Exercise Mitigates Alcohol Induced Endoplasmic Reticulum Stress Mediated Cognitive Impairment through ATF6-Herp Signaling.
Exercise Mitigates Alcohol Induced Endoplasmic Reticulum Stress Mediated Cognitive Impairment through ATF6-Herp Signaling.
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DOI：
10.1038/s41598-018-23568-z
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发表时间：
2018-03-26
影响因子：
4.6
通讯作者：
Tyagi N
中科院分区：
文献类型：
--
作者：
George AK;Behera J;Kelly KE;Mondal NK;Richardson KP;Tyagi N
慢性乙醇/酒精（AL）给药导致同型半胱氨酸（Hcy）水平升高，这导致称为高同型半胱氨酸血症（HHcy）的病症。HHCy通过调节内质网（ER）应激来增强氧化应激和血脑屏障（BBB）破坏;部分通过表观遗传改变，导致认知障碍。临床医生推荐运动作为一种治疗方法;然而，它对认知功能的保护作用尚未得到充分探讨。本研究旨在观察运动（EX）对酒精诱导的表观遗传和分子改变导致脑血管功能障碍的保护作用。对野生型小鼠进行AL给药（1.5 g/kg-bw），随后进行跑步机EX，持续12周（5天/周，7 -11 m/min）。AL通过增加氧化和ER应激标志物，SAHH和DNMT的交替，而减少CBS，CSE，MTHFR，紧密连接蛋白和细胞H2S水平来影响小鼠脑。机制研究表明，AL增加了Herp启动子的表观遗传DNA低甲基化。在AL处理的小鼠中观察到BBB功能障碍和认知障碍。AL介导的转录变化被取消的ER应激抑制剂DTT的管理。总之，运动恢复Hcy和H2S的基础水平，同时改善AL诱导的ER应激，减少BBB功能障碍，并通过ATF 6-Herp信号改善认知功能。EX对AL诱导的神经毒性具有保护作用。
Chronic ethanol/alcohol (AL) dosing causes an elevation in homocysteine (Hcy) levels, which leads to the condition known as Hyperhomocysteinemia (HHcy). HHcy enhances oxidative stress and blood-brain-barrier (BBB) disruption through modulation of endoplasmic reticulum (ER) stress; in part by epigenetic alternation, leading to cognitive impairment. Clinicians have recommended exercise as a therapy; however, its protective effect on cognitive functions has not been fully explored. The present study was designed to observe the protective effects of exercise (EX) against alcohol-induced epigenetic and molecular alterations leading to cerebrovascular dysfunction. Wild-type mice were subjected to AL administration (1.5 g/kg-bw) and subsequent treadmill EX for 12 weeks (5 day/week@7–11 m/min). AL affected mouse brain through increases in oxidative and ER stress markers, SAHH and DNMTs alternation, while decreases in CBS, CSE, MTHFR, tight-junction proteins and cellular H2S levels. Mechanistic study revealed that AL increased epigenetic DNA hypomethylation of Herp promoter. BBB dysfunction and cognitive impairment were observed in the AL treated mice. AL mediated transcriptional changes were abolished by administration of ER stress inhibitor DTT. In conclusion, exercise restored Hcy and H2S to basal levels while ameliorating AL-induced ER stress, diminishing BBB dysfunction and improving cognitive function via ATF6-Herp-signaling. EX showed its protective efficacy against AL-induced neurotoxicity.
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硫化氢可减轻小鼠中脑内施用的同型半胱氨酸诱导的神经变性和神经血管功能障碍。
影响因子：
3.3
作者：
Kamat PK;Kalani A;Givvimani S;Sathnur PB;Tyagi SC;Tyagi N
通讯作者：
Tyagi N
DOI：
10.1111/j.1530-0277.2011.01503.x
发表时间：
2011-09
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Ke Z;Wang X;Liu Y;Fan Z;Chen G;Xu M;Bower KA;Frank JA;Li M;Fang S;Shi X;Luo J
通讯作者：
Luo J
DOI：
10.1007/s12031-013-0122-5
发表时间：
2014-02
期刊：
Journal of molecular neuroscience : MN
影响因子：
--
作者：
Kalani A;Kamat PK;Givvimani S;Brown K;Metreveli N;Tyagi SC;Tyagi N
通讯作者：
Tyagi N
影响因子：
4.7
作者：
Ho, PI;Collins, SC;Shea, TB
通讯作者：
Shea, TB
影响因子：
4.8
作者：
Kimura, Y;Kimura, H
通讯作者：
Kimura, H