摘要
目的:探讨川芎嗪对对乙酰氨基酚(APAP)诱导的肝损伤的保护作用及其作用机制.方法:将60只7～8周龄无特定病原体(SPF)级雄性C57BL/6小鼠,采用简单随机化法分为对照组,模型组,川芎嗪低、中、高剂量组,以及阳性对照组,每组10只.川芎嗪低、中、高剂量组小鼠分别灌胃给予30、100、300 mg/kg的川芎嗪,阳性对照组灌胃给予150 mg/kg的N-乙酰半胱氨酸(NAC),连续给药12 d,在末次给药2 h后,除对照组外,其余组小鼠均腹腔注射300 mg/kg的APAP进行造模,14 h后取样.结果:与对照组比较,模型组小鼠肝脏指数、铁离子、丙二醛(MDA)、核因子E2相关因子2(Nrf2)及炎症介质和趋化因子均显著升高(均P＜0.05),Nrf2、NAD(P)H醌氧化还原酶1(NQO1)、谷胱甘肽过氧化物酶4(GPX4)、血红素氧合酶-1(HO-1)蛋白水平均显著降低(均P＜0.05);与模型组比较,川芎嗪组肝脏指数、铁离子、MDA、长链脂酰辅酶A合成酶4(ACSL4),以及炎症介质和趋化因子均显著降低(均P＜0.05),Nrf2、NQO1、HO-1、GPX4蛋白水平均显著升高(均P＜0.05).结论:川芎嗪可通过抑制炎症反应和铁死亡途径改善APAP所致药物性肝损伤,这可能与激活Nrf2/NQO1/HO-1通路有关.
Abstract
Objective:To investigate the protective effect of ligustrazine on the liver injury induced by acetaminophen(APAP)and the underlying mechanism.Methods:Sixty specific pathogen free(SPF)-grade male C57BL/6 mice of 7 to 8 weeks old were ran-domized into control,model,low-,medium-,high-dose(30,100,and 300 mg/kg,respectively)ligustrazine,and positive control(150 mg/kg N-acetylcysteine)group,with 10 mice in each group.Mice were administrated with corresponding drugs by gavage for 12 consecutive days.Two hours after the last administration,mice in other groups except the control group were intraperitoneally injec-ted with 300 mg/kg APAP for modeling,and samples were collected 14 h later.Results:Compared with the control group,the model group showed increased liver index,elevated levels of iron ion,malondialdehyde(MDA),acyl-CoA synthetase long-chain family member 4(ACSL4),pro-inflammatory cytokines,and chemokines(all P＜0.05),and down-regulated protein levels of nuclear E2-related factor 2(Nrf2),NAD(P)H:quinone oxidoreductase 1(NQO1),heme oxygenase-1(HO-1),and glutathione peroxidase(GPX4)(all P＜0.05).Compared with the model group,ligustrazine decreased the liver index,lowered the levels of iron ion,MDA,ACSL4,pro-inflammatory cytokines,and chemokines(all P＜0.05),and up-regulated the protein levels of Nrf2,NQO1,HO-1,and GPX4(all P＜0.05).Conclusion:Ligustrazine can alleviate the APAP-induced liver injury by inhibiting inflammatory re-sponse and ferroptosis pathway,which may be associated with the activation of the Nrf2/NQO1/HO-1 pathway.
基金项目
四川省应用基础研究计划项目(N2014JY0058)
绵阳市科技局课题(2019YFZJ018)
维普
万方数据