UPLC-QTOF/MS结合网络药理学探讨诃子与草乌配伍“异病同治”类风湿性关节炎和痛风性关节炎作用机制

Mechanism of Terminalia chebula and Aconiti Kusnezoffii Radix Compatibility in Treating RA and GA Based on UPLC-QTOF/MS and Network Pharmacology

目的:探讨诃子与草乌配伍“异病同治”类风湿性关节炎(RA)和痛风性关节炎(GA)的作用机制。方法:采用数据挖掘技术找出治疗“图赖”病的核心药物组合(诃子-草乌),并使用超高效液相色谱-四极杆飞行时间质谱法(UPLC-QTOF/MS)检测大鼠灌胃诃子与草乌配伍药物后的入血成分;运用PubChem、Swiss Target Prediction、GeneCards、OMIM、DisGeNET、Metascape等多个数据库检索诃子与草乌化学成分对应靶点、RA和GA的疾病靶点,以及代谢通路等信息,利用Cytoscape3.8.2软件构建成分-靶点-通路-疾病网络,并利用分子对接方法证实诃子与草乌的主要成分与关键靶点之间的高亲合力。结果:诃子与草乌入血成分相应靶点与RA靶点交集后得到323个交集靶点、与GA靶点交集后得到24个交集靶点,两者共有靶点24个,主要有肿瘤坏死因子(TNF)、肿瘤蛋白p53(TP53)、基质金属蛋白酶-9(MMP-9)、前列腺素内过氧化物合酶2(PTGS2)和信号转导和转录激活因子3(STAT3),与十八碳四烯酸、绢酸、5-(3-羟基-4-乙酰氧基-1-丁基)-2,2'-联噻吩、灵芝酸H等有紧密联系,涉及通路有TNF信号通路、破骨细胞分化通路、癌症通路等。分子对接结果显示灵芝酸H和TNF、5-(3-羟基-4-乙酰氧基-1-丁基)-2,2'-联噻吩和MMP-9有强烈对接活性。结论:蒙古族药诃子与草乌配伍治疗RA和GA具有多靶点效应,可能通过炎症反应的调节、细胞对生物刺激的反应、对细菌源分子的反应、磷酸盐代谢的正调控和对激素的反应等通路发挥“异病同治”作用。

Objective:To explore the mechanism of Terminalia chebula and Aconiti Kusnezoffii Radix compatibility in the treatment of rheumatoid arthritis(RA)and gouty arthritis(GA).Methods:Data mining technology was used to find out the core drug combination(Terminalia chebula-Aconiti Kusnezoffii Radix)for the treatment of'Tulai'disease,and ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-QTOF-MS)was used to detect the components of Terminalia chebula and Aconiti Kusnezoffii Radix compatibility in the blood of rats,and multiple databases such as PubChem,SwissTargetPrediction,GeneCards,OMIM,DisGeNET,and Metascape were used to search the corresponding chemical component targets of Terminalia chebula and Aconiti Kusnezoffii Radix,the disease targets of RA and GA,and the metabolic pathways.Cytoscape 3.8.2 software was used to construct the network of"component-target-pathway-disease",and the high affinity between major components and key targets of Terminalia chebula and Aconiti Kusnezoffii Radix was confirmed by the molecular docking method.Results:After the corresponding targets in the blood intersect with RA targets,323 intersecting targets were obtained,and after they intersect with GA targets,24 intersecting targets were obtained.There were 24 common targets,including tumor necrosis factor(TNF),cellular tumor antigen p53(TP53),matrix metalloproteinase-9(MMP-9),prostaglandin-endoperoxide synthase 2(PTGS2),and signal transducer and activator of transcription 3(STAT3),which were closely related to stearidonic acid,sericic acid,5-(3-hydroxy-4-acetoxybut-1-ynyl)-2,2′-bithiophene,and ganoderic acid H,involving pathways such as TNF signaling pathway,osteoclast differentiation,and cancer pathway.The results of molecular docking showed that ganoderic acid H had strong docking activity with TNF,and 5-(3-hydroxy-4-acetoxybut-1-ynyl)-2,2′-bithiophene had strong docking activity with MMP9.Conclusion:The compatibility of Mongolian Medicine Terminalia chebula and Aconiti Kusnezoffii Radix has a multi-target effect on RA and GA.It may treat different diseases with the same method through the regulation of inflammatory response,cellular response to biotic stimulus,response to molecule of bacterial origin,positive regulation of phosphate metabolism,and response to hormones.