Neuroprotection of resveratrol against cadmium-poisoning acts through dual inhibition of mTORC1/2 signaling.
Neuroprotection of resveratrol against cadmium-poisoning acts through dual inhibition of mTORC1/2 signaling.
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白藜芦醇通过双重抑制 mTORC1/2 信号传导对镉中毒发挥神经保护作用
DOI：
10.1016/j.neuropharm.2022.109236
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发表时间：
2022-11-15
影响因子：
4.7
通讯作者：
Chen, Long
中科院分区：
文献类型：
--
作者：
Liu, Chunxiao;Zhang, Ruijie;Yang, Liu;Ji, Tong;Zhu, Cuilan;Liu, Beibei;Zhang, Hai;Xu, Chong;Zhang, Nana;Huang, Shile;Chen, Long
Resveratrol is a natural polyphenol with neuroprotective function. The underlying mechanism is not well understood. Our previous studies have identified that resveratrol antagonizes cadmium (Cd) neurotoxicity via targeting PP2A/PP5-mediated Erk1/2 and JNK pathways. Here we show that resveratrol protected against Cd-poisoning also by blocking Cd-induced activation of mTORC1 and mTORC2 pathways in PC12 cells and murine primary neurons. Co-treatment with inhibitors of mTORC1 (rapamycin), mTORC1/2 (PP242), Erk1/2 (U0126) and/or JNK (SP600125), knockdown of mTOR, or disruption of mTORC1 and/or mTORC2 by silencing raptor, rictor or raptor/rictor, respectively, markedly potentiated the inhibitory effects of resveratrol on Cd-induced phosphorylation of S6K1/4E-BP1 (mTORC1 substrates), Akt (mTORC2 substrate), Erk1/2 and/or JNK/c-Jun, cleavage of caspase-3 and cell death in PC12 cells and/or primary neurons. Knockdown of S6K1 or 4E-BP1, or ectopic expression of constitutively hypophosphorylated 4E-BP1 (4E-BP1–5A) reinforced the resveratrol’s inhibition on Cd-evoked cell death, whereas ectopic expression of constitutively active S6K1 or knockdown of 4E-BP1 attenuated the resveratrol’s inhibition on Cd-induced cell death. Co-treatment with Akt inhibitor or overexpression of dominant negative Akt (dn-Akt) strengthened the resveratrol’s suppression on Cd-induced ROS, Erk1/2 activation and apoptosis, whereas overexpression of constitutively active Akt (myr-Akt) conferred high resistance to the resveratrol’s inhibitory effects in the neuronal cells. Taken together, the results indicate that resveratrol attenuates Cd-induced neuronal apoptosis partly through inhibition of mTORC1/2 pathways. Our studies highlight that resveratrol can be exploited for the prevention of Cd toxicity related to neurodegenerative diseases.
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影响因子：
5.9
作者：
Oliveira ALB;Monteiro VVS;Navegantes-Lima KC;Reis JF;Gomes RS;Rodrigues DVS;Gaspar SLF;Monteiro MC
通讯作者：
Monteiro MC
影响因子：
7.4
作者：
Chen, Long;Xu, Baoshan;Liu, Lei;Luo, Van;Zhou, Hongyu;Chen, Wenxing;Shen, Tao;Han, Xiuzhen;Kontos, Christopher D.;Huang, Shile
通讯作者：
Huang, Shile
影响因子：
4.5
作者：
Eybl, Vladislav;Kotyzova, Dana;Koutensky, Jaroslav
通讯作者：
Koutensky, Jaroslav
CaMKII 参与镉激活 MAPK 和 mTOR 通路，导致神经元细胞死亡
影响因子：
4.7
作者：
Chen S;Xu Y;Xu B;Guo M;Zhang Z;Liu L;Ma H;Chen Z;Luo Y;Huang S;Chen L
通讯作者：
Chen L
影响因子：
3.7
作者：
Li, Zhiguo;Han, Xinwei
通讯作者：
Han, Xinwei