摘要
目的 探究中医药治疗肺结节(pulmonary nodule,PN)的用药规律,预测核心药物组合的潜在作用机制,以期为后续实验研究和临床应用提供依据和参考。方法 检索中英文数据库中关于中医药治疗肺结节的文献,并进行归纳总结,构建肺结节处方数据库,运用R语言对处方进行频次统计和关联规则、聚类分析。利用网络药理学方法预测核心药物的潜在作用靶点和通路,从TCMSP数据库和OMIM等数据库中分别获取药物与肺结节相关的靶点,取交集靶点后上传至STRING数据库构建蛋白质-蛋白质互作网络,导入Cytoscape 3.7.2软件中,运用Network Analyzer工具计算网络拓扑参数并得到关键靶点。最后通过分子对接技术对关键成分与靶点进行反向验证。结果 数据库共筛选得到53首处方,涉及213味中药,统计发现这些中药多味甘、苦,性寒,归肺经。关联规则分析提示甘草与茯苓、半夏是具有强关联性的3组合药对。核心药物组合“甘草-茯苓-半夏”与肺结节的交集靶点85个,经拓扑分析得到其治疗肺结节的17个关键靶点,包括转录激活因子3(signal transducer and activator of transcription 3,STAT3)、丝氨酸/苏氨酸激酶1(serine/threonine kinase 1,AKT1)等。基于DIVID平台进行京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)通路富集分析,提示主要涉及肿瘤相关信号通路如癌症中的蛋白多糖(proteoglycans in cancer)、白细胞介素-17(interleukin-17,IL-17)信号通路和丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路,以及病毒相关通路如乙型肝炎(hepatitis B)、卡波济肉瘤相关疱疹病毒感染(Kaposi sarcoma-associated herpesvirus infection)和糖尿病并发症中晚期糖基化终产物及其受体(advanced glycation end products-receptor for advanced glycation end products,AGE-RAGE)信号通路等多种复杂信号通路。分子对接结果显示关键活性成分与靶点对接良好,其中黄芩素与MAPK3结合性最好。结论 中医药治疗肺结节组方用药多以健脾益肺、行气化痰、活血祛瘀为主,辅以清热散结的同时,注重调畅气机;其核心药物组合“甘草-茯苓-半夏”治疗肺结节的潜在靶点和作用机制主要参与炎症反应、免疫调控等生物学过程,为中医药治疗肺结节提供理论依据,以及进一步发掘其潜在作用机制提供方向。
Objective To explore the medication rules of traditional Chinese medicine(TCM) in the treatment of pulmonary nodule(PN)and predict the potential mechanism of core herbs combination,so as to provide a reference basis for future experimental research and clinical application. Methods Literature on the treatment of pulmonary nodules by traditional Chinese medicine was retrieved from Chinese and English databases and summarized,and a lung nodules prescription database was constructed. The R language was employed to perform frequency statistics,association rules and cluster analysis of prescriptions. The network pharmacology method was used to predict the potential targets and pathways of core herbs. Then the traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP) database was used to retrieve TCMs and collect the corresponding targets. In addition,the targets related to PN were obtained from the Online Mendelian Inheritance in Man(OMIM) database. The intersection targets were selected and uploaded to search tool for the retrieval of interacting genes/proteins(STRING) database to construct a protein-protein interaction network,which was imported into Cytoscape 3.7.2 software. Network Analyzer was used to calculate network topology parameters and obtain key targets.Finally,the interactions between the obtained core ingredients and targets were verified by reverse molecular docking technology. Results A total of 53 formulas were screened from the database,mainly involving 213 TCMs. The statistics indicated that most TCMs were sweet and bitter in taste,cold in nature,and attributed to the lung meridian. The results of association rule analysis showed that Gancao(Glycyrrhizae Radix et Rhizoma) had strong correlation with Fuling(Poria) and Banxia(Pinelliae Rhizoma). There were 85 intersection targets between the core herb combination “Glycyrrhizae Radix et Rhizoma-Poria-Pinelliae Rhizoma” and PN,and 17 key targets in the treatment of PN were obtained by topological analysis,including signal transducer and activator of transcription 3(STAT3),serine/threonine kinase 1(AKT1),etc. The Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis was performed based on the database for annotation,visualization and integrated discovery(DAVID) platform and found that many targets were enriched in tumor-related pathways,such as proteoglycans in cancer,interleukin-17(IL-17) signaling pathway,and mitogen-activated protein kinase(MAPK) signaling pathway,etc. While some other targets were enriched in virus-related pathways such as hepatitis B,Kaposi sarcoma-associated herpesvirus infection,as well as several other pathways such as advanced glycation end products-receptor for advanced glycation end products(AGE-RAGE) signaling pathway in diabetic complications. The molecular docking revealed promising results for key active ingredients in the form of effective binding with corresponding targets,and baicalein had the best binding ability with MAPK3. Conclusion The TCM in the treatment of PN mainly focused on invigorating spleen and tonifying lung,moving qi and resolving phlegm,activating blood to resolve stasis,clearing heat and dispelling nodules,as well as regulating qi activity. The potential therapeutic targets and mechanism of the core herbs combination “Glycyrrhizae Radix et Rhizoma-Poria-Pinelliae Rhizoma” in the treatment of PN were mainly involved in various biological processes such as immune regulation and inflammatory responses,which may provide the theoretical basis for TCM in the treatment of PN,and the direction for further study of the potential mechanism.
作者
董敬
彭小芸
付西
任益锋
张龙飞
李林炯
祝捷
由凤鸣
DONG Jing;PENG Xiao-yun;FU Xi;REN Yi-feng;ZHANG Long-fei;LI Lin-jiong;ZHU Jie;YOU Fengming(Sichuan Key Laboratory of Traditional Chinese Medicine Regulation of Metabolic Diseases,Affiliated Hospital of Chengdu University of Traditional Chinese Medicine,Chengdu 610075,China;Cancer Institute,Chengdu University of Traditional Chinese Medicine,Chengdu 610075,China)
出处
《中草药》
CAS
CSCD
北大核心
2022年第20期6544-6557,共14页
Chinese Traditional and Herbal Drugs
基金
国家自然科学基金资助项目(82074315)
四川省科技厅重大科技专项项目(2022ZDZX0022)。
关键词
中医药
肺结节
数据挖掘
网络药理学
分子对接
用药规律
作用机制
甘草-茯苓-半夏
traditional Chinese medicine
pulmonary nodule
data mining
network pharmacology
molecular docking
compatibility rules
mechanism of action
Glycyrrhizae Radix et Rhizoma-Poria-Pinelliae Rhizoma
