川贝母药理作用机制的网络药理学研究

Network Pharmacology Research of Pharmacological Mechanism of Fritillaria Cirrhosa

目的探讨川贝母药理作用机制及可能适用的临床病症。方法采用中药系统药理学数据库与分析平台(TSMSP)获取川贝母的有效化学成分,以口服生物利用度(OB)≥30%及药物相似性(DL)≥0.18为标准,鉴定潜在活性成分;采用UniProt数据库进行靶点基因转换;采用DAVID 6.8数据库和Cytoscape 3.5.1软件的ClueGo插件进行基因本体(GO)及京都基因与基因组百科全书(KEGG)等生物信息学进行分析;采用String 10.0数据库对获得的活性成分构建川贝母活性成分-靶点网络、靶蛋白相互作用网络(PPI)。结果筛选出川贝母活性成分13种,包括酞酸双(2-乙基己基)酯、β-谷甾醇、谷甾醇、贝母辛碱、环贝母碱等,靶点转换获得40个靶蛋白,GO分析获得显著富集(P<0.05)的生物过程(BP)60条、细胞组分(CC)26条、分子功能(MF)42条;KEGG分析获得显著富集(P<0.05)通路53条,疾病富集分析提示对303种疾病有治疗学意义(P<0.05),包括3种肺部相关疾病(慢性阻塞性肺疾病、肺癌及哮喘),1种炎性疾病(感染/发炎);OMIM分析提示有92种疾病显著富集(P<0.05),药物靶标数据库(TTD)分析结果提示有4种疾病显著富集(P<0.05),均不包括呼吸系统疾病。结论川贝母的活性成分为酞酸双(2-乙基己基)酯及β-谷甾醇,主要治疗靶点为热休克蛋白HSP90AA1基因、转录因子AP-1(JUN)及半胱天冬酶3(CASP3),治疗作用可能与影响细胞外配体门控离子通道活性、药物结合等分子功能及突触后膜、质膜及细胞连接等细胞组分,药物反应、胆碱能突触传递及腺苷酸环化酶抑制G蛋白耦联乙酰胆碱受体信号通路等生物学过程,刺激神经组织的配体-受体相互作用及(或)钙信号通路等机制有关。

Objective To investigate the pharmacological mechanism of Fritillaria cirrhosa and the possible clinical conditions treated with Fritillaria cirrhosa.Methods The effective chemical components of Fritillaria cirrhosa was obtained by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TSMSP).The potential active ingredients were identified with oral bioavailability(OB)≥30%and drug-likeness(DL)≥0.18 as the criteria.Uniprot database was used for target gene conversion.DAVID 6.8 database and Cytoscape 3.5.1 plugin ClueGo were used for bioinformatics analysis such as Gene Ontology(GO)and Kyoto Encyclopedia of Genes And Genomes(KEGG).String 10.0 database was used to construct the active ingredient-target network and target protein-protein interaction(PPI)network of Fritillaria cirrhosa for the obtained active ingredients.Results A total of 13 active ingredients of Fritillaria cirrhosa were screened,including bis(2-ethylhexyl)phthalate,beta-sitosterol,sitosterol,peimisine and cyclopamine,and 40 targets were obtained after target conversion.GO analysis showed that 60 biological processes(BP),26 cellular components(CC)and 42 molecular functions(MF)were significantly enriched(P<0.05).KEGG analysis showed that 53 pathways were significantly enriched(P<0.05).Disease enrichment analysis showed that it had therapeutic significance for 303 kinds of diseases(P<0.05),including three kinds of lung-related diseases(chronic obstructive pulmonary disease,lung cancer and asthma)and one inflammatory disease(infection/inflammation).Online Mendelian Inheritance in Man(OMIM)analysis showed that 92 kinds of diseases were significantly enriched(P<0.05),and drug target database(TTD)analysis showed that four kinds of diseases were significantly enriched(P<0.05),none of them including respiratory diseases.Conclusion The active ingredients of Fritillaria cirrhosa were bis(2-ethylhexyl)phthalate and beta-sitosterol.The main therapeutic targets are heat shock protein HSP90(HSP90 AA1),transcription factor AP-1(JUN)and cysteine aspartase 3(CASP3),the therapeutic effect of Fritillaria cirrhosa may be related to the molecular functions such as extracellular ligand-gated ion channel activity,drug binding,and the cellular components such as post-synaptic membrane,plasma membrane,and cell junctions,as well as the biological processes such as drug response,cholinergic synaptic transmission and adenylate cyclase inhibition of G protein-coupled acetylcholine receptor signaling pathway,and it play a therapeutic role in stimulating nerve-ligand-receptor interactions and/or calcium signaling pathways.