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1.
Exp Eye Res ; 203: 108388, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33333046

RESUMO

PURPOSE: To explore the role of nucleotide-binding oligomerization domain-like receptors (NLRs) family caspase-activation and the recruitment domain containing 4 (NLRC4) inflammasome in retinal ganglion cell (RGC) injury induced by an acute glaucoma mouse model. METHOD: A mouse model of acute ocular hypertension, which can lead to retinal ischemia-reperfusion (I/R) injury, was established. The expression level of NLRC4 was detected by polymerase chain reaction and western blotting. Localized expression of NLRC4 was detected by examining immunofluorescence in eyeball sections. Intravitreal adeno-associated virus 2(AAV2) administration was used to knockdown retinal Nlrc4. Fluoro-Gold labeled RGCs and TdT-mediated dUTP nick end labeling were used to evaluate the survival and apoptosis of RGCs. Tlr4-/- mice were utilized to explore whether NLRC4 inflammasome is influenced by Toll-like receptor4 (TLR4). RESULTS: NLRC4, expressed in RGCs and microglial cells, was actively involved in mouse retinal I/R injury. Knockdown of Nlrc4 using an AAV2 vector caused an obvious reduction in the generation of IL-1ß led by the rapidly elevated intraocular pressure, and thereby improved the RGC survival. In addition, activation of the NLRC4 inflammasome could influence the phosphorylation of p38 and Jun N-terminal kinase, which was largely dependent on TLR4 signaling. CONCLUSION: Our study demonstrated the role of NLRC4 inflammasome in promoting RGC damage in mouse retinal I/R injury. Inhibition of NLRC4 might be leveraged as a potential therapeutic target in glaucomatous retinopathy.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Proteínas de Ligação ao Cálcio/fisiologia , Morte Celular/fisiologia , Glaucoma/patologia , Inflamassomos/metabolismo , Células Ganglionares da Retina/patologia , Doença Aguda , Animais , Western Blotting , Dependovirus , Modelos Animais de Doenças , Glaucoma/metabolismo , Marcação In Situ das Extremidades Cortadas , Pressão Intraocular , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Hipertensão Ocular/metabolismo , Hipertensão Ocular/patologia , Parvovirinae/genética , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Traumatismo por Reperfusão/metabolismo , Retina/metabolismo , Células Ganglionares da Retina/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Mol Med Rep ; 21(3): 1606-1614, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32016457

RESUMO

Long non­coding RNAs (lncRNAs) are a group of non­coding transcripts of >200 nucleotides. They can act as competing endogenous RNAs (ceRNAs) and suppress microRNA (miRNA) function by preventing them from binding to and interacting with target mRNAs. However, the specific role of the lncRNA­associated ceRNA network in the pathogenesis of glaucoma has not yet been elucidated. To study this, data were downloaded from the Gene Expression Omnibus database (GSE126170), which contained three human trabecular meshwork cell (HTMC) samples treated with 300 µm hydrogen peroxide and three control samples treated with vehicle. Differentially expressed lncRNAs and mRNAs of HTMCs were obtained using the R package limma. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of differentially expressed mRNAs were performed using the R package clusterProfiler. Finally, the ceRNA network was constructed using the mircode, miRDB, miRTarBase and TargetScan databases, and visualized using Cytoscape v3.6.1. The results showed that 70 lncRNAs and 558 mRNAs were identified to be significantly dysregulated (|log2FoldChange| >1 and adjusted P<0.05) in HTMCs under oxidative stress compared to those in HTMCs under control conditions. Moreover, 24 lncRNAs, 24 miRNAs and 40 mRNAs were closely connected, and were part of the ceRNA network. Among these, the expression levels of 19 lncRNAs were upregulated, and those of 5 lncRNAs were downregulated. To conclude, using bioinformatics analysis, the differential expression profiles of lncRNAs were reported and a lncRNA­associated ceRNA network in HTMCs under oxidative stress was constructed. These results may bring to light a new pathological mechanism or a potential therapeutic target for glaucoma.


Assuntos
Biologia Computacional , MicroRNAs/genética , Estresse Oxidativo , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Malha Trabecular/citologia , Malha Trabecular/metabolismo , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Transcriptoma
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