基于网络药理学及动物实验探讨栀子大黄汤治疗肝豆状核变性的作用机制  

Mechanism of treatment of hepatolenticular degeneration with Gardenia and Rhubarb decoction based on network pharmacology and animal experiments

作　　者：王永杰 李闪闪 吴宗耀 慕文理 魏雨润 魏丹丹[5] WANG Yong-jie;LI Shan-shan;WU Zong-yao;MU Wen-li;WEI Yu-run;WEI Dan-dan(Dept of Traditional Chinese Medicine,the Third People’s Hospital of Henan Province(Henan Institute of Occupational Health),Zhengzhou 450000,China;the First Clinical Medical College,Henan University of Chinese Medicine,Zhengzhou 450046,China;Tibetan Medicine Research Institute of Tibet University of Tibetan Medicine,Lhasa 850007,China;College of Acupuncture and Massage,Henan University of Chinese Medicine,Zhengzhou 450000,China;Postgraduate Dept,the First Affiliated Hospital of Henan University of Chinese Medicine,Zhengzhou 450046,China)

机构地区：[1]河南省第三人民医院(河南省职业病医院)中医科,河南郑州450000 [2]河南中医药大学第一临床医学院,河南郑州450046 [3]西藏藏医药大学藏医药研究所,西藏拉萨850007 [4]河南中医药大学针灸推拿学院,河南郑州450046 [5]河南中医药大学第一附属医院针灸科,河南郑州450046

出　　处：《中国药理学通报》2024年第11期2165-2173,共9页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金青年项目(No 82204971);全国老中医药专家传承工作室建设项目(国中医药人教函〔2022〕75号);河南省联合共建项目(No LHGJ20210266)。

摘　　要：目的基于网络药理学及动物实验探究栀子大黄汤治疗肝豆状核变性的作用机制。方法利用TCMSP平台检索栀子大黄汤的化学成分和作用靶点;通过检索DisGeNET、GeneCards数据库获得疾病靶点;通过STRING数据库构建PPI网络,利用DAVID数据库进行GO功能和KEGG通路富集分析,预测其作用通路。通过采用灌胃五水合硫酸铜构建铜负荷WD大鼠模型进行实验验证,共36只,随机分为正常组、模型组、青霉胺组、栀子大黄低、中、高剂量组。检测WD大鼠相关指标及肝组织病理学变化等。结果网络药理学筛选出栀子大黄汤潜在活性成分68个,疾病与药物交集靶点30个,涉及TNF、IL10、IGF1、IL1B、TP53、CASP3、PPARG、IL6、CXCL8、IL1A、TGFB1等关键靶点,主要与MAPK、AGE-RAGE signaling pathway in diabetic complications等信号通路相关。体内实验方面,与正常组相比,模型组大鼠的尿铜、肝铜、血铜、肝脏系数以及血清和肝脏ALT、AST、TNF-α、CASP3、P53均明显升高(P<0.05);肝细胞肿大,胞质疏松呈丝网状,出现羽毛状变性及网状坏死等病理变化;与模型组比较,青霉胺组、栀子大黄汤各组大鼠的尿铜、肝铜、血铜、肝脏系数以及血清和肝脏ALT、AST、TNF-α、CASP3、P53均明显降低(P<0.05),青霉胺组和栀子大黄汤组各组大鼠的肝细胞网状坏死程度明显减轻。结论栀子大黄汤具有调节铜代谢及减轻肝损伤的作用,其作用机制可能与逆转细胞凋亡,下调MAPK信号通路TNF-α、CASP3、P53等蛋白表达有关。Aim To investigate the mechanism of treatment of hepatolenticular degeneration with Gardenia and Rhubarb decoction based on network pharmacology and animal experiments.Methods The chemical components and target sites of Gardenia and Rhubarb decoction were retrieved using the Traditional Chinese Medicine System Pharmacology Analysis Platform(TCMSP).The disease targets were obtained by searching the databases of DisGeNET,GeneCards.The PPI network of active compound target sites was constructed using the STRING database.GO function and KEGG pathway enrichment analysis were performed using the DAVID database to predict the action pathway.A copper-loaded WD rat model was established by intragastric administration of copper sulfate pentahydrate.A total of 36 rats were randomly divided into the normal group,model group,penicillamine group and the low,medium and high dose groups of gardenia rhubarb.The relevant indicators and pathological changes of liver tissue were detected in WD rats.Results Network pharmacology screening identified 68 potential active components of Gardenia and Rhubarb Decoction,30 intersection targets of diseases and drugs,involving key targets such as TNF,IL10,IGF1,IL1B,TP53,CASP3,PPARG,IL6,CXCL8,IL1A,TGFB1,mainly related to signal pathways such as MAPK,AGE-RAGE signaling pathway in diabetic complications.In the animal experiments,compared with the normal group,the urine copper,liver copper,blood copper,liver coefficient,serum and liver ALT,AST,TNF-α,CASP3,P53 levels in the model group rats significantly increased(P<0.05);hepatocyte swelling,cytoplasm loose reticular appearance,feather-like degeneration and reticular necrosis were observed in liver tissue pathology;compared with the model group,the urine copper,liver copper,blood copper,liver coefficient,serum and liver ALT,AST,TNF-α,CASP3,P53 levels in the penicillamine group and Gardenia and Rhubarb decoction groups were significantly reduced(P<0.05),and the degree of reticular necrosis in the rat liver cells in the penicillamine group and the

关 键 词：栀子大黄汤 肝豆状核变性 作用机制 

分 类 号：R285.5[医药卫生—中药学]