miR-135a-5p通过抑制DDX3X/NLRP3通路介导的焦亡来减轻脑缺血再灌注损伤。

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Yong Liu , Xin Jiang , Yunfei Zhang , Guofeng Tong , Kai Tang , Yanlin Gui , Lan Wen , Changqing Li
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引用次数: 0

摘要

MicroRNAs (miRNAs)广泛参与脑缺血再灌注损伤(CIRI)过程中的信号转导和调控。本研究探讨了早期CIRI特异性miRNA/DDX3X/NLRP3通路的分子机制,并探讨了其潜在的临床应用。通过公开数据库分析,确定CIRI后靶向DDX3X的miR-135a-5p。MCAO/R后DDX3X、NLRP3炎性体、GSDMD-N水平升高。miR-135a-5p的上调抑制了这些蛋白的水平。上调miR-135a-5p也减少了梗死体积和神经元焦亡,同时改善了MCAO/R小鼠的神经学评分。Co-IP证实了CIRI模型中DDX3X和NLRP3之间的蛋白相互作用。此外,miR-135a-5p模拟物减轻了OGD/R细胞后的焦亡,抑制了DDX3X/NLRP3通路的激活,而miR-135a-5p抑制剂产生了相反的效果。双荧光素酶报告试验证实DDX3X是miR-135a-5p的直接靶点。临床上,CIRI患者取栓后血清miR-135a-5p水平明显低于对照组。CIRI组DDX3X、NLRP3、IL-18水平升高,而IL-1β水平两组间差异无统计学意义(p = 0.055)。CIRI患者miR-135a-5p与DDX3X水平呈负相关,但线性回归分析无统计学意义(R2 = 0.12,p = 0.061)。本研究表明miR-135a-5p/DDX3X/NLRP3通路在早期CIRI中起关键作用。上调miR-135a-5p通过靶向DDX3X抑制nlrp3介导的神经元焦亡,从而减轻CIRI,改善神经功能。该信号轴在治疗CIRI的未来临床应用中具有前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
miR-135a-5p alleviates cerebral ischemia-reperfusion injury by inhibiting pyroptosis mediated through the DDX3X/NLRP3 pathway
MicroRNAs (miRNAs) are widely involved in signal transduction and regulation during cerebral ischemia-reperfusion injury (CIRI). This study investigates the molecular mechanisms of the specific miRNA/DDX3X/NLRP3 pathway in early-stage CIRI and explores its potential clinical applications. Through public database analysis, miR-135a-5p targeting DDX3X after CIRI was determined. The levels of DDX3X, NLRP3 inflammasome, and GSDMD-N were increased after MCAO/R. Upregulation of miR-135a-5p suppressed these protein levels. Upregulating miR-135a-5p also reduced infarct volume and neuronal pyroptosis, while improved neurological scores in MCAO/R mice. Co-IP confirmed protein interaction between DDX3X and NLRP3 in CIRI models. Furthermore, miR-135a-5p mimics alleviated pyroptosis and inhibited DDX3X/NLRP3 pathway activation after OGD/R cells, whereas miR-135a-5p inhibitor produced the opposite effect. The dual-luciferase reporter assay validated that DDX3X was a direct target of miR-135a-5p. Clinically, the serum level of miR-135a-5p was significantly lower in CIRI patients after thrombectomy compared to controls. The levels of DDX3X, NLRP3, and IL-18 were elevated in the CIRI group, while the difference of IL-1β levels between the two groups was not statistically significant (p = 0.055). Although an inverse correlation was observed between miR-135a-5p and DDX3X levels in CIRI patients, the linear regression analysis did not reach statistical significance (R2 = 0.12, p = 0.061). This study indicated that miR-135a-5p/DDX3X/NLRP3 pathway is pivotal in early-stage CIRI. Upregulation of miR-135a-5p inhibits NLRP3-mediated neuronal pyroptosis by targeting DDX3X, thereby alleviating CIRI and improving neurological function. This signaling axis holds promise for future clinical applications in treating CIRI.
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来源期刊
Experimental Neurology
Experimental Neurology 医学-神经科学
CiteScore
10.10
自引率
3.80%
发文量
258
审稿时长
42 days
期刊介绍: Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.
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