microRNA-421-3p prevents inflammatory response in cerebral ischemia/reperfusion injury through targeting m6A Reader YTHDF1 to inhibit p65 mRNA translation |
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Affiliation: | 1. School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;2. Department of Traditional Chinese Medicine, Second People''s Hospital of Guangdong Province, Guangzhou 510310, China;3. The Second Institute of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China |
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Abstract: | ObjectiveIschemic stroke is one of the leading causes of death globally, and inflammation is considered as a vital contributor to the pathophysiology of ischemic stroke. Recently, microRNA-421-3p-derived macrophages is found to promote motor function recovery in spinal cord injury. Here, we explored whether microRNA-421-3p is involved in inflammation responses during cerebral ischemia/reperfusion (I/R) injury and its molecular mechanism.MethodsAn in vivo experimental animal model of intraluminal middle cerebral artery occlusion/reperfusion (MCAO/R) and in vitro model of microglial subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) were used. The effects of microRNA-421-3p on cerebral I/R injury and its underlying mechanism were detected by quantitative real-time PCR, western blotting, immunofluorescence staining, RNA immunoprecipitation, flow cytometry, luciferase reporter assay, and bioinformatics analysis.ResultsWe find that microRNA-421-3p is significantly decreased in cerebral I/R injury in vitro and in vivo. Furthermore, overexpression of microRNA-421-3p evidently suppresses pro-inflammatory factor expressions and inhibits NF-κB p65 protein expression and nuclear translocation in BV2 microglia cells treated with OGD/R. However, microRNA-421-3p neither promotes p65 mRNA expression, nor affects p65 mRNA or protein stability. Moreover, we find the m6A ‘reader’ protein YTH domain family protein 1 (YTHDF1) is the specific target of microRNA-421-3p, and YTHDF1 specifically binds to the m6a site of p65 mRNA to promote its translation.ConclusionmicroRNA-421-3p prevents inflammatory response in cerebral ischemia/reperfusion injury through targeting YTHDF1 to inhibit p65 mRNA translation. These findings provide novel insights into understanding the molecular pathogenesis of cerebral I/R injury. |
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Keywords: | Ischemic stroke microRNA-421-3p m6A modification YTHDF1 Inflammation MCAO/R" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" middle cerebral artery occlusion/reperfusion OGD/R" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" oxygen-glucose deprivation and reoxygenation YTHDF1" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" YTH domain family protein 1 rtPA" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" recombinant tissue plasminogen activator I/R" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" ischemia and reperfusion miRNAs" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" microRNAs 3′-UTR" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," _" :" 3′-untranslated region m6A" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" N6-Methyladenosine METTL3" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" methyltransferase-like 3 WTAP" },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," _" :" wilms tumor associated protein FTO" },{" #name" :" keyword" ," $" :{" id" :" k0135" }," $$" :[{" #name" :" text" ," _" :" fat-mass and obesity-associated protein ALKBH5" },{" #name" :" keyword" ," $" :{" id" :" k0145" }," $$" :[{" #name" :" text" ," _" :" α-ketoglutarate-dependent dioxygenase alkB homolog 5 YTH" },{" #name" :" keyword" ," $" :{" id" :" k0155" }," $$" :[{" #name" :" text" ," _" :" YT521-B homology mNSS" },{" #name" :" keyword" ," $" :{" id" :" k0165" }," $$" :[{" #name" :" text" ," _" :" modified Neurological Severity Score ActD" },{" #name" :" keyword" ," $" :{" id" :" k0175" }," $$" :[{" #name" :" text" ," _" :" Actinomycin D CHX" },{" #name" :" keyword" ," $" :{" id" :" k0185" }," $$" :[{" #name" :" text" ," _" :" cycloheximide RIP" },{" #name" :" keyword" ," $" :{" id" :" k0195" }," $$" :[{" #name" :" text" ," _" :" RNA immunoprecipitation iNOS" },{" #name" :" keyword" ," $" :{" id" :" k0205" }," $$" :[{" #name" :" text" ," _" :" inducible nitric oxide synthase IL6" },{" #name" :" keyword" ," $" :{" id" :" k0215" }," $$" :[{" #name" :" text" ," _" :" interleukin 6 TNFα" },{" #name" :" keyword" ," $" :{" id" :" k0225" }," $$" :[{" #name" :" text" ," _" :" tumor necrosis factor α CXCL10" },{" #name" :" keyword" ," $" :{" id" :" k0235" }," $$" :[{" #name" :" text" ," _" :" C-X-C motif ligand 10 MAPK" },{" #name" :" keyword" ," $" :{" id" :" k0245" }," $$" :[{" #name" :" text" ," _" :" mitogen-activated protein kinase NF-κB" },{" #name" :" keyword" ," $" :{" id" :" k0255" }," $$" :[{" #name" :" text" ," _" :" nuclear factor kappa B VEZF1" },{" #name" :" keyword" ," $" :{" id" :" k0265" }," $$" :[{" #name" :" text" ," _" :" vascular endothelial zinc finger 1 LPGAT1" },{" #name" :" keyword" ," $" :{" id" :" k0275" }," $$" :[{" #name" :" text" ," _" :" lysophosphatidylglycerol acyltransferase 1 SYT14" },{" #name" :" keyword" ," $" :{" id" :" k0285" }," $$" :[{" #name" :" text" ," _" :" synaptotagmin 14 FAM172a" },{" #name" :" keyword" ," $" :{" id" :" k0295" }," $$" :[{" #name" :" text" ," _" :" family with sequence similarity 172 member a ERGIC2" },{" #name" :" keyword" ," $" :{" id" :" k0305" }," $$" :[{" #name" :" text" ," _" :" ERGIC and golgi 2 |
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