ABSTRACT
Stroke has been considered the second leading cause of death worldwide, and ischemic stroke accounts for the vast majority of stroke cases. Some of the main features of ischemic stroke are increased brain permeability, ischemia/reperfusion injury, oxidative stress, and acute inflammation. Antagonism of cysLT1R has been shown to provide cardiovascular and neural benefits. In the present study, we investigated the effects of the cysLT1R antagonist zafirlukast both in vivo and in vitro using a middle cerebral artery occlusion (MCAO) mouse model and human brain microvascular endothelial cells (HBMVECs). In vivo, we found that zafirlukast pretreatment could reduce MCAO-induced increased brain permeability by rescuing the expression levels of the tight junction proteins occludin and ZO-1. In vitro, we found that zafirlukast could suppress the increase in endothelial monolayer permeability induced by OGD/R via rescue of occludin and ZO-1 expression; additionally, we found that zafirlukast prevented OGD/R-induced degradation of the extracellular matrix via inhibition of MMP-2 and MMP-9 expression. Finally, we found that zafirlukast could also inhibit OGD/R-induced activation of the critical proinflammatory regulator NF-κB by preventing phosphorylation and nuclear translocation of p65 protein. Together, our findings demonstrate a promising role for zafirlukast in preventing damage induced by ischemic stroke and reperfusion injury.
Subject(s)
Blood-Brain Barrier/drug effects , Tosyl Compounds/pharmacology , Animals , Blood-Brain Barrier/metabolism , Brain Infarction/etiology , Brain Infarction/prevention & control , Cell Membrane Permeability/drug effects , Disease Models, Animal , Down-Regulation/drug effects , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Indoles , Infarction, Middle Cerebral Artery/complications , Infarction, Middle Cerebral Artery/pathology , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Occludin/genetics , Occludin/metabolism , Phenylcarbamates , Sulfonamides , Tosyl Compounds/therapeutic use , Zonula Occludens-1 Protein/genetics , Zonula Occludens-1 Protein/metabolismABSTRACT
BACKGROUND: The exosomal miRNAs have been emerged as biomarkers and therapeutic targets for various diseases, however, the function of exosomal miRNAs in stroke remains largely unknown. METHODS: The blood samples from acute ischemic stroke (AIS) patients and normal controls were collected. The exosomes were isolated from the blood samples, which were confirmed by electron microscopy and western blot with the specific exosomes biomarker CD9, CD63 and Tsg101. RESULTS: RT-qPCR analysis showed that exosomal miR-134 was significantly increased in AIS patients within 24 h after stroke onset compared with that of control group. Highly expressed exosomal miR-134 was correlated with the National Institutes of Health Stroke Scale (NIHSS) scores, infarct volume and positively associated with the worse prognosis of the stroke patients. Additionally, the exosomal miR-134 was strong positively correlated with the expression of serum interleukin 6 (IL-6) and plasma high-sensitivity C relative protein (hs-CRP). The receiver operating characteristic (ROC) curve suggested that miR-134 might be a potential factor to discriminate AIS patients from non-stroke controls. CONCLUSIONS: The exosomal miR-134 as a possible novel biomarker for the diagnosis and prognosis of stroke.
Subject(s)
Biomarkers/blood , MicroRNAs/blood , Stroke/blood , Aged , Exosomes , Female , Humans , Interleukin-6/blood , Male , Middle Aged , Prognosis , ROC Curve , Sensitivity and Specificity , Stroke/diagnosis , United StatesABSTRACT
Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is an autoimmune disorder characterized by memory deficits, psychiatric symptoms, and autonomic instability. The lack of suitable biomarkers targeting anti-NMDAR encephalitis makes the immunotherapy and prognosis challenging. In this study, we found that the Th17 cells were significantly accumulated in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients than that of control individuals. The concentration of the cytokines and chemokines including interleukin (IL)-1ß, IL-17, IL-6, and CXCL-13 were significantly increased in the CSF of anti-NMDAR encephalitis patients. IL-6 and IL-17 were found to promote the differentiation of CD4+ T cells into Th17 lineage. The chemotaxis assay showed that CCL20 and CCL22 play essential roles in the migration of Th17 cells. Notably, the correlation between the expression of IL-17 and the outcome of anti-NMDAR encephalitis patients was analyzed. The data showed that high level of IL-17 was significantly correlated with the limited response to the treatment and relapse of anti-NMDAR encephalitis patients. Our results suggested the potential important involvement of IL-17 in anti-NMDAR encephalitis.