褪黑素通过调节Erk / Akt / NFkB途径改善H2O2诱导的氧化应激。,Biological Research

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褪黑素通过调节Erk / Akt / NFkB途径改善H2O2诱导的氧化应激。
Biological Research ( IF 4.3 ) Pub Date : 2018-06-13 , DOI: 10.1186/s40659-018-0168-5
Mahammed Moniruzzaman ₁ , Indranath Ghosal ₁ , Debjit Das ₁ , Suman Bhusan Chakraborty ₁

Affiliation

背景技术对活性氧（ROS）消除过程的不当控制和自由基的形成导致组织功能障碍。松果激素褪黑激素被认为是不同脊椎动物中这种氧化损伤的有效调节剂。当前交流的目的是评估氧化应激和ROS诱导的损伤水平，以及通过褪黑激素诱导的信号通路激活来改善氧化状态。从成年Labeo rohita分离肝细胞，并以三种不同剂量（12.5、25和50 µM）暴露于H2O2中，以观察过氧化物诱导的鱼肝细胞损伤。针对最高剂量的H2O2施用褪黑激素（25、50和100μg/ ml）。酶促和非酶促抗氧化剂，例如丙二醛（MDA），超氧化物歧化酶（SOD），用分光光度法测量过氧化氢酶（CAT）和谷胱甘肽（GSH）。还通过蛋白质印迹分析测量了热休克蛋白（HSP70和HSP90），与HSPs相关的信号分子（Akt，ERK，胞质和核NFkB）以及褪黑激素受体的表达水平。结果H2O2诱导的氧化应激显着改变（P <0.05）MDA和GSH水平，SOD和CAT活性，并上调鲤鱼肝细胞中HSP70和HSP90的表达。从其在暴露于H2O2的鱼肝细胞中的表达模式可以看出，与对照肝细胞相比，信号蛋白表现出差异调节。褪黑素处理H2O2胁迫的鱼肝细胞以剂量依赖性方式恢复了基础细胞的氧化状态。通过调节信号分子和褪黑激素受体，观察到褪黑激素是信号传导过程的诱导剂。结论结果表明，要改善H2O2胁迫的鱼肝细胞的氧化状态，需要100 µg / ml的外源褪黑激素。在暴露于H2O2的肝细胞中，褪黑激素调节HSP70和HSP90的表达，从而使肝细胞能够通过改变信号传导途径中的ERK，Akt，胞质和核NFkB的作用而变得耐逆并生存。研究还证实褪黑激素可以通过与ERK / Akt信号通路偶联的褪黑激素受体发挥作用。对褪黑素调节应激肝细胞中氧化状态的机制的这种了解，可能会在将来引发新的肝病治疗策略的开发。结论结果表明，要改善H2O2胁迫的鱼肝细胞的氧化状态，需要100 µg / ml的外源褪黑激素。在暴露于H2O2的肝细胞中，褪黑激素调节HSP70和HSP90的表达，从而使肝细胞能够通过改变信号传导途径中的ERK，Akt，胞质和核NFkB的作用而变得耐逆并生存。研究还证实褪黑激素可以通过与ERK / Akt信号通路偶联的褪黑激素受体发挥作用。对褪黑素调节应激肝细胞中氧化状态的机制的这种了解，可能会在将来引发新的肝病治疗策略的开发。结论结果表明，要改善H2O2胁迫的鱼肝细胞的氧化状态，需要100 µg / ml的外源褪黑激素。在暴露于H2O2的肝细胞中，褪黑激素调节HSP70和HSP90的表达，从而使肝细胞能够通过改变信号传导途径中的ERK，Akt，胞质和核NFkB的作用而变得耐逆并生存。研究还证实褪黑激素可以通过与ERK / Akt信号通路偶联的褪黑激素受体发挥作用。对褪黑素调节应激肝细胞中氧化状态的机制的这种了解，可能会在将来引发新的肝病治疗策略的开发。

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Melatonin ameliorates H2O2-induced oxidative stress through modulation of Erk/Akt/NFkB pathway.

BACKGROUND Improper control on reactive oxygen species (ROS) elimination process and formation of free radicals causes tissue dysfunction. Pineal hormone melatonin is considered a potent regulator of such oxidative damage in different vertebrates. Aim of the current communication is to evaluate the levels of oxidative stress and ROS induced damage, and amelioration of oxidative status through melatonin induced activation of signaling pathways. Hepatocytes were isolated from adult Labeo rohita and exposed to H2O2 at three different doses (12.5, 25 and 50 µM) to observe peroxide induced damage in fish hepatocytes. Melatonin (25, 50 and 100 μg/ml) was administered against the highest dose of H2O2. Enzymatic and non-enzymatic antioxidants such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) was measured spectrophotometrically. Expression level of heat shock proteins (HSP70 and HSP90), HSPs-associated signaling molecules (Akt, ERK, cytosolic and nuclear NFkB), and melatonin receptor was also measured by western blotting analysis. RESULTS H2O2 induced oxidative stress significantly altered (P < 0.05) MDA and GSH level, SOD and CAT activity, and up regulated HSP70 and HSP90 expression in carp hepatocytes. Signaling proteins exhibited differential modulation as revealed from their expression patterns in H2O2-exposed fish hepatocytes, in comparison with control hepatocytes. Melatonin treatment of H2O2-stressed fish hepatocytes restored basal cellular oxidative status in a dose dependent manner. Melatonin was observed to be inducer of signaling process by modulation of signaling molecules and melatonin receptor. CONCLUSIONS The results suggest that exogenous melatonin at the concentration of 100 µg/ml is required to improve oxidative status of the H2O2-stressed fish hepatocytes. In H2O2 exposed hepatocytes, melatonin modulates expression of HSP70 and HSP90 that enable the hepatocytes to become stress tolerant and survive by altering the actions of ERK, Akt, cytosolic and nuclear NFkB in the signal transduction pathways. Study also confirms that melatonin could act through melatonin receptor coupled to ERK/Akt signaling pathways. This understanding of the mechanism by which melatonin regulates oxidative status in the stressed hepatocytes may initiate the development of novel strategies for hepatic disease therapy in future.

更新日期：2019-11-01

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