Department of Pathology, College of Basic Medicine, Chongqing Medical University, 400016 Chongqing, People's Republic of China; Department of Pathology, The Lu'an Hospital Affiliated of Anhui Medical University, 237000 Anhui, People's Republic of China; Department of Pathology, The Lu' an People's Hospital, 237000 Anhui, People's Republic of China.
Department of Pathology, College of Basic Medicine, Chongqing Medical University, 400016 Chongqing, People's Republic of China; Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, 400016 Chongqing, People's Republic of China; Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, 400016 Chongqing, People's Republic of China.
Neuroscience. 2022 Nov 10;504:33-46. doi: 10.1016/j.neuroscience.2022.09.016. Epub 2022 Sep 24.
DJ-1 plays a neuroprotective role in cerebral ischemia- reperfusion (I/R) injury and participates in the apoptosis of brain nerve cells, but the underlying mechanism is unclear. We explored the molecular pathways underlying this role using in vivo and in vitro approaches. Middle cerebral artery occlusion- reperfusion (MCAO/R) rat models and oxygen- glucose deprivation- reoxygenation (OGD/R) HAPI cell cultures were used to simulate cerebral ischemia-reperfusion injury. The interaction between DJ-1 and Notch1 was enhanced after MCAO/R in rats. After treatment of rats with DJ-1 siRNA, the expression of Notch1 and Nrf2 was down-regulated, and apoptosis was promoted. In contrast, the DJ-1 based peptide ND-13 upregulated the expression of Notch1 and Nrf2, and prevented apoptosis. In vitro, the Notch1 signaling pathway inhibitor DAPT reversed the neuroprotective effect of ND-13 and promoted apoptosis, weakened the interaction between DJ-1 and Notch1, and decreased the expression of proteins in the Notch1 and Nrf2 pathways. Thus, we found that DJ-1 inhibits apoptosis by regulating the Notch1 signaling pathway and Nrf2 expression in cerebral I/R injury. These results imply that DJ-1 is a potential therapeutic target for cerebral I/R injury.
DJ-1 在脑缺血再灌注（I/R）损伤中发挥神经保护作用，并参与脑神经元细胞的凋亡，但具体机制尚不清楚。我们通过体内和体外方法探讨了其发挥作用的分子途径。采用大脑中动脉闭塞再灌注（MCAO/R）大鼠模型和氧葡萄糖剥夺复氧（OGD/R）HAPI 细胞培养来模拟脑缺血再灌注损伤。MCAO/R 后大鼠 DJ-1 与 Notch1 的相互作用增强。用 DJ-1 siRNA 处理大鼠后，Notch1 和 Nrf2 的表达下调，促进细胞凋亡。相反，基于 DJ-1 的肽 ND-13 上调 Notch1 和 Nrf2 的表达，预防细胞凋亡。在体外，Notch1 信号通路抑制剂 DAPT 逆转了 ND-13 的神经保护作用并促进细胞凋亡，减弱了 DJ-1 与 Notch1 的相互作用，并降低了 Notch1 和 Nrf2 通路中蛋白的表达。因此，我们发现 DJ-1 通过调节 Notch1 信号通路和脑 I/R 损伤中的 Nrf2 表达来抑制细胞凋亡。这些结果表明 DJ-1 是脑 I/R 损伤的潜在治疗靶点。
