Melatonin protects mouse granulosa cells against oxidative damage by inhibiting FOXO1-mediated autophagy: Implication of an antioxidation-independent mechanism.
Melatonin protects mouse granulosa cells against oxidative damage by inhibiting FOXO1-mediated autophagy: Implication of an antioxidation-independent mechanism.
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褪黑激素通过抑制 FOXO1 介导的自噬保护小鼠颗粒细胞免受氧化损伤：抗氧化依赖机制的含义
DOI：
10.1016/j.redox.2018.07.004
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发表时间：
2018-09
期刊：
影响因子：
11.4
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Shen M;Cao Y;Jiang Y;Wei Y;Liu H
氧化应激已被描述为卵泡闭锁期间颗粒细胞（GCs）死亡的主要驱动因素。越来越多的证据表明褪黑激素在保护GC免受氧化损伤中的潜在作用，但其潜在机制仍在很大程度上尚未确定。在此，我们首次提出了通过一些新的调节剂抑制自噬有助于褪黑素介导的GC在氧化应激条件下的存活。褪黑激素给药后，氧化剂诱导的GC活力损失显着降低，这与体内和体外氧化刺激后减弱的自噬信号相关。与褪黑素处理相比，抑制自噬对氧化应激期间GC死亡显示出类似的预防作用，但褪黑素在用自噬抑制剂预处理的GC中没有提供额外的保护。值得注意的是，我们发现，褪黑激素的自噬性死亡的直接调节是独立的抗氧化/自由基清除能力。进一步的研究确定FOXO 1作为褪黑激素的关键下游效应子，促进GC从氧化应激诱导的自噬中存活。具体地说，通过褪黑素-磷脂酰肌醇3-激酶（PI 3 K）-AKT轴抑制FOXO 1不仅提高了GC对氧化应激的抵抗力，而且消除了自噬反应，从基因表达到自噬空泡的形成。此外，SIRT 1信号的激活是褪黑激素介导的FOXO 1的脱乙酰化及其与ATG蛋白的相互作用所必需的，以及在遭受氧化应激的GC中抑制自噬性死亡。这些发现揭示了褪黑素通过抑制FOXO 1来防御GC氧化损伤的全新机制，FOXO 1可能是无排卵性疾病的潜在治疗靶点。氧化应激期间GC中褪黑激素介导的自噬调节的示意图。褪黑激素抑制GC中的氧化损伤，而不清除氧化应激本身。褪黑素通过抑制自噬性细胞死亡保护GC免受氧化损伤。褪黑激素对FOXO 1依赖性自噬的抑制可降低GC中的氧化损伤。通过褪黑激素-PI 3 K-AKT-FOXO 1轴抑制自噬改善GC存活。褪黑激素通过抑制SIRT 1-FOXO 1-ATG 7依赖性自噬来减少氧化损伤。
Oxidative stress has been described as a prime driver of granulosa cell (GCs) death during follicular atresia. Increasing evidence suggests potential roles of melatonin in protecting GCs from oxidative injury, though the underlying mechanisms remain largely undetermined. Here we first proposed that the inhibition of autophagy through some novel regulators contributes to melatonin-mediated GCs survival under conditions of oxidative stress. Oxidant-induced loss of GCs viability was significantly reduced after melatonin administration, which was correlated with attenuated autophagic signals upon oxidative stimulation both in vivo and in vitro. Compared with melatonin treatment, suppression of autophagy displayed similar preventive effect on GCs death during oxidative stress, but melatonin provided no additional protection in GCs pretreated with autophagy inhibitors. Notably, we found that melatonin-directed regulation of autophagic death was independent of its antioxidation/radical scavenging ability. Further investigations identified FOXO1 as a critical downstream effector of melatonin in promoting GCs survival from oxidative stress-induced autophagy. Specifically, suppression of FOXO1 via the melatonin-phosphatidylinositol 3-kinase (PI3K)-AKT axis not only improved GCs resistance to oxidative stress, but also abolished the autophagic response, from genes expression to the formation of autophagic vacuoles. Moreover, the activation of SIRT1 signaling was required for melatonin-mediated deacetylation of FOXO1 and its interaction with ATG proteins, as well as the inhibition of autophagic death in GCs suffering oxidative stress. These findings reveal a brand new mechanism of melatonin in defense against oxidative damage to GCs by repressing FOXO1, which may be a potential therapeutic target for anovulatory disorders. A schematic representation of melatonin-mediated autophagy regulation in GCs during oxidative stress. Melatonin inhibits oxidative damage in GC without scavenging oxidative stress itself. Melatonin protects GC from oxidative damage via inhibiting autophagic cell death. Inhibition of FOXO1-dependent autophagy by melatonin reduces oxidative damage in GC. Suppression of autophagy through melatonin-PI3K-AKT-FOXO1 axis improves GC survival. Melatonin reduces oxidative injury by inhibiting SIRT1-FOXO1-ATG7-dependent autophagy.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1186/1477-7827-10-49
发表时间：
2012-06-29
期刊：
Reproductive biology and endocrinology : RB&E
影响因子：
--
作者：
Agarwal A;Aponte-Mellado A;Premkumar BJ;Shaman A;Gupta S
通讯作者：
Gupta S
影响因子：
13.3
作者：
Dadakhujaev, Shorafidinkhuja;Jung, Eun Joo;Kim, Deok Ryong
通讯作者：
Kim, Deok Ryong
Sirt1 和 Keap1/Nrf2/ARE 抗氧化通路之间的串扰形成正反馈环路，抑制大鼠肾小球系膜细胞中 FN 和 TGF-β1 的表达
影响因子：
3.7
作者：
Huang, Kaipeng;Gao, Xiang;Wei, Wentao
通讯作者：
Wei, Wentao
DOI：
10.1017/cbo9780511545566.022
发表时间：
2008-01-01
期刊：
CAMBRIDGE TEXTBOOK OF BIOETHICS
影响因子：
--
作者：
Levi, Benjamin H.
通讯作者：
Levi, Benjamin H.