基于代谢组学和血清药物化学研究益肾固络合剂治疗慢性肾小球肾炎的效应物质及作用机制  

Effective substances and mechanism of Yishen Guluo Mixture in treatment of chronic glomerulonephritis based on metabolomics and serum pharmacochemistry

作　　者：卞振华 张文明 唐静月 费倩倩 胡敏敏[1] 陈晓伟 袁晓航[1] 陆兔林[2] BIAN Zhen-hua;ZHANG Wen-ming;TANG Jing-yue;FEI Qian-qian;HU Min-min;CHEN Xiao-wei;YUAN Xiao-hang;LU Tu-lin(Department of Pharmacy,Wuxi Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine,Wuxi 214071,China;College of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China)

机构地区：[1]南京中医药大学无锡附属医院药学部,江苏无锡214071 [2]南京中医药大学药学院,江苏南京210023

出　　处：《中国中药杂志》2023年第2期492-506,共15页China Journal of Chinese Materia Medica

基　　金：无锡市卫生健康委科研项目(MS201941,2020ZHYB17);无锡市科技发展资金项目(N20202009,N20192038);无锡市卫生健康委员会中青年拔尖人才计划项目(HB2020059);江苏省研究生科研创新计划项目(KYCX20_1513);国家自然科学基金项目(81873008)。

摘　　要：基于代谢组学和血清药物化学研究益肾固络合剂治疗慢性肾小球肾炎(chronic glomerulonephritis,CGN)的效应物质及作用机制。建立阳离子化牛血清白蛋白(cationic bovine serum albumin,C-BSA)诱导的CGN大鼠模型,益肾固络合剂灌胃给药后,进行肾脏功能相关生化指标(24 h尿蛋白、血清尿素氮和肌酐)测定以及组织病理形态观察等药效评价;采用UPLC-Q-TOF-MS技术结合多元统计分析筛选益肾固络合剂治疗CGN的血清生物标志物,并进行代谢通路分析;依据质谱离子碎片信息和代谢途径,结合PeakView 1.2和MetabolitePilot 2.0.4软件对益肾固络合剂入血成分(原型及代谢产物)进行鉴定分析;整合代谢组学和血清药物化学数据,构建血清生物标志物和入血成分相关性分析的数理模型,筛选益肾固络合剂治疗CGN的潜在效应物质。益肾固络合剂显著降低CGN大鼠的24 h尿蛋白、血清尿素氮和肌酐水平,以及改善肾脏组织病理损伤;代谢组学共筛选出花生四烯酸和溶血磷脂酰胆碱类化合物等20个益肾固络合剂治疗CGN的血清生物标志物,涉及花生四烯酸代谢、甘油磷脂代谢等途径;基于血清药物化学方法,鉴定益肾固络合剂含药血清中8个原型入血成分和20个血中代谢产物;基于代谢组学和血清药物化学相关性分析,筛选了益肾固络合剂入血成分中染料木苷等12个化合物为其治疗CGN的潜在效应物质。基于代谢组学和血清药物化学方法分析和阐释了益肾固络合剂治疗CGN的效应物质及作用机制,为开发治疗中医临床优势病种CGN的创新中药研究提供新思路。This study aimed to investigate the effective substances and mechanism of Yishen Guluo Mixture in the treatment of chronic glomerulonephritis(CGN)based on metabolomics and serum pharmacochemistry.The rat model of CGN was induced by cationic bovine serum albumin(C-BSA).After intragastric administration of Yishen Guluo Mixture,the biochemical indexes related to renal function(24-hour urinary protein,serum urea nitrogen,and creatinine)were determined,and the efficacy evaluations such as histopathological observation were carried out.The serum biomarkers of Yishen Guluo Mixture in the treatment of CGN were screened out by ultra-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry(UPLC-Q-TOF-MS)combined with multivariate statistical analysis,and the metabolic pathways were analyzed.According to the mass spectrum ion fragment information and metabolic pathway,the components absorbed into the blood(prototypes and metabolites)from Yishen Guluo Mixture were identified and analyzed by using PeakView 1.2 and MetabolitePilot 2.0.4.By integrating metabolomics and serum pharmacochemistry data,a mathematical model of correlation analysis between serum biomarkers and components absorbed into blood was constructed to screen out the potential effective substances of Yishen Guluo Mixture in the treatment of CGN.Yishen Guluo mixture significantly decreased the levels of 24-hour urinary protein,serum urea nitrogen,and creatinine in rats with CGN,and improved the pathological damage of the kidney tissue.Twenty serum biomarkers of Yishen Guluo Mixture in the treatment of CGN,such as arachidonic acid and lysophosphatidylcholine,were screened out,involving arachidonic acid metabolism,glycerol phosphatide metabolism,and other pathways.Based on the serum pharmacochemistry,8 prototype components and 20 metabolites in the serum-containing Yishen Guluo Mixture were identified.According to the metabolomics and correlation analysis of serum pharmacochemistry,12 compounds such as genistein absorbed into the blood from Yi

关 键 词：益肾固络合剂 慢性肾小球肾炎 代谢组学 生物标志物 入血成分 效应物质 作用机制 

分 类 号：R285.5[医药卫生—中药学]