SOD2
化学
蛋白激酶B
褪黑素
PI3K/AKT/mTOR通路
氟化钠
SIRT3
氧化应激
内分泌学
NADPH氧化酶
下调和上调
内科学
活性氧
锡尔图因
信号转导
生物
超氧化物歧化酶
生物化学
乙酰化
医学
无机化学
基因
氟化物
作者
Chao Song,Jiamin Zhao,Binying Fu,Dan Li,Tingchao Mao,Wei Peng,Haibo Wu,Yong Zhang
标识
DOI:10.1016/j.freeradbiomed.2017.09.005
摘要
Mitochondrial reactive oxygen species (ROS) production has been implicated in the pathogenesis of fluoride toxicity in liver. Melatonin, an indolamine synthesized in the pineal gland, was previously shown to protect against sodium fluoride (NaF)-induced hepatotoxicity. This study investigated the protective effects of melatonin pretreatment on NaF-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. Reducing mitochondrial ROS by melatonin substantially attenuated NaF-induced NADPH oxidase 4 (Nox4) upregulation and cytotoxicity in L-02 cells. Melatonin exerted its hepatoprotective effects by upregulating Sirtuin 3 (Sirt3) expression level and its activity. Melatonin increased the activity of manganese superoxide dismutase (SOD2) by promoting Sirt3-mediated deacetylation and promoted SOD2 expression through Sirt3-regulated DNA-binding activity of forkhead box O3 (FoxO3a), thus inhibiting the production of mitochondrial ROS induced by NaF. Notably, increased peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) by melatonin activated the Sirt3 expression, which was regulated by an estrogen-related receptor (ERR) binding element (ERRE) mapped to Sirt3 promoter region. Analysis of the cell signaling pathway profiling systems and specific pathway inhibition indicated that melatonin enhances PGC-1α expression by activating the PI3K/AKT signaling pathway. Importantly, inhibition of melatonin receptor (MT)-1 blocked the melatonin-activated PI3K/AKT-PGC-1α-Sirt3 signaling. Mechanistic study revealed that the protective effects of melatonin were associated with down-regulation of JNK1/2 phosphorylation. Our findings provided a theoretical basis that melatonin mitigated NaF-induced hepatotoxicity, which, in part, was mediated through the activation of the Sirt3 pathway.
科研通智能强力驱动
Strongly Powered by AbleSci AI