Yong Liu , Xin Jiang , Yunfei Zhang , Guofeng Tong , Kai Tang , Yanlin Gui , Lan Wen , Changqing Li
{"title":"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。","authors":"Yong Liu , Xin Jiang , Yunfei Zhang , Guofeng Tong , Kai Tang , Yanlin Gui , Lan Wen , Changqing Li","doi":"10.1016/j.expneurol.2024.115127","DOIUrl":null,"url":null,"abstract":"<div><div>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 (<em>p</em> = 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 (R<sup>2</sup> = 0.12, <em>p</em> = 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.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115127"},"PeriodicalIF":4.6000,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"miR-135a-5p alleviates cerebral ischemia-reperfusion injury by inhibiting pyroptosis mediated through the DDX3X/NLRP3 pathway\",\"authors\":\"Yong Liu , Xin Jiang , Yunfei Zhang , Guofeng Tong , Kai Tang , Yanlin Gui , Lan Wen , Changqing Li\",\"doi\":\"10.1016/j.expneurol.2024.115127\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 (<em>p</em> = 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 (R<sup>2</sup> = 0.12, <em>p</em> = 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.</div></div>\",\"PeriodicalId\":12246,\"journal\":{\"name\":\"Experimental Neurology\",\"volume\":\"385 \",\"pages\":\"Article 115127\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-12-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014488624004539\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Neurology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014488624004539","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
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.
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.