基于病症模型的经方四妙丸防治高尿酸血症痛风的药效物质探讨  

Study on the Pharmacodynamic Substances of Simiao Wan for Treatment of Hyperuricemia and Gout Based on Disease and Syndrome Model

作　　者：曾永长[1,2] 梁少瑜 吴俊洪[1] 徐丹丹 刘常青 何康 金宇 吴正治[1,3] ZENG Yongchang;LIANG Shaoyu;WU Junhong;XU Dandan;LIU Changqing;HE Kang;JIN Yu;WU Zhengzhi(Department of Integrated Traditional and Western Medicine,the First Affiliated Hospital of Shenzhen University,Shenzhen 518035 Guangdong,China;The Affiliated Traditional Chinese Medicine Hospital of Guangzhou Medical University,Guangzhou 510180 Guangdong,China;Department of Neurology,the First Affiliated Hospital of Shenzhen University,Shenzhen 518035 Guangdong,China;Guizhou University of Traditional Chinese Medicine,Guiyang 550002 Guizhou,China;Guangzhou Zeli Pharmaceutical Technology Co.Ltd,Guangzhou 510663 Guangdong,China)

机构地区：[1]深圳大学第一附属医院中西结合科,广东深圳518035 [2]广州医科大学附属中医医院,广东广州510180 [3]深圳大学第一附属医院神经内科,广东深圳518035 [4]贵州中医药大学,贵州贵阳550002 [5]广州泽力医药科技有限公司,广东广州510663

出　　处：《中药新药与临床药理》2024年第8期1152-1162,共11页Traditional Chinese Drug Research and Clinical Pharmacology

基　　金：国家自然科学基金项目(81603669);广东省自然科学基金项目(2021A1515010978、2021A1515012474);岭南中医药现代化重点专项(2020B1111120003);深圳市科技计划项目(JCYJ20210324121610029)。

摘　　要：目的探索经方四妙丸防治高尿酸血症痛风的药效物质。方法建立高尿酸血症药理模型,采用超高效液相色谱串联四极杆静电场轨道阱质谱联用技术(UPLC-Q-Exactive-MS)分析四妙丸体内外化学成分;以入血成分为基础,采用网络药理学构建四妙丸调控高尿酸血症痛风“活性成分-靶点-通路”网络;以关键活性成分与高尿酸血症痛风关键靶点尿酸生成酶(XDH),尿酸转运体(ABCG2、GLUT9、OAT1、URAT1)及炎症靶点(PTGS2、TLR2、TLR4)进行分子对接,根据对接结果进行实验验证,探讨四妙丸防治高尿酸血症痛风的关键药效物质。结果UPLC-Q-Exactive-MS法共鉴定四妙丸89个成分,包含74个入血成分,即候选成分;网络药理学构建了“入血成分-靶点-通路”网络,入血成分匹配116个高尿酸靶点和173痛风靶点,涉及调节糖脂代谢、氧化应激、炎症反应、ERK1、ERK2和MAPK级联反应、PI3K信号传导等生物过程;调节血脂与动脉粥样硬化、凋亡、AGE-RAGE、TNF、PI3K-Akt、MAPK、TLRs、JAK-STAT、NF-κB等信号通路,发挥多途径调控高尿酸血症痛风疾病网络的作用。分子对接研究表明小檗碱、黄柏碱、木兰花碱、药根碱、巴马汀、黄柏酮、柠檬苦素、苍术素、花旗松素、白术内酯Ⅲ及β-蜕皮甾酮等成分与尿酸合成酶、尿酸转运体及炎症靶点的亲和力良好,Western Blot验证发现花旗松素具有负调节尿酸盐转运蛋白1(URAT1)表达的作用,其是四妙丸防治高尿酸血症痛风的主要药效物质。结论该研究阐述了四妙丸调控高尿酸血症痛风的主要药效物质,可为四妙丸临床应用、质量评价和标准提升提供科学依据。Objective To explore the pharmacodynamic substances of Simiao Wan for the treatment of hyperuricemia and gout.Methods The pharmacological model of hyperuricemia was established.The chemical components in vivo and in vitro of Simiao Wan were analyzed by UPLC-Q-Exactive-MS.Based on the components absorbed in blood,the“active ingredient-target-pathway”network of Simiao Wan for regulating hyperuricemia and gout was constructed by network pharmacology method.The key ingredients were used for molecular docking with key targets[uricogenase(XDH),uric acid transporter(ABCG2,GLUT9,OAT1,URAT1)and inflammatory targets(PTGS2,TLR2,TLR4)]of hyperuricemia and gout.Finally,experimental verification was conducted according to the results of molecular docking.Our aim is to identify the key pharmacodynamic substances of Simiao Wan for the treatment of hyperuricemia and gout.Results Eighty-nine components of Simiao Wan were identified by UPLC-Q-Exactive-MS analysis,including 74 components absorbed in blood,which were confirmed as candidate ingredients.Network pharmacology was used to constructed“components absorbed in blood-target-pathway”network,and components absorbed in blood were matched with 116 targets of hyperuricemia and 173 targets of gout.It is involved in the regulation of biological processes,such as glucose and lipid metabolism,oxidative stress,inflammatory response,ERK1 and ERK2 cascade,MAPK cascade,PI3K signal transduction.Moreover,Simiao Wan plays a role in regulating the network of hyperuricemia and gout through regulating blood lipids and atherosclerosis,apoptosis,AGE-RAGE,TNF,PI3K-Akt,MAPK,TLRs,JAK-STAT,NFκB and other signaling pathways.Molecular docking studies showed that berberine,phellodendrine,magnoflorine,jatrorrhizine,palmatine,obacunone,limonin,atractylodin,taxifolin,atractylenolideⅢandβ-ecdysterone had good affinity with uric acid synthase,uric acid transporter and inflammatory targets.Western Blot test showed that taxifolin negatively regulates the expression of URAT1.The above-mentioned compo

关 键 词：高尿酸血症痛风 四妙丸 花旗松素 血清药物化学 药效物质基础 质量控制 人肾上皮细胞HK2细胞 大鼠 

分 类 号：R285.5[医药卫生—中药学]