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首页> 外文期刊>Drug Design, Development and Therapy >Melatonin Plays a Protective Role by Regulating miR-26a-5p-NRSF and JAK2-STAT3 Pathway to Improve Autophagy, Inflammation and Oxidative Stress of Cerebral Ischemia-Reperfusion Injury
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Melatonin Plays a Protective Role by Regulating miR-26a-5p-NRSF and JAK2-STAT3 Pathway to Improve Autophagy, Inflammation and Oxidative Stress of Cerebral Ischemia-Reperfusion Injury

机译：褪黑激素通过调节miR-26a-5p-nRSF和JAK2-STAT3途径来改善脑缺血再灌注损伤的自噬，炎症和氧化应激来发挥保护作用

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Background: Melatonin (MT) has potential protective effect on cerebral ischemia-reperfusion injury (CIRI), but its underlying regulatory mechanism has not been identified. Purpose: This study aimed to explore the role of miR-26a-5p-neuron-restrictive silencing factor (NRSF/REST), Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) pathway in the protection mechanism of MT against CIRI in vivo and in vitro. Methods: Sprague Dawley rats were induced with ischemia-reperfusion (IR) in vivo model; PC12 cells were induced with oxygen-glucose deprivation/reperfusion (OGD/R) in vitro model; and MT intervention was conducted before the model was established. The effect of MT on autophagy factors (LC3II/LC3I, P62), inflammatory factors (TNF-α, IL-6, IL-10) and oxidative stress indexes (MDA, GSHPx, SOD) was explored, and then the above three indexes were determined by real-time quantitative PCR, ELISA, and detection kit corresponding to oxidative stress indexes. The neuroprotective effect of MT pretreatment on brain IR injury was evaluated by neurological deficit scores and TUNEL method. The levels of miR-26a-5p and NRSF were detected by real-time quantitative PCR and Western blot, and the interaction between them was evaluated by dual luciferase report. The role of JAK2-STAT3 pathway in MT protection mechanism was verified by pathway blocker (AG490) and Western blot. Results: MT pretreatment can significantly reduce neurological deficit score and neuronal apoptosis, inhibit CIRI autophagy, inflammation and oxidative stress in vivo and in vitro, reduce LC3II/LC3I, TNF-α, IL-6, MDA and increase P62, IL-10, GSHPx, SOD. Further analysis identifies that downregulating miR-26a-5p or upregulating NRSF can eliminate the protective effect of MT, and NRSF is the direct target of miR-26a-5p. The protective effect of MT can also be eliminated under AG490 intervention. Conclusion: MT plays a protective role by regulating miR-26a-5p-NRSF and JAK2-STAT3 pathway to improve CIRI autophagy, inflammation and oxidative stress.
机译：背景：褪黑激素（MT）对脑缺血再灌注损伤（CIRI）具有潜在的保护作用，但其潜在的调节机制尚未确定。目的：本研究旨在探讨miR-26a-5p-neuron限制性沉默因子（nrsf /静止），Janus激酶-2（JAK2） - 保护 - 3（STAT3）途径的激活剂在保护中的作用体内和体外中Mt对肝素的机制。方法：在体内模型中诱导Sprague Dawley大鼠缺血（IR）;用氧 - 葡萄糖剥夺/再灌注（OGD / R）在体外模型中诱导PC12细胞;在建立模型之前进行了MT干预。探讨了MT对自噬因子（LC3II / LC3I，P62），炎症因子（TNF-α，IL-6，IL-10）和氧化应激指数（MDA，GSHPX，SOD）的影响，然后是上述三个指标通过实时定量PCR，ELISA和对应于氧化应激指数的检测试剂盒确定。通过神经缺陷分数和TUNEL方法评估MT预处理MT预处理的神经保护作用。通过实时定量PCR和Western印迹检测miR-26A-5P和NRSF的水平，并通过双荧光素酶报告评估它们之间的相互作用。 JAK2-STAT3途径在MT保护机制中的作用是通过途径阻滞剂（AG490）和Western印迹验证的。结果：MT预处理可显着降低神经缺陷分数和神经元细胞凋亡，抑制体内和体外炎症，炎症和氧化应激，降低LC3II / LC3I，TNF-α，IL-6，MDA和增加P62，IL-10， GSHPX，SOD。进一步的分析鉴定下调miR-26a-5p或上调NRSF可以消除MT的保护作用，NRSF是miR-26a-5p的直接靶标。在AG490干预下也可以消除MT的保护作用。结论：MT通过调节miR-26A-5P-NRSF和JAK2-STAT3途径来改善CIRI自噬，炎症和氧化应激的途径来发挥保护作用。

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