Wang Yong-Sheng, Huang Yuan-Cheng, Wang Yong-Qi, Zheng Yi-Xuan, Gao Ying-Ren, Wu Min-Xia, Gao Fang-Hong, Wang Hong-Zhang, Liu Kun, Yan Lin
Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, China.
Xiamen Clinical Research Center for Cancer Therapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, China.
Biochem Genet. 2025 Jun 7. doi: 10.1007/s10528-025-11155-7.
Ischemic stroke remains a leading cause of morbidity and mortality worldwide. Current therapeutic approaches for ischemic stroke are limited, particularly in targeting the interconnected mechanisms of neuroinflammation and oxidative stress. There is a critical need for effective neuroprotective agents that address these pathways to mitigate I/R-induced injury. Here, we used bioinformatics analysis to identify differentially expressed genes (DEGs) associated with ischemic stroke and performed enrichment analysis to uncover hub genes and signaling pathways central to disease progression. MG-132, a proteasome inhibitor, was identified as a promising candidate and investigated for its neuroprotective efficacy in middle cerebral artery occlusion/reperfusion (MCAO/R) models. MG-132 treatment significantly reduced infarct size, decreased cerebral edema, and improved neurological outcomes. Mechanistically, MG-132 downregulated PTGS2 expression, inhibited NF-κB activation, and reduced pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-17. Furthermore, MG-132 alleviated oxidative stress and apoptosis, as evidenced by decreased malondialdehyde (MDA) levels and fewer TUNEL-positive cells. These findings demonstrate that MG-132 exerts robust neuroprotection by modulating the PTGS2/NF-κB signaling pathway, addressing key pathological processes in I/R injury. This study provides a foundation for developing targeted therapeutic strategies that mitigate neuroinflammation and oxidative stress in ischemic stroke, advancing the search for effective interventions in this critical area of unmet medical need.
缺血性中风仍然是全球发病和死亡的主要原因。目前针对缺血性中风的治疗方法有限，尤其是在针对神经炎症和氧化应激的相互关联机制方面。迫切需要有效的神经保护剂来解决这些途径，以减轻缺血/再灌注（I/R）诱导的损伤。在这里，我们使用生物信息学分析来识别与缺血性中风相关的差异表达基因（DEG），并进行富集分析以揭示对疾病进展至关重要的枢纽基因和信号通路。蛋白酶体抑制剂MG-132被确定为一个有前景的候选药物，并在大脑中动脉闭塞/再灌注（MCAO/R）模型中研究了其神经保护功效。MG-132治疗显著减小了梗死体积，减轻了脑水肿，并改善了神经功能结局。机制上，MG-132下调了PTGS2的表达，抑制了NF-κB的激活，并减少了促炎细胞因子如TNF-α、IL-1β和IL-17。此外，MG-132减轻了氧化应激和细胞凋亡，丙二醛（MDA）水平降低和TUNEL阳性细胞减少证明了这一点。这些发现表明，MG-132通过调节PTGS2/NF-κB信号通路发挥强大的神经保护作用，解决了I/R损伤中的关键病理过程。本研究为制定减轻缺血性中风中神经炎症和氧化应激的靶向治疗策略奠定了基础，推动了在这一关键的未满足医疗需求领域寻找有效干预措施的研究。
