Yu Youxin, Shi Yu, Hu Ziwei, Pang Jiahui, Wang Xianglong, Liu Sishi, Xie Yu, Wu Wen
Center of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; School of Rehabilitation Sciences, Southern Medical University, Guangzhou 510515, China; GuangDong Engineering Technology Research Center of Brain Function Assessment and Neuroregulation Rehabilitation, Guangzhou 510635, China.
Center of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Neuroscience. 2025 Aug 6;580:124-138. doi: 10.1016/j.neuroscience.2025.06.046. Epub 2025 Jun 21.
Acute ischemic stroke (AIS), a high-risk condition associated with significant morbidity and disability, could be further exacerbated by a high-salt diet (HSD). Although intermittent theta-burst stimulation (iTBS) is a clinically effective rehabilitation modality, its neuroprotective mechanisms remain unclear. This study aimed to elucidate the pathways through which HSD exacerbates early AIS injury, identify potential biomarkers, and assess the impact of iTBS intervention. First, bioinformatics techniques were employed to identify core genes associated with early ischemia and differentially expressed microglial genes (DEMGs) in mice subjected to middle cerebral artery occlusion (MCAO) with or without HSD. Subsequently, key pathways enriched among these DEMGs were elucidated. Next, co-expressed genes linked to HSD-exacerbated AIS mechanisms were selected as potential biomarkers and validated in vivo and in vitro. Finally, iTBS effects on biomarker expression were evaluated. As a result, integrative bioinformatics analysis implicated ATF3 as a potential biomarker for HSD-exacerbated AIS injury, mechanistically linked to HSD-induced microglial apoptosis. Consistently, HSD significantly upregulated ATF3 expression in both in vivo and in vitro AIS models. Furthermore, iTBS intervention significantly downregulated ATF3 expression within the HSD-exacerbated AIS context. Critically, iTBS also specifically downregulated ATF3 expression notably within hippocampal microglia of HSD-fed MCAO mice. Collectively, these findings suggest ATF3 serves as a potential biomarker for the combined injury induced by HSD and AIS and represents a promising therapeutic target for iTBS.
急性缺血性卒中（AIS）是一种与严重发病和残疾相关的高危病症，高盐饮食（HSD）可能会使其进一步恶化。尽管间歇性theta波爆发刺激（iTBS）是一种临床有效的康复方式，但其神经保护机制仍不清楚。本研究旨在阐明HSD加重早期AIS损伤的途径，识别潜在的生物标志物，并评估iTBS干预的影响。首先，采用生物信息学技术识别与早期缺血相关的核心基因以及在接受或未接受HSD的大脑中动脉闭塞（MCAO）小鼠中差异表达的小胶质细胞基因（DEMGs）。随后，阐明这些DEMGs中富集的关键途径。接下来，选择与HSD加重的AIS机制相关的共表达基因作为潜在的生物标志物，并在体内和体外进行验证。最后，评估iTBS对生物标志物表达的影响。结果，综合生物信息学分析表明ATF3是HSD加重的AIS损伤的潜在生物标志物，其机制与HSD诱导的小胶质细胞凋亡有关。一致的是，HSD在体内和体外AIS模型中均显著上调ATF3的表达。此外，在HSD加重的AIS背景下，iTBS干预显著下调了ATF3的表达。至关重要的是，iTBS还特别显著下调了HSD喂养的MCAO小鼠海马小胶质细胞内的ATF3表达。总体而言，这些发现表明ATF3是HSD和AIS联合损伤的潜在生物标志物，并且是iTBS的一个有前景的治疗靶点。
