豨加精方调控Nrf2/GPX4防治5-氟尿嘧啶所致小鼠心脏毒性  

Xijiajing Formula Regulates Nrf2/GPX4 to Prevent 5-Fluorouracil-Induced Cardiotoxicity in Mice

作　　者：王文惠 卫晓红 许倩倩 林宏远 彭梦琪 张晓维 商洪才 WANG Wenhui;WEI Xiaohong;XU Qianqian;LIN Hongyuan;PENG Mengqi;ZHANG Xiaowei;SHANG Hongcai(School of Integrated Chinese and Western Medicine,Hunan University of Chinese Medicine,Changsha 410208,China;Key Laboratory of Chinese Internal Medicine of Ministry of Education,Dongzhimen Hospital,Beijing University of Chinese Medicine,Beijing 100700,China;Shandong Second Medical University,Weifang 261053,China)

机构地区：[1]湖南中医药大学中西医结合学院,长沙410208 [2]北京中医药大学东直门医院中医内科学教育部和北京市重点实验室,北京100700 [3]山东第二医科大学,潍坊261053

出　　处：《中国中医基础医学杂志》2025年第4期632-638,共7页JOURNAL OF BASIC CHINESE MEDICINE

基　　金：国家科技重大专项(2023ZD0502700,2023ZD0502705);北京市通州区2023年度医药健康产业发展项目(JX2023YJ024)。

摘　　要：目的探究豨加精方对5-氟尿嘧啶所致小鼠心脏毒性的作用及其机制。方法C57BL/6J小鼠随机分为5组:对照组、5-氟尿嘧啶组、豨加精方低剂量组、豨加精方中剂量组、豨加精方高剂量组。每组小鼠按10mL/kg容量腹腔注射或灌胃相应药物。腹腔注射5-氟尿嘧啶,每次5mg/mL,每周1次,注射4周,建立小鼠心脏毒性模型。豨加精方各组在腹腔注射5-氟尿嘧啶的基础上,予以低、中、高剂量豨加精方灌胃给药(0.5525g/mL、1.105g/mL、2.210g/mL),每日1次,连续4周。第4周干预结束后行超声心动图评估小鼠心脏功能;ELISA法检测各组小鼠心肌损伤标志物水平,评价小鼠体内氧化应激状态;HE和Massson染色评估小鼠心肌组织形态结构变化及心肌组织纤维化;蛋白印迹法检测小鼠心肌组织中核因子-E2相关因子2(Nrf2)/谷胱甘肽过氧化物酶4(GPX4)蛋白表达。结果与对照组比较,5-氟尿嘧啶组小鼠左室射血分数(LVEF)、左室短轴缩短率(LVFS)均显著降低(P<0.05),心肌损伤标志物乳酸脱氢酶(LDH)、肌酸激酶同工酶(CK-MB)含量显著升高(P<0.05),心肌纤维排列紊乱、胶原纤维增多;与5-氟尿嘧啶组比较,豨加精方组小鼠LVEF和LVFS提高,LDH和CK-MB含量降低,心肌病理损伤改善,心肌纤维化减轻。进一步研究发现,5-氟尿嘧啶显著增加小鼠体内氧化应激指标丙二醛(MDA)和活性氧(ROS)含量(P<0.05),降低抗氧化产物还原型谷胱甘肽(GSH)和超氧化物歧化酶(SOD)的表达水平(P<0.05),降低小鼠心肌组织中抗氧化蛋白Nrf2和GPX4的水平(P<0.05);而豨加精方组能显著抑制5-氟尿嘧啶导致的氧化应激反应。结论豨加精方可能通过激活Nrf2/GPX4抗氧化系统,促进抗氧化酶表达,抑制5-氟尿嘧啶导致的氧化应激反应,从而减轻心脏毒性。Objective To explore the effect and mechanism of Xijiajing formula on 5-fluorouracil-induced cardiotoxicity in mice.Methods C57BL/6J mice were randomly divided into five groups:Control group,5-fluorouracil group,low-dose Xijiajing formula group,medium-dose Xijiajing formula group,and high-dose Xijiajing formula group.Each group was administered the corresponding drugs via intraperitoneal injection or gavage at a volume of 10 mL/kg.The cardiotoxicity model was established by intraperitoneal injection of 5-fluorouracil at a dose of 5 mg/mL once a week for 4 weeks.In addition to the 5-fluorouracil injection,the Xijiajing formula groups were administered low,medium,or high doses of Xijiajing formula(0.5525 g/mL,1.105 g/mL,2.210 g/mL)via gavage once daily for 4 weeks.After the 4-week intervention,echocardiography was performed to evaluate changes in cardiac function and structure.ELISA was used to measure myocardial injury markers and assess oxidative stress levels in mice.HE and Masson staining were employed to evaluate morphological changes and myocardial fibrosis in cardiac tissues.Western blotting was used to detect the expression of Nrf2/GPX4 proteins in myocardial tissues.Results Compared to the Control group,the 5-fluorouracil group showed a significant decrease in LVEF and LVFS(P<0.05),a significant increase in myocardial injury markers LDH and CK-MB levels(P<0.05),disordered myocardial fiber arrangement,and increased collagen fibers.In comparison to the 5-fluorouracil group,the Xijiiajing formula group exhibited improved LVEF and LVFS,reduced LDH and CK-MB levels,ameliorated myocardial pathological damage,and alleviated myocardial fibrosis.Further research found that 5-fluorouracil significantly increased the oxidative stress indicators MDA and ROS levels in mice(P<0.05),decreased the expression levels of antioxidant products GSH and SOD(P<0.05),and decreased the levels of antioxidant proteins Nrf2 and GPX4 in myocardial tissue(P<0.05).In contrast,the Xijiiajing formula group significantly inhibited the oxida

关 键 词：5-氟尿嘧啶 豨加精方 心脏毒性 氧化应激 Nrf2/GPX4 

分 类 号：R223.1[医药卫生—中医基础理论]