摘要
目的探讨登革热的高频证候用药规律,并基于生物信息学及网络药理学方法探讨中药治疗登革热卫气同病证与气营两燔证的作用机制。方法(1)通过数据挖掘分析登革热高频证候用药规律。运用R4.0.2软件进行描述性统计分析及关联规则、核心药物挖掘分析。分别统计登革热高频证型的治法分布、处方分布、药物频次,并基于Apriori算法挖掘高频证型所涉及的关联规则及核心中药。(2)探索卫气同病证与气营两燔证核心中药治疗登革热的机制。进行核心中药活性成分筛选及靶点注释,筛选登革热疾病基因,构建核心中药治疗登革热的“活性成分-疾病靶点”网络。筛选核心中药治疗登革热的关键靶点及其器官表达情况,进行通路注释及生物功能注释。结果(1)登革热高频证型分别是卫气同病证及气营两燔证。卫气同病证药物挖掘得到的关联规则以(葛根、金银花)→黄芩、(甘草、金银花)→黄芩、(甘草、黄芩)→金银花为首,核心中药组成包括黄芩、连翘、葛根、金银花、柴胡、甘草6味药物,槲皮素、山柰酚、熊果酸等在卫气同病证中靶向的治疗靶点最丰富。气营两燔证挖掘得到的关联规则以(赤芍、牡丹皮)→玄参、(赤芍、牡丹皮)→生地黄为首,核心中药组成包括牡丹皮、赤芍、黄芩、连翘、生地黄、玄参、水牛角、知母、甘草9味药物,山柰酚、槲皮素、邻苯二甲酸二丁酯等在气营两燔证中靶向的治疗靶点最丰富。(2)将2221个登革热疾病靶点与不同证型下核心中药活性成分靶点(卫气同病证1201个作用靶点,气营两燔证1248个作用靶点)互相映射,提取到175个卫气同病证及187个气营两燔证的核心中药治疗登革热的潜在作用靶点。提取到5个卫气同病证符合多重科学算法的核心靶点:HSP90AA1、HSP90AB1、PSMB9、PSMB8、SRC,4个气营两燔证符合多重科学算法的核心靶点:HSP90AA1、HSP90AB1、JUN、TP53,共有2个相同的核心靶点,5个不同的核心靶点。槲皮素、山柰酚、熊果酸、木犀草素、异鼠李素可能为治疗卫气同病证登革热的关键活性成分;山柰酚、槲皮素、邻苯二甲酸二丁酯、熊果酸、黄芩素可能为治疗气营两燔证登革热的关键活性成分。HSP90AB1在两个证型靶点中表达量最高,主要表达在肺、肌肉-骨骼、神经、肾上腺4个器官。核心中药治疗登革热的KEGG通路主要与炎症、免疫失衡、血管通透性、血管内皮功能障碍等病理环节相关,气营两燔证核心中药靶点在炎症和免疫调节方面的通路显著性较卫气同病证高。卫气同病证和气营两燔证核心中药靶点共有18条相同的条目,4条不同的条目。对比两个证型,气营两燔证中高表达基因的数目较卫气同病证多,且在炎症和血管内皮功能障碍方面的通路显著性较卫气同病证高。结论登革热临床最常见证型为卫气同病证及气营两燔证,卫气同病证治疗以清热解毒、化湿透表为主,气营两燔证治疗以清热解毒凉血为主。相对于卫气同病证,中医治疗气营两燔证登革热更侧重于抗炎及减轻血管内皮损伤,可能是通过调节IL-17信号通路、细胞凋亡、NOD样受体信号通路发挥药理作用。
Objective To explore the medication rule for high-frequency syndrome of dengue and to analyze the potential mechanism of traditional Chinese medicine(TCM)in the treatment of dengue with syndrome involving weifen and qifen and syndrome of flaring heat in qifen and yingfen based on bioinformatics and network pharmacology.Methods(1)We mined the medication rule for high-frequency syndrome of dengue with TCM through data analysis.R 4.0.2 software was used for descriptive statistical analysis,and mining analysis of association rules and core drug.The distribution of treatment methods,prescription distribution,and medication frequency for high-frequency syndrome of dengue were respectively checked.The association rules and core TCM involved in high-frequency syndrome were mined using Apriori algorithm.(2)To explore the mechanism of TCM in the treatment of dengue with syndrome involving weifen and qifen and syndrome of flaring heat in qifen and yingfen,we carried out a screen for core ingredients in TCM,annotation of targets,and a screen for disease genes of dengue.Then“active ingredients-disease targets”network of core TCM for the treatment of dengue was constructed.The key targets of core TCM for the treatment of dengue and its organ distribution were screened.Pathway analyses and biological function annotation were conducted.Results The high-frequency syndrome types of dengue were syndrome involving weifen and qifen,syndrome of flaring heat in qifen and yingfen,respectively.The association rules obtained from the mining of drugs for syndrome involving weifen and qifen were as follows:(Puerariae Lobatae Radix,Lonicerae Japonicae Flos)→Scutellariae Radix,(Glycyrrhizae Radix,Lonicerae Japonicae Flos)→Scutellariae Radix,(Glycyrrhizae Radix,Scutellariae Radix)→Lonicerae Japonicae Flos.The core TCM were Scutellariae Radix,Forsythiae Fructus,Puerariae Lobatae Radix,Lonicerae Japonicae Flos,Bupleuri Radix and Glycyrrhizae Radix.Quercetin,kaempferol and ursolic acid have the most abundant therapeutic targets in syndrome involving weifen and qifen.The association rules obtained from the mining of drug for syndrome of flaring heat in qifen and yingfen were as follows:(Paeoniae Radix Rubra,Moutan Cortex)→Scrophulariae Radix,(Paeoniae Radix Rubra,Moutan Cortex)→Rehmanniae Radix.The core TCM were Moutan Cortex,Paeoniae Radix Rubra,Scutellariae Radix,Forsythiae Fructus,Rehmanniae Radix,Scrophulariae Radix,Bubali Cornu,Anemarrhenae Rhizoma and Glycyrrhizae Radix.Quercetin,kaempferol and dibutyl phthalate have the most abundant therapeutic targets in syndrome of flaring heat in qifen and yingfen.