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IF 3.2 3区医学 Q2 ENDOCRINOLOGY & METABOLISM

Metabolic brain disease Pub Date : 2025-03-13 DOI:10.1007/s11011-025-01572-3

Yuanyuan Zhu, Juan Tong, Jianzhong Jiang, Keyun Shi, Jing Xie, Yan Zhu, Yuefeng Li, Yuhao Xu

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引用次数: 0

摘要

慢性脑灌注不足诱发的白质损伤（WMI）是造成血管性认知障碍的一个重要原因。新的证据表明，miR-218 可能参与了 WMI 的发病机制。然而，人们对 miR-218 与慢性低灌注诱导的 WMI 之间关系的了解仍然不足。我们的研究从临床、动物和细胞水平研究了 miR-218 与慢性低灌注诱导的 WMI 之间的关系。我们发现，血清 miR-218 表达在临床 WMI 患者中升高，对 WMI 有一定的诊断效果，并与 WMI 的程度、认知评分和血清炎症因子相关。此外，我们还构建了双侧颈动脉狭窄（BCAS）小鼠模型来模拟慢性低灌注诱导的 WMI，并检测到 BCAS 小鼠白质中 miR-218 的表达增加。对 BCAS 小鼠的白质施用 Lv-sh-miR-218 后，认知障碍和 WMI 都得到了改善。此外，Lv-sh-miR-218 还减少了小胶质细胞的 M1 极化和白质内的神经炎症。随后，我们通过生物信息学分析和荧光素酶报告基因实验证实了 SOCS3 是 miR-218 的特异性靶点。向白质注射 LV-SOCS3 还能改善 BCAS 小鼠的认知障碍和 WMI，同时减少小胶质细胞的 M1 极化和神经炎症。此外，我们还在原代培养的小胶质细胞中证实，慢性缺氧后，miR-218 通过 SOCS3/STAT3 通路调节炎症因子。总之，我们目前的研究结果表明，miR-218 水平升高与慢性低灌注诱导的 WMI 之间存在密切的相关性，而下调 miR-218 的表达可通过上调 SOCS3 改善神经炎症，从而改善 WMI 和认知障碍。

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Suppression of miR-218 promotes SOCS3 expression to alleviate cognitive impairment and white matter injury after chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion-induced white matter injury (WMI) is a significant cause of vascular cognitive impairment. Emerging evidence suggests that miR-218 may be involved in the pathogenesis of WMI. However, understanding of the relationship between miR-218 and chronic hypoperfusion-induced WMI remains insufficient. Our study investigated the relationship between miR-218 and chronic hypoperfusion-induced WMI at clinical, animal, and cellular levels. We found that serum miR-218 expression was elevated in clinical WMI patients, had a certain diagnostic efficacy for WMI, and was correlated with the degree of WMI, cognitive scores, and serum inflammatory factors. In addition, we constructed a mouse model with bilateral carotid artery stenosis (BCAS) to simulate chronic hypoperfusion-induced WMI and detected an increase in miR-218 expression in the white matter of BCAS mice. Following administration of Lv-sh-miR-218 to the white matter of BCAS mice, improvements were observed in both cognitive impairment and WMI. Furthermore, Lv-sh-miR-218 also reduced M1 polarization of microglia and neuroinflammation within the white matter. Subsequently, we confirmed that SOCS3 is the specific target of miR-218 through bioinformatics analysis and luciferase reporter gene assays. Injection of LV-SOCS3 into the white matter also led to improvements in cognitive impairment and WMI in BCAS mice, along with reduced M1 polarization of microglia and neuroinflammation. Moreover, in primary cultured microglia cells, we demonstrated that after chronic hypoxia, miR-218 regulates inflammatory factors through the SOCS3/STAT3 pathway. In summary, our current results indicate a strong correlation between elevated miR-218 levels and chronic hypoperfusion-induced WMI, and downregulation of miR-218 expression can improve neuroinflammation by upregulating SOCS3, thereby ameliorating WMI and cognitive impairment.

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来源期刊

Metabolic brain disease 医学-内分泌学与代谢

CiteScore

5.90

自引率

5.60%

发文量

248

审稿时长

6-12 weeks

期刊介绍： Metabolic Brain Disease serves as a forum for the publication of outstanding basic and clinical papers on all metabolic brain disease, including both human and animal studies. The journal publishes papers on the fundamental pathogenesis of these disorders and on related experimental and clinical techniques and methodologies. Metabolic Brain Disease is directed to physicians, neuroscientists, internists, psychiatrists, neurologists, pathologists, and others involved in the research and treatment of a broad range of metabolic brain disorders.