC-related targets were collected from the Genecards and OMIM databases. The Venny online tool was used to obtain the intersection of the herbal medicine targets and the disease targets. Subsequently, drug-target network and protein–protein interaction (PPI) network were constructed by Cytoscape software and String platform. GO enrichment analysis and KEGG pathway analysis were performed to analysis the functions and pathways enriched by key genes. The expression of key genes in HCC and its effect on survival were analyzed by the GEPIA database. The Human Protein Atlas (HPA) was used to analyze the immunohistochemical expression of key genes in HCC. Finally, molecular docking was carried out to investigate interactions between the top five targets and their related active compounds. Results A total of 50 active components were screened and 12 common targets were identified related to MT and HCC. Scutellarein-4-Methylether, Tenasogenin, Sinapic Acid, Dresgenin and Kaempferol were considered as the critical components. JUN, MMP9 and PTGS2 were recognized as key therapeutic targets. The GO analyses demonstrated that key targets mainly involved in the process of gene silencing and inflammatory response. KEGG analysis suggested that key targets were enriched in TNF signaling pathway and IL-17 signaling pathway. Survival analysis by the GEPIA showed significant differences in the expression of ESR1, MMP1, MMP9, JUN, and PPARG between high and low risk groups. Immunohistochemical results showed that ESR1 and MMP9 were differentially expressed in normal and hepatocellular carcinoma tissues. The molecular docking results verified that the drug active ingredient could be stably bound to the target protein. Conclusion This study reflected the multi-component, multi-target and multi-pathway characteristics of the MT in the treatment of HCC, which could provide a scientific basis for the clinical application of MT in HCC.
keywords:Marsdenia tenacissima  hepatocellular carcinoma  bioinformatics  network pharmacology  molecular docking technology
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