鞣花酸对纳米二氧化钛颗粒诱导肝损伤的保护作用及其机制

The protective effect and mechanism of ellagic acid on liver injury induced by titanium dioxide nanoparticles

目的探讨鞣花酸(EA)对纳米二氧化钛颗粒(TiO_(2)NPs)诱导的肝损伤发挥保护作用的机制。方法小鼠随机分为对照组、EA组、TiO_(2)NPs组和TiO_(2)NPs+EA组,对照组不做任何处理,TiO_(2)NPs组接受TiO_(2)NPs 150 mg/(kg·d)灌胃处理,EA组接受EA 50 mg/(kg·d)灌胃处理,TiO_(2)NPs+EA组在TiO_(2)NPs 150 mg/(kg·d)给药基础上灌胃给予EA 50 mg/(kg·d)。8周后取材,检测各组肝损伤指标,并观察肝组织病理学形态改变。Western blot检测各组氧化应激相关Ogg1、脂质合成相关Srebp-1c、内质网应激相关Bip、Pdi、ATF6-p50、ATF6-p90、p-Ire1α、Xbp1s、Xbp1u、p-eIf2α、ATF4和肝纤维化相关α-SMA表达。qPCR检测各组维持脂质代谢稳态相关Acox2、Ces1g、Acot7、Pparα、Cpt1a、Scad、Srebf1、Mlxipl、Lxrα、Xbp1s、内质网应激相关Atf4、Chop和肝纤维化相关Tgfb、Col 1α1、α-Sma的mRNA水平。结果与对照组相比,TiO_(2)NPs组小鼠肝指数增加,肝脏结构紊乱。Ogg1、Srebp-1c、Bip、ATF6-p50、ATF6-p90、p-Ire1α、Xbp1s、Xbp1u、p-eIf2α、ATF4及α-SMA的表达显著增多。Acox 2、Ces 1 g、Acot 7、Cpt1a及Scad的mRNA水平显著下降,而Pparα、Srebf 1、Mlxipl、Lxrα、Xbp 1 s、Atf 4、Chop、Tgfb、Col 1α1及α-Sma的mRNA水平显著升高。与TiO_(2)NPs组相比,TiO_(2)NPs+EA组小鼠以上指标呈现相反趋势。结论EA通过减轻氧化应激、内质网应激和脂质代谢紊乱缓解TiO_(2)NPs诱导的肝损伤。

Objective To explore the protective mechanism of ellagic acid(EA)on liver injury induced by nano titanium dioxide particles(TiO_(2)NPs).Methods 40 mice were randomly divided into Control group,EA group,TiO_(2)NPs group and TiO_(2)NPs+EA group.The Control group did not receive any treatment.The TiO_(2)NPs group received TiO_(2)NPs 150 mg/(kg·d)by gavage,the EA group received EA 50 mg/(kg·d),and the TiO_(2)NPs+EA group received EA 50 mg/(kg·d)by gavage on the basis of TiO_(2)NPs 150 mg/(kg·d)administration.8 weeks later,the liver injury indexes were detected,and the pathological changes of liver tissue were observed.Western blot was used to detect the expression of oxidative stress-related Ogg1,lipid synthesis related Srebp-1c,and endoplasmic reticulum stress-related Bip,Pdi,ATF6-p50,ATF6-p90,p-Ire1α,Xbp1s,xbp1u,p-eIf2α,ATF4,and liver fibrosis relatedα-SMA expression in each group.qRCR was used to detect the mRNA levels of maintaining lipid metabolism homeostasis related Acox2,Ces1g,Acot7,Cpt1a,Scad,Srebf1,Mlxipl,Lxrα,Xbp1s,endoplasmic reticulum stress related Atf4,Chop and liver fibrosis related Tgfb,Col 1α1 andα-Sma in each group.Results Compared with the Control group,the liver index of mice in TiO_(2)NPs group increased.The liver structure was disordered.The expression of Ogg1,Srebp-1c,Bip,ATF6-p50,ATF6-p90,p-Ire1α,Xbp1s,xbp1u,p-eIf2α,ATF4 andα-SMA significantly increased.The mRNA levels of Acox 2,Ces 1 g,Acot 7,Cpt 1 a,Scad significantly decreased,while Pparα,Srebf 1,Mlxipl,Lxrα,Xbp 1 s,Atf 4,Chop,Tgfb,Col 1α1 andα-Sma expression significantly increased.Compared with the TiO_(2)NPs group,the above indicators of mice in the TiO_(2)NPs+EA group showed recovery towards Control.Conclusion EA relieves TiO_(2)NPs induced liver injury by alleviating oxidative stress,endoplasmic reticulum stress and lipid metabolism disorder.