基于网络药理学与数据可视化探究《伤寒论》中生姜与干姜治疗呕吐作用机制的差异性

Exploring the Difference between Ginger and Dried Ginger in Treating Vomiting in “Treatise on Febrile Diseases” Based on Network Pharmacology and Data Visualization

摘要: 目的：探究《伤寒论》中生姜与干姜治疗呕吐用法差异性及其药理学依据。方法：通过将《伤寒论》内治疗呕吐方剂中含有生姜或干姜的方剂进行数据可视化展示，探究《伤寒论》中治呕方剂与药物的应用的规律与逻辑。基于中药系统药理学数据库和分析平台(TCMSP)、蛋白质数据库(Uniprot)等平台，筛选生姜与干姜的有效成分及其潜在治疗靶标，基于人类基因数据库(Genecard)获取呕吐相关差异表达基因，取交集筛选出生姜、干姜治疗呕吐的潜在作用靶点，构建化合物—靶点网络、蛋白互作(PPI)网络，并对交集靶点进行GO富集分析与KEGG富集分析，分析其应用差异的分子学依据。结果：《伤寒论》中含“呕吐”相关字词的条文87条，治呕方剂共31首，其中含生姜的方剂14首，含干姜的方剂13首。生姜用量较大，所在方剂药味数较多，多用于三阳经，常与甘草、半夏、大枣、黄芩、人参、芍药等药进行配伍。干姜用量较小，所在方剂药味数较小，多用于三阴经，常与甘草、人参、黄连、附子等药进行配伍。经指定条件筛选后，获得生姜有效成分5个，作用靶点166个，干姜有效成分5个，作用靶点312个。二者共有关键成分为β-谷甾醇(beta-sitosterol)，生姜核心成分为二氢辣椒素(Dihydrocapsaicin)和豆甾醇(Stigmasterol)。干姜核心成分为六倍体磷脂(Sexangularetin)和谷甾醇(sitosterol)。呕吐相关靶点2608个，生姜治疗呕吐关键靶点为MTOR、CASP3、PTGS2等，干姜治疗呕吐关键靶点为MTOR、AKT1、ERBB2等，二者治疗呕吐在细胞组分(Cellular component, CC)相关的通路相同最多，在Pathways in cancers、protein binding等通路富集度较高。结论：《伤寒论》中生姜与干姜对于呕吐的治疗有较大差异性，二氢辣椒素(Dihydrocapsaicin)和豆甾醇(Stigmasterol)可能是生姜治疗呕吐疗效区别于干姜的关键成分。Pathways in cancers、protein binding可能是生姜与干姜治疗呕吐的关键通路。

Abstract: Objective: The objective of this paper is to investigate the disparity between ginger and dried gin-ger in managing vomiting as per Treatise on Febrile Diseases, along with its pharmacological ra-tionale. Methods: Through data visualization of the prescription for treating vomiting containing ginger or dried ginger in Treatise on Febrile Diseases, we explored the rules and logic behind the application of this prescription and drug for treating vomiting. Using the Traditional Chinese Medi-cine System Pharmacology Database and Analysis Platform (TCMSP), protein database (Uniprot), and other platforms, we screened for effective components of ginger and dried ginger as well as their potential therapeutic targets. Additionally, we obtained differentially expressed genes related to vomiting from the human gene database (Genecard) and screened for potential therapeutic tar-gets of ginger and dried ginger in treating vomiting through intersection analysis, constructed compound target networks and protein interaction (PPI) networks, performed GO enrichment analysis and KEGG enrichment analysis on intersecting targets, and analyzed the molecular basis underlying their differences in application. Results: The Treatise on Febrile Diseases contained a total of 87 articles that discussed terms related to "vomiting," along with 31 prescriptions specifi-cally designed for treating vomiting. Among these prescriptions, 14 included ginger as an ingredi-ent, while 13 contained dried ginger. Ginger was predominantly used in larger quantities and fea-tured a greater variety of medicinal flavors in the prescription, often combined with licorice, pinel-lia, jube, scutellaria, ginseng, peony, and other herbs. On the other hand, dried ginger was used in smaller amounts and had fewer medicinal tastes associated with it. It was commonly mixed with licorice, ginseng, coptis chinensis (goldthread), aconite root (monkshood), and other herbs. Through screening under specific conditions, we identified five active components of ginger that targeted 166 specific proteins and five active components of dried ginger that targeted 312 specific proteins. Beta-sitosterol emerged as a key component shared by both types of ginger extracts; however Di-hydrocapsaicin and Stigmasterol were identified as core components unique to regular ginger ex-tract while Sexangularetin and sitosterol were found to be core components unique to dried ginger extract. Conclusion: There exists a significant disparity in the therapeutic effects of ginger and dried ginger on vomiting in Treatise on Febrile Diseases. Dihydrocapsaicin and Stigmasterol may be the key components of ginger in the treatment of vomiting. Pathways in cancers, protein binding may be the key pathways of ginger and dried ginger in the treatment of vomiting.