(2)A total of 2221 dengue targets were mapped to targets of TCM active ingredients(1201 targets for syndrome involving weifen and qifen,1248 targets for syndrome of flaring heat in qifen and yingfen)in different syndrome types,then 175 potential targets for syndrome involving weifen and qifen and 187 potential targets for syndrome of flaring heat in qifen and yingfen were obtained.Five core targets for syndrome involving weifen and qifen that complied with multiple scientific algorithms,including HSP90AA1,HSP90AB1,PSMB9,PSMB8 and SRC were extracted.Four core targets for syndrome of flaring heat in qifen and yingfen that complied with multiple scientific algorithms including HSP90AA1,HSP90AB1,JUN and TP53 were extracted.There are two identical core targets and five different core targets.Quercetin,kaempferol,ursolic acid,luteolin and isorhamnetin may be the key ingredients for the treatment of dengue with syndrome involving weifen and qifen.Kaempferol,quercetin,dibutyl phthalate,ursolic acid and baicalein may be the key ingredients for the treatment of dengue with syndrome of flaring heat in qifen and yingfen.The expression level of HSP90AB1 was the highest in the targets of two syndromes,which was mainly expressed in lungs,musculoskeletal system,nerves,and adrenal gland.The KEGG pathway of core TCM for the treatment of dengue is mainly related to pathological processes such as inflammation,immune imbalance,vascular permeability,and endothelial dysfunction.The pathway in inflammation and immune regulation of the targets of core TCM for syndrome of flaring heat in qifen and yingfen showed more significant than those for syndrome involving weifen and qifen.There are eighteen identical entries and four different entries.Compared with the two syndrome types,the number of highly expressed genes in syndrome of flaring heat in qifen and yingfen was more than that in syndrome involving weifen and qifen,and the pathway in inflammation and vascular endothelial dysfunction was significantly higher than that in syndrome involving weifen and qifen.Conclusion The most common clinical syndromes of dengue were syndrome involving weifen and qifen and syndrome of flaring heat in qifen and yingfen.The syndrome involving weifen and qifen was mainly focused on clearing away heat and detoxification,resolving dampness and relieving superficies,while the syndrome of flaring heat in qifen and yingfen was focused on clearing away heat and detoxification and cooling blood.Compared to syndrome involvingweifenandqifen,TCM treatment of dengue with syndrome of flaring heat in qifen and yingfen emphasize particularly on anti-inflammation and reducing vascular endothelial injury,which may play a pharmacological role by regulating IL-17 signal pathway,apoptosis and NOD-like receptor signal pathway.
作者
王婷
刘城鑫
黄慧婷
詹少锋
王凯
温武金
WANG Ting;LIU Chengxin;HUANG Huiting;ZHAN Shaofeng;WANG Kai;WEN Wujin(The First Clinical Medical College,Guangzhou University of Chinese Medicine,Guangzhou 510405 Guangdong,China;The First Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510405 Guangdong,China;Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine,Shenzhen 518104 Guangdong,China)
出处
《中药新药与临床药理》
北大核心
2025年第1期90-102,共13页
Traditional Chinese Drug Research and Clinical Pharmacology
基金
国家自然科学基金面上项目(82274418)
广东省重点领域研发计划项目(2020B1111100002)
深圳市“医疗卫生三名工程”建设项目(SZZYSM202206013,SZZYSM202106006)
广州中医药大学“双一流”和高水平大学学科协同创新团队项目(2021XK16)
广州市科技计划项目(2023A04J1168)。
关键词
登革热
卫气同病证
气营两燔证
数据挖掘
生物信息学
网络药理学
同病异治
Dengue
syndrome involving weifen and qifen
syndrome of flaring heat in qifen and yingfen
data mining
bioinformatics
network pharmacology
different treatment of the same disease
