Downregulation of matrix metalloproteinase-9 by melatonin during prevention of alcohol-induced liver injury in mice
Downregulation of matrix metalloproteinase-9 by melatonin during prevention of alcohol-induced liver injury in mice
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DOI：
10.1016/j.biochi.2011.02.007
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发表时间：
2011-05-01
期刊：
影响因子：
3.9
通讯作者：
Swarnakar, Snehasikta
中科院分区：
文献类型：
--
作者：
Mishra, Amartya;Paul, Sumit;Swarnakar, Snehasikta
基质金属蛋白酶（MMPs）参与了多种疾病的炎症和降解过程。本研究旨在探讨MMP-9在小鼠酒精性急性肝损伤中的调控机制及褪黑素的保护作用。通过乙醇给药在雌性Balb/C小鼠中诱导酒精诱导的急性肝损伤，并使用众所周知的抗氧化分子褪黑激素进行保护研究。通过肝组织的组织学和生化分析来监测肝损伤程度。小鼠灌胃乙醇后，血清丙氨酸氨基转移酶（ALT）活性显著升高。乙醇处理后，肝组织谷胱甘肽耗竭，脂质过氧化和蛋白质氧化增强。然而，褪黑激素通过抑制ALT活性和氧化应激表现出有效的保肝活性。另外。MMP-9的表达增加乙醇的剂量和时间依赖性的方式在肝组织和血清中。proMMP-9分泌的增加与促炎细胞因子的表达密切相关，肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1 β和IL 6。褪黑素通过下调肝组织MMP-9和上调肝组织金属蛋白酶组织抑制剂（TIMP-1）的表达发挥保肝作用。核因子（NF）-κ B（B）在氧化应激过程中诱导炎性基因表达中起重要作用，因此研究NF-κ B（B）在乙醇诱导的肝损伤中的作用。乙醇诱导NF-κ B核转位，并增加肝组织中NF-κ B抑制剂（IxB α）的降解。此外，褪黑素还能显著抑制乙醇诱导的NF-κ B B向细胞核内的转位。本研究首次阐明了NF-κ B依赖性通路在乙醇诱导的小鼠急性肝损伤中诱导MMP-9表达的作用。这项研究还确定了褪黑激素通过MMP-9下调在肝脏保护中的新作用。(C)2011年Elsevier Masson SAS。All rights reserved.
Matrix metalloproteinases (MMPs) have been implicated in inflammatory and degradative processes in several diseases. The study aims to explore the mechanism of MMP-9 regulation in alcohol-induced acute liver injury and its protection by melatonin in mice. Alcohol-induced acute liver injury was induced in female Balb/C mice by ethanol administration and protection studies were carried out with a well-known antioxidant molecule, melatonin. Degree of liver injury was monitored by histological and biochemical analysis of liver tissues. Oral administration of ethanol in mouse caused significant increase in alanine amino transferase (ALT) activity in serum. Depletion of glutathione and enhancement of lipid peroxidation as well as protein oxidation was observed in liver tissues following ethanol treatment. However, melatonin exhibited potent hepatoprotective activity by inhibiting ALT activity and oxidative stress. Additionally. MMP-9 expression was increased by ethanol in a dose and time dependent manner in liver tissue and serum. Increased secretion of proMMP-9 was strongly correlated with the expression of proinflammatory cytokines e.g., tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL6. Melatonin showed hepatoprotective role by downregulation of MMP-9 and upregulation of tissue inhibitor of metalloproteases (TIMP-1) expression in liver tissue. Nuclear factor (NF)-kappa B, plays an important role in inducing inflammatory genes during oxidative stress, thus the role of NF-kappa B in ethanol-induced liver injury was investigated. Ethanol induced nuclear translocation of NF-kappa B and increased degradation of inhibitor of NF-kappa B (IxB alpha) in liver tissues. Moreover, ethanol-induced NF-kappa B translocation into nucleus was inhibited significantly by melatonin. This is the first study to elucidate the induction of MMP-9 expression by NF-kappa B-dependent pathway in ethanol-induced acute liver injury in mice. This study also identifies the novel role of melatonin in hepatoprotection via MMP-9 down regulation. (C) 2011 Elsevier Masson SAS. All rights reserved.