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NPD1 inhibits excessive autophagy by targeting RNF146 and wnt/β-catenin pathway in cerebral ischemia-reperfusion injury
Journal of Receptors and Signal Transduction ( IF 2.8 ) Pub Date : 2020-04-24 , DOI: 10.1080/10799893.2020.1756325
Qiong Mu 1 , Hailong Zhou 2 , Yingning Xu 1 , Qian He 1 , Xiao Luo 1 , Wansong Zhang 1 , Haibing Li 1
Affiliation  

Abstract Objective: Cerebral ischemia-reperfusion (I/R) injury is a common pathological feature in ischemic stroke. Autophagy plays a key role in I/R-induced neuronal death. Neuroprotectin D1 (NPD1) is a docosahexaenoic acid derivative with neuroprotective and anti-inflammatory properties. The purpose of this study was to investigate the mediatory role of NPD1 on I/R-induced injury and to elucidate the underlying mechanisms involved in this process. Methods: An I/R injury model was established in PC12 cells induced by oxygen and glucose deprivation/reoxygenation (OGD/R). NPD1 at increasing doses (5, 10, 20, 50, 100 nM) were added to cells one hour before OGD/R. To investigate the effect of ring finger protein 146 (RFP146) deficiency in I/R injury, PC12 cells were transiently transfected with small interfering RNF146 before further experiment. Results: Compared to the controls, OGD/R-challenged cells exhibited significantly decreased cell viability, induced oxidative stress, and excessive autophagic cell death following OGD/R. Pretreatment with NPD1 protected cells against ischemic injury as evidenced by enhanced cell survival, decreased oxidative stress markers, and a lower level of autophagy compared to drug-free group. OGD/R also increased the level of RFP146 and inhibited the expression of β-catenin in PC12 cells. NPD1 treatment promoted the production of RNF146 and β-catenin in cells following OGD/R experiment. Moreover, RNF146 deficiency significantly inhibited β-catenin expression and reversed the protective effects of NPD1 in OGD/R-induced cells. Conclusion: NPD1 alleviated excessive autophagy via regulating RNF146 and Wnt/β-catenin signaling, suggesting the potential therapeutic use of NPD1 for the protection against cerebral I/R injury.

中文翻译:

NPD1通过靶向RNF146和wnt/β-catenin通路抑制脑缺血再灌注损伤中的过度自噬

摘要 目的:脑缺血再灌注(I/R)损伤是缺血性脑卒中的常见病理特征。自噬在 I/R 诱导的神经元死亡中起关键作用。神经保护素 D1 (NPD1) 是一种二十二碳六烯酸衍生物,具有神经保护和抗炎特性。本研究的目的是研究 NPD1 在 I/R 诱导的损伤中的中介作用,并阐明该过程中涉及的潜在机制。方法:建立氧糖剥夺/复氧(OGD/R)诱导的PC12细胞I/R损伤模型。在 OGD/R 前一小时将增加剂量 (5、10、20、50、100 nM) 的 NPD1 添加到细胞中。为了研究无名指蛋白 146 (RFP146) 缺乏对 I/R 损伤的影响,在进一步实验前用小干扰 RNF146 瞬时转染 PC12 细胞。结果:与对照组相比,OGD/R 攻击的细胞在 OGD/R 后表现出显着降低的细胞活力、诱导的氧化应激和过度的自噬细胞死亡。与无药物组相比,NPD1 预处理可以保护细胞免受缺血性损伤,这可以通过提高细胞存活率、减少氧化应激标志物和降低自噬水平来证明。OGD/R 还增加了 RFP146 的水平并抑制了 PC12 细胞中 β-catenin 的表达。在OGD/R实验后,NPD1处理促进细胞中RNF146和β-连环蛋白的产生。此外,RNF146 缺乏显着抑制了 β-连环蛋白的表达并逆转了 NPD1 在 OGD/R 诱导的细胞中的保护作用。结论:NPD1 通过调节 RNF146 和 Wnt/β-catenin 信号减轻过度自噬,
更新日期:2020-04-24
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