Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network.
Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network.
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Celastrol 通过靶向 JNK 和 PTEN-Akt/mTOR 网络来防止镉诱导的神经细胞死亡。
DOI：
10.1111/jnc.12474
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发表时间：
2014-01
影响因子：
4.7
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Chen S;Gu C;Xu C;Zhang J;Xu Y;Ren Q;Guo M;Huang S;Chen L
镉 (Cd) 是一种有毒环境污染物，会诱发神经退行性疾病。雷公藤红醇是一种植物来源的三萜，在多种疾病模型中显示出神经保护作用。然而，关于雷公藤红醇对镉诱导的神经毒性的影响知之甚少。在这里，我们证明雷公藤红素可以防止镉诱导的神经元细胞凋亡。雷公藤红素显着减弱 Cd 诱导的活力降低、形态变化、核碎裂和浓缩，以及神经元细胞中 caspase-3 的激活，这一发现支持了这一点。同时，雷公藤红素显着阻断 Cd 诱导的神经元细胞中 c-Jun N 末端激酶 (JNK) 的磷酸化，但不阻断细胞外信号调节激酶 1/2 和 p38。 SP600125 对 JNK 的抑制或显性负性 c-Jun 的过度表达增强了雷公藤红醇对镉诱导的细胞死亡的保护作用。此外，雷公藤红素预处理可防止 Cd 下调 10 号染色体上缺失的磷酸酶和张力蛋白同源物 (PTEN)，以及神经元细胞中磷酸肌醇 3'-激酶/蛋白激酶 B (Akt)/哺乳动物雷帕霉素靶标 (mTOR) 信号传导的激活。野生型 PTEN 的过度表达增强了雷公藤红醇对 Cd 激活的 Akt/mTOR 信号传导和神经元细胞死亡的抑制作用。研究结果表明，雷公藤红素通过靶向 JNK 和 PTEN-Akt/mTOR 网络来预防 Cd 诱导的神经元细胞死亡。我们的结果强烈表明雷公藤红素可用于预防镉引起的神经退行性疾病。
Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Celastrol, a plant-derived triterpene, has shown neuroprotective effects in various disease models. However, little is known regarding the effect of celastrol on Cd-induced neurotoxicity. Here, we show that celastrol protected against Cd-induced apoptotic cell death in neuronal cells. This is supported by the findings that celastrol strikingly attenuated Cd-induced viability reduction, morphological change, nuclear fragmentation, and condensation, as well as activation of caspase-3 in neuronal cells. Concurrently, celastrol remarkably blocked Cd-induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinases 1/2 and p38, in neuronal cells. Inhibition of JNK by SP600125 or over-expression of dominant negative c-Jun potentiated celastrol protection against Cd-induced cell death. Furthermore, pre-treatment with celastrol prevented Cd down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and activation of phosphoinositide 3′-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in neuronal cells. Over-expression of wild-type PTEN enhanced celastrol inhibition of Cd-activated Akt/mTOR signaling and cell death in neuronal cells. The findings indicate that celastrol prevents Cd-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. Our results strongly suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders.
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影响因子：
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