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p38丝裂原活化蛋白激酶-丝裂原活化蛋白激酶2信号通路调控热应激诱导的活性氧积累,活性氧介导神经胶质细胞的凋亡性细胞死亡。

p38 MAPK-MK2 pathway regulates the heat-stress-induced accumulation of reactive oxygen species that mediates apoptotic cell death in glial cells.

作者信息

Li Hongbo, Liu Yanan, Gu Zhengtao, Li Li, Liu Yunsong, Wang Lin, Su Lei

机构信息

Graduate School Department, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.

Department of Intensive Care Unit, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China.

出版信息

Oncol Lett. 2018 Jan;15(1):775-782. doi: 10.3892/ol.2017.7360. Epub 2017 Nov 8.

DOI:10.3892/ol.2017.7360
PMID:29387240
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5768138/
Abstract

Previous studies have demonstratedf that heat stress can induce injury of the central nervous system and lead to neuronal cell apoptosis. However, the molecular mechanisms underlying these cellular changes remain unclear. In the present study, flow cytometry was used to investigate heat-stress-induced apoptosis, and caspase-3 activation was also assessed in neurons. The role of reactive oxygen species (ROS) accumulation in the heat-stress-induced apoptosis of neurons was demonstrated using the antioxidant drug manganese (III) tetrakis (4-benzoic acid)porphyrin. The present study presents evidence that heat stress induces mitogen-activated protein kinase (MAPK) activation in rat malignant glioma F98 cells. Following the inhibition of different MAPKs with a range of specific inhibitors, SB203580 (an inhibitor of p38 MAPK), but not PD98059 (an inhibitor of extracellular signal-regulated kinases) or SP600125 (an inhibitor of c-Jun N-terminal kinases), diminished the production of ROS and apoptosis, and prevented activation of the p38-downstream kinase MAPK-activated protein kinase 2 (MK2) in neurons. Inhibiting MK2 with dominant negative adenoviral constructs or a specific inhibitor significantly decreased normal and heat-stress-induced ROS accumulation and cell apoptosis, whereas inhibition of another kinase downstream of p38 MAPK, MAPK-activated protein kinase 5, by transfection with another adenoviral construct did not exert the same effects. Taken together, these findings indicate that heat stress stimulation induces p38-MK2 pathway activation, which exerts a pro-apoptotic effect by regulating ROS accumulation in neurons.

摘要

先前的研究已证明,热应激可诱导中枢神经系统损伤并导致神经元细胞凋亡。然而,这些细胞变化背后的分子机制仍不清楚。在本研究中,使用流式细胞术研究热应激诱导的凋亡,并对神经元中的半胱天冬酶-3激活情况进行了评估。使用抗氧化药物锰(III)四(4-苯甲酸)卟啉证明了活性氧(ROS)积累在热应激诱导的神经元凋亡中的作用。本研究提供的证据表明,热应激可诱导大鼠恶性胶质瘤F98细胞中的丝裂原活化蛋白激酶(MAPK)激活。用一系列特异性抑制剂抑制不同的MAPK后,SB203580(p38 MAPK的抑制剂)而非PD98059(细胞外信号调节激酶的抑制剂)或SP600125(c-Jun N端激酶的抑制剂)可减少ROS的产生和凋亡,并阻止神经元中p38下游激酶MAPK激活的蛋白激酶2(MK2)的激活。用显性负性腺病毒构建体或特异性抑制剂抑制MK2可显著降低正常和热应激诱导的ROS积累及细胞凋亡,而通过转染另一种腺病毒构建体抑制p38 MAPK下游的另一种激酶MAPK激活的蛋白激酶5则未产生相同效果。综上所述,这些发现表明热应激刺激可诱导p38-MK2途径激活,该途径通过调节神经元中的ROS积累发挥促凋亡作用。

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