基于血清代谢组学研究佛手柑内酯治疗肝纤维化的作用机制  

Serum metabolomics-based study on the mechanism of action of bergapten in the treatment of liver fibrosis

作　　者：吴辉星 张振华[2] 龙昌锐 郭桂芬 王炎玉 陈燕纯 付钜雄 乡世健 周本杰 鲁澄宇 WU Huixing;ZHANG Zhenhua;LONG Changrui;GUO Guifen;WANG Yanyu;CHEN Yanchun;FU Juxiong;XIANG Shijian;ZHOU Benjie;LU Chengyu(School of Pharmacy,Guangdong Medical University,Guangdong Dongguan 523808,China;Dept.of Pharmacy,the Seventh Affiliated Hospital of Sun Yat-sen University,Guangdong Shenzhen 518107,China;Blood Purification Center of Huidong County People’s Hospital,Guangdong Huizhou 513600,China;Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research,Guangdong Shenzhen 518107,China)

机构地区：[1]广东医科大学药学院,广东东莞523808 [2]中山大学附属第七医院药学部,广东深圳518107 [3]惠东县人民医院血液净化中心,广东惠州513600 [4]深圳市中药活性物质筛选与转化重点实验室,广东深圳518107

出　　处：《中国药房》2024年第13期1570-1575,共6页China Pharmacy

基　　金：国家自然科学基金项目(No.82074078);广东基础与应用基础研究基金项目(No.2022A1515220027);深圳市科技计划项目(No.ZDSYS20220606100801003)。

摘　　要：目的 基于血清代谢组学技术研究佛手柑内酯(BP)治疗肝纤维化的作用及机制。方法 将40只小鼠分为正常对照组(0.5%羧甲基纤维素钠溶液)、模型组(0.5%羧甲基纤维素钠溶液)和BP低、高剂量组(50、100 mg/kg),每组10只。除正常对照组外其余3组小鼠均采用四氯化碳诱导肝纤维化模型。同时,各组小鼠灌胃相应药物/溶剂,每日1次,连续8周。末次给药后,检测小鼠血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)水平,观察小鼠肝组织病理形态学变化,检测小鼠肝组织中α-平滑肌肌动蛋白(α-SMA)、Ⅰ型胶原蛋白(CollagenⅠ)表达,同时对小鼠血清进行代谢组学分析。结果 与模型组比较,BP低、高剂量组小鼠血清中ALT、AST水平和肝组织中α-SMA、CollagenⅠ蛋白表达水平均显著降低(P<0.05),肝组织的纤维化程度显著改善。代谢组学结果显示,BP高剂量组和模型组共有175个血清差异代谢物,其中18个物质上调、157个物质下调,涉及的主要代谢途径有嘧啶代谢、丁酸盐代谢、脂肪酸合成、酪氨酸代谢、β-丙氨酸代谢、烟酸和烟酰胺代谢以及谷胱甘肽代谢等。结论 BP可能通过调节肝纤维化小鼠血清中嘧啶代谢、丁酸盐代谢和谷胱甘肽代谢等途径达到治疗肝纤维化的作用。OBJECTIVE To study the effects of bergapten in the treatment of liver fibrosis and its mechanism based on serum metabolomics.METHODS Forty mice were divided into normal control group(0.5%carboxymethyl cellulose sodium solution),model group(0.5%carboxymethyl cellulose sodium solution),and BP low-dose and high-dose groups(50,100 mg/kg),with 10 mice in each group.Except for the normal control group,the other three groups were all treated with carbon tetrachloride to induce liver fibrosis model;they were given relevant medicine/solution intragastrically,once a day,for consecutive 8 weeks.After the last medication,the levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in serum were detected,and liver pathological changes were observed;the expressions ofα-smooth muscle actin(α-SMA)and CollagenⅠwere detected in liver tissue;the serum of the mice was collected for metabolomics analysis.RESULTS Compared with the model group,serum levels of ALT and AST and protein expressions ofα-SMA and CollagenⅠin liver tissue were decreased significantly in BP high-dose and low-dose groups(P<0.05),while liver fibrosis was improved significantly.Meanwhile,metabolomics analyses showed that there were a total of 175 serum differential metabolites in the BP high-dose group and model group,of which 18 substances were upregulated and 157 substances were downregulated;the main metabolic pathways involved in bergapten intervention were pyrimidine metabolism,butanoate metabolism,fatty acid synthesis,tyrosine metabolism,β-alanine metabolism,nicotinic acid and nicotinamide metabolism,glutathione metabolism,etc.CONCLUSIONS BP is effective in the treatment of liver fibrosis by regulating pyrimidine metabolism,butanoate metabolism,glutathione metabolism and so on in rats with liver fibrosis.

关 键 词：佛手柑内酯 肝纤维化 血清代谢组学 差异代谢物 代谢途径 

分 类 号：R965[医药卫生—药理学]