Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-κB regulation
Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-κB regulation
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DOI：
10.1152/ajpcell.00345.2012
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发表时间：
2013-04-01
影响因子：
5.5
通讯作者：
Singh, Dhirendra P.
中科院分区：
文献类型：
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作者：
Chhunchha, Bhavana;Fatma, Nigar;Singh, Dhirendra P.
Chchha B，Fatma N，Kubo E，Rai P，Singh SP，Singh DP。姜黄素通过控制Prdx6和核因子-kappaB的调控减轻缺氧诱导的氧化应激诱导的内质网应激介导的小鼠海马细胞(HT22)细胞死亡。Am J Physiol Cell Physiol 304：C636-C655,2013。2013年1月30日首次出版；doi：10.1152/ajpcell.00345.2012。-氧化应激和内质网(ER)应激正在成为许多神经退行性疾病的病因学中的关键事件。虽然膳食化合物姜黄素的神经保护作用已经被认识到，但姜黄素在氧化和内质网应激下的神经保护作用的分子机制仍然不清楚。在这里，我们表明，姜黄素保护HT22免受低氧(1%O-2或CoCl2处理)引起的氧化和内质网应激，其机制是通过增强过氧化还蛋白6(Prdx6)的表达。暴露于CoCl2的细胞表现为Prdx6表达减少，而ROS表达增加，并通过I kappa B磷酸化激活了核因子-kappaB。当用核因子-kappaB的抑制剂SN50或姜黄素处理的细胞阻断核因子-kappa B的活性时，Prdx6表达的抑制被恢复，提示核因子-kappaB参与了Prdx6的表达调控。这些细胞富含内质网应激蛋白、C/EBP同源蛋白(CHOP)、GRP/78和钙网蛋白，并具有caspase12、9和3的激活状态。姜黄素增强了Prdx6在HT22细胞中的表达，通过抑制ROS的增殖和钝化ER应激信号来重建生存信号。有趣的是，Prdx6的反义敲除揭示了Prdx6的缺失通过维持内质网应激反应的促凋亡蛋白水平的升高而导致细胞死亡，这是由于ROS产生的增加，这表明Prdx6缺乏是ROS介导的内质网应激诱导的细胞凋亡的原因之一。我们认为，使用姜黄素增强自然产生的Prdx6的表达，减弱基于ROS的内质网应激和核因子-kappaB介导的异常信号，可以提高细胞存活率，并可能为治疗和/或延缓与ROS或ER应激相关的疾病提供一条途径。
Chhunchha B, Fatma N, Kubo E, Rai P, Singh SP, Singh DP. Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-kappa B regulation. Am J Physiol Cell Physiol 304: C636-C655, 2013. First published January 30, 2013; doi:10.1152/ajpcell.00345.2012.-Oxidative stress and endoplasmic reticulum (ER) stress are emerging as crucial events in the etiopathology of many neurodegenerative diseases. While the neuroprotective contributions of the dietary compound curcumin has been recognized, the molecular mechanisms underlying curcumin's neuroprotection under oxidative and ER stresses remains elusive. Herein, we show that curcumin protects HT22 from oxidative and ER stresses evoked by the hypoxia (1% O-2 or CoCl2 treatment) by enhancing peroxiredoxin 6 (Prdx6) expression. Cells exposed to CoCl2 displayed reduced expression of Prdx6 with higher reactive oxygen species (ROS) expression and activation of NF-kappa B with I kappa B phosphorylation. When NF-kappa B activity was blocked by using SN50, an inhibitor of NF-kappa B, or cells treated with curcumin, the repression of Prdx6 expression was restored, suggesting the involvement of NF-kappa B in modulating Prdx6 expression. These cells were enriched with an accumulation of ER stress proteins, C/EBP homologous protein (CHOP), GRP/78, and calreticulin, and had activated states of caspases 12, 9, and 3. Reinforced expression of Prdx6 in HT22 cells by curcumin reestablished survival signaling by reducing propagation of ROS and blunting ER stress signaling. Intriguingly, knockdown of Prdx6 by antisense revealed that loss of Prdx6 contributed to cell death by sustaining enhanced levels of ER stress-responsive proapoptotic proteins, which was due to elevated ROS production, suggesting that Prdx6 deficiency is a cause of initiation of ROS-mediated ER stress-induced apoptosis. We propose that using curcumin to reinforce the naturally occurring Prdx6 expression and attenuate ROS-based ER stress and NF-kappa B-mediated aberrant signaling improves cell survival and may provide an avenue to treat and/or postpone diseases associated with ROS or ER stress.