Anesthesiology Department, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Anesthesiology Department, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Int Immunopharmacol. 2021 Jul;96:107595. doi: 10.1016/j.intimp.2021.107595. Epub 2021 Mar 31.
Dipeptidyl-peptidase 3 (DPP3) plays a key role in regulating apoptosis, oxidative stress and inflammation under various pathological conditions, however, whether DPP3 regulates apoptosis and oxidative stress in neurons undergoing cerebral ischemia/reperfusion injury has not yet been well studied. The goals of this work were to evaluate the role of DPP3 in the regulation of oxygen-glucose deprivation/reoxygenation (OGD/R)-induced apoptosis, oxidative stress and inflammation in HT22 hippocampal neurons. Here, we showed that DPP3 expression was elevated in response to OGD/R in neurons. Knockdown of DPP3 exacerbated OGD/R-induced apoptosis, oxidative stress and inflammation, whilst up-regulation of DPP3 alleviated OGD/R-induced apoptosis, oxidative stress and inflammation in HT22 neurons. Further results revealed that DPP3 enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and promoted transcriptional activity of the anti-oxidant response element (ARE). Additionally, DPP3 was shown to regulate Nrf2/ARE activation in a kelch-like ECH-associated protein 1 (Keap1)-dependent manner. Notably, inhibition of Nrf2 markedly reversed the DPP3-mediated neuroprotective effects against OGD/R injury. Taken together, these findings demonstrate that DPP3 exerts a neuroprotective role in OGD/R-injured neurons by suppressing neuronal apoptosis, oxidative stress and inflammation via modulation of Keap1/Nrf2 signaling. This work suggests DPP3 as a potential target for providing neuroprotective effects during cerebral ischemia/reperfusion injury.
二肽基肽酶 3（DPP3）在各种病理条件下调节细胞凋亡、氧化应激和炎症中发挥关键作用，然而，DPP3 是否调节脑缺血/再灌注损伤过程中神经元的细胞凋亡和氧化应激尚未得到很好的研究。本研究旨在评估 DPP3 在调节 HT22 海马神经元氧葡萄糖剥夺/复氧（OGD/R）诱导的细胞凋亡、氧化应激和炎症中的作用。结果表明，DPP3 在神经元中对 OGD/R 有反应性地上调表达。DPP3 敲低加剧了 OGD/R 诱导的细胞凋亡、氧化应激和炎症，而上调 DPP3 则减轻了 HT22 神经元中 OGD/R 诱导的细胞凋亡、氧化应激和炎症。进一步的研究结果表明，DPP3 增强了核因子红细胞 2 相关因子 2（Nrf2）的核转位，并促进了抗氧化反应元件（ARE）的转录活性。此外，DPP3 被证明以 Kelch 样 ECH 相关蛋白 1（Keap1）依赖的方式调节 Nrf2/ARE 的激活。值得注意的是，Nrf2 的抑制显著逆转了 DPP3 介导的对 OGD/R 损伤的神经保护作用。总之，这些发现表明 DPP3 通过调节 Keap1/Nrf2 信号通路抑制神经元凋亡、氧化应激和炎症，在 OGD/R 损伤神经元中发挥神经保护作用。本研究表明 DPP3 可能成为脑缺血/再灌注损伤期间提供神经保护作用的潜在靶点。
