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木犀草素对对乙酰氨基酚诱导肝损伤的保护作用
张治杰1, 潘阳阳1, 姚亚乐,等1
甘肃农业大学 动物医学院
摘要:
【目的】基于内质网应激(ERS)和氧化应激途径,探讨木犀草素(luteolin)对对乙酰氨基酚(APAP)诱导的肝损伤的保护效果及其潜在的作用机制。【方法】将48只昆明小白鼠随机分为6组,分别为正常对照组(NC)、木犀草素对照组(MD)、APAP肝损伤模型组(APAP)以及木犀草素低、中、高剂量组(ML、MM、MH),每组8只小鼠,NC和MD组腹腔注射生理盐水,其余各组小鼠按300 mg/kg的剂量腹腔注射APAP注射液,每天2次,连续注射4 d,给药4 d后NC组和APAP组灌胃生理盐水,MD、ML、MM、MH小鼠分别按照100,25,50,100 mg/kg的剂量灌胃木犀草素药液,每天2次,连续灌胃3 d,最后一次灌胃12 h后,分别检测小鼠血液中的谷丙转氨酶(ALT)和谷草转氨酶(AST)活性以及肝脏中的氧化应激指标(超氧化物歧化酶(SOD)活性及过氧化氢(H2O2)、谷胱甘肽(GSH)和丙二醛(MDA)含量),在显微镜下观察各组小鼠肝组织的病理变化,并采用探针药物法测定肝脏微粒体细胞色素P450 2E1酶(CYP2E1)活性,采用qRT-PCR检测CYP2E1 mRNA表达水平,用Western Blot检测肝组织葡萄糖调节蛋白78(GRP78)、增强子CCAAT结合蛋白同源蛋白(CHOP)、CYP2E1蛋白表达水平。【结果】与NC组相比,APAP模型组的ALT和AST活性极显著升高,MD组上述2种酶活性无显著变化。与APAP模型组相比,MM、MH组ALT和AST活性显著或极显著下降。与APAP模型组相比,ML、MM、MH组的GSH含量和SOD活性均明显增加,MDA和H2O2含量均明显降低。小鼠肝组织病理形态显微观察结果表明,MM、MH组可以改善APAP导致的肝索消失以及肝细胞排列散乱和细胞核溶解等病理症状。探针药物法测定结果显示,0.1,0.01和0.001 mg/mL的木犀草素可以显著降低CYP2E1活性。qRT-PCR和Western Blot结果显示,木犀草素可以显著或极显著降低CYP2E1基因及其蛋白的表达水平,极显著降低GRP78和CHOP蛋白表达水平。【结论】木犀草素具有明显的抗APAP诱导的肝损伤作用,其作用机理可能是通过抑制CYP2E1的表达、减轻氧化应激和内质网应激水平,从而减轻APAP诱导的肝损伤。
关键词:  木犀草素  对乙酰氨基酚肝损伤  内质网应激  氧化应激
DOI:
分类号:
基金项目:甘肃农业大学青年导师扶持基金项目(GAU-QDFC-2021-05);甘肃省自然科学基金项目(22JR5RA868);国家自然科学基金项目(32160850)
Protective effects of luteolin on acetaminophen-induced liver injury
ZHANG Zhijie,PAN Yangyang,YAO Yale,et al
Abstract:
【Objective】This study explored the protective effects and potential mechanisms of luteolin on acetaminophen (APAP) induced liver injury based on endoplasmic reticulum stress (ERS) and oxidative stress pathways.【Method】A total of 48 Kunming mice were randomly divided into six groups of normal control (NC),luteolin control (MD),APAP model (APAP),luteolin low-dose (ML),medium dose (NM) and high-dose (MH).The NC and MD groups were injected intraperitoneally with saline,while the remaining groups were injected intraperitoneally with 300 mg/kg APAP,twice a day for 4 days.Four days after administration,the NC and APAP groups were given by gavage with saline,while the MD,ML,MM and MH groups were given by gavage with 100,25,50 and 100 mg/kg of luteolin solution twice a day for 3 days.Twelve hours after the last gavage,alanine aminotransterase (ALT) and aspartate aminotransferase (AST) activities and oxidative stress indicators including superoxide dismutase (SOD) activity and levels of hydrogen peroxide (H2O2),glutathione (GSH) and malondialdehyde (MDA) in livers were measured.The pathological changes in liver tissue were observed under the microscope,and the activity of liver microsomal cytochrome P450 enzyme 2E1 (CYP2E1) was measured by probe drug method.The expression levels of CYP2E1 mRNA were detected by qRT-PCR,and the expression levels of glucoseregulated protein78 (GRP78),C/EBP homologous protein (CHOP) and CYP2E1 protein in liver tissue were detected by Western Blot.【Result】The APAP model group showed highly significant increases in ALT and AST activities compared to the NC group,while the MD group showed no significant changes.Compared with the APAP model group,ALT and AST activities in the MM and MH groups were significantly or very significantly decreased.Compared with the APAP model group,GSH and SOD activities of the ML,MM and MH groups were significantly increased,while MDA and H2O2 contents were significantly decreased.Microscopic observation of liver histology in mice showed that the MM and MH groups improved pathological symptoms of APAP,such as loss of liver cords,disorganized hepatocytes and nucleolysis.Probe drug method showed that 0.1,0.01 and 0.001 mg/mL luteolin significantly reduced CYP2E1 activity.Results of qRT-PCR and Western Blot showed that luteolin significantly or very significantly reduced expression levels of CYP2E1 gene and its protein,and very significantly reduced expression levels of GRP78 and CHOP protein.【Conclusion】Luteolin had significant anti-APAP-induced liver injury effects and may ameliorate-APAP-induced liver injury by inhibiting CYP2E1 expression and reducing oxidative stress and endoplasmic reticulum stress levels.
Key words:  luteolin  acetaminophen liver injury  endoplasmic reticulum stress  oxidative stress

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