Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.646
Filtrar
1.
Gene ; 767: 145148, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32949698

RESUMO

Ischemic stroke is a common clinical cardiovascular disease and often accompanied by central nervous system injury. It often causes paralysis or loss of motor function after central nervous system injury and significantly reduces the patient's quality of life. At present, there is no effective treatment strategy for nerve damage caused by ischemic stroke. Therefore, it is urgently need to explore effective treatment targets. The protein expression of SOX5, VEGF and apoptosis related proteins were measured by western blot. The mRNA expression of SOX5 and VEGF were detected by RT-qPCR. The concentration of S100B and GFAP which are related to nerve damage were detected using ELISA assay. The transcriptional regulation of SOX5 on VEGF was detected using ChIP-PCR and dual luciferase reporter gene assays. The cell apoptosis was measured by TUNEL assay and cell viability was detected by CCK-8 assay. In our study, we found that the expression of SOX5 was significantly reduced when LPS induced apoptosis in PC-12 cells. Overexpression of SOX5 repaired LPS-induced apoptosis. SOX5 promotes VEGF expression as a transcription factor to activate the PI3K/AKT pathway. VEGF also repairs nerve injury and brain tissue injury caused by ischemic stroke. In conclusion, SOX5 transcription regulates the expression of VEGF to activate the PI3K/AKT pathway, which repaired nerve damage caused by ischemic stroke. Therefore, SOX5 could be a new targetto regulate VEGF which can repair nerve injury induced by ischemic stroke.


Assuntos
/tratamento farmacológico , Fatores de Transcrição SOXD/metabolismo , Animais , Apoptose/fisiologia , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Morte Celular , Proliferação de Células , Regulação da Expressão Gênica/genética , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/fisiologia , Transdução de Sinais/genética , Acidente Vascular Cerebral/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-33375320

RESUMO

BACKGROUND: Carotid intima-media thickness (cIMT) has been associated with an elevated risk of ischemic stroke (IS) in several studies, but the results are inconsistent. We investigated whether the association between cIMT and IS varied across different IS subtypes, and further assessed gene-cIMT interactions' association with IS risk. METHODS: A total of 1048 IS cases (795 large-artery atherosclerosis (LAA) cases, 103 small-vessel occlusion (SVO) cases, and 150 other subtypes) and 2696 IS-free controls across 2179 families were included in the analysis. Self-reported IS cases were confirmed through medical records' review and head imaging by computed tomography and/or magnetic resonance imaging. The mean values of the common cIMT obtained in bilateral distal and proximal carotid artery segments were used. The genotype information of rs2910164 polymorphism in microRNA-146a (miR-146a) was also collected. RESULTS: We found that cIMT was significantly associated with a higher risk of IS and LAA subtype but not SVO subtype in the multivariate-adjusted models. The odds ratio (OR) and 95% confidence interval (CI) in the highest quartile versus the lowest quartile of cIMT was 2.48 (1.92-3.20) for IS and 2.75 (2.08-3.64) for LAA (both p trend <0.001). The results also showed that there was a significant interaction between cIMT and rs2910164 genotype with the risk of IS (p interaction = 0.03) and LAA (p interaction = 0.02). The associations of cIMT with IS and LAA were strengthened among participants carried rs2910164_GG genotype compared with those with rs2910164_CC genotype. CONCLUSIONS: Our results indicate that higher cIMT levels were significantly associated with IS and LAA subtype but not SVO subtype, and the relations were modified by rs2910164 polymorphism in miR-146a.


Assuntos
Isquemia Encefálica , Espessura Intima-Media Carotídea , Idoso , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/genética , China/epidemiologia , Saúde da Família , Feminino , Humanos , /genética , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Fatores de Risco , População Rural
5.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 712-718, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958128

RESUMO

Objective To investigate the effect of Yiqihuoxue herb Naoluoxintong on cerebral vascular regeneration in rats of middle cerebral artery occlusion-reperfusion(MCAO-R)experimental model with Qi deficiency and blood stasis syndrome, and explore the possible mechanisms. Methods A total of 60 SD rats were randomly divided into a control group, a model group and three Naoluoxintong-treated groups [(1 200, 800 and 400 mg/(kg.d)], with 12 rats each. Except for the control group, the other groups were treated with modified suture method combined with multi-factor compound simulation to establish the models with both MCAO-R and syndrome of Qi deficiency accompanied by blood stasis. Neural functional deficit, blood stasis syndrome and Qi deficiency syndrome were scored by quantitative criteria for biological characteristics score. The regional cerebral blood flow (rCBF) was dynamically monitored with laser Doppler scanning. HE staining was used to observe the pathological changes of brain tissue. The mRNA expression levels of Wnt5a, glycogen synthase kinase-3ß (GSK-3ß) were determined by real-time fluorescent quantitative PCR, and the protein expression levels of ß-catenin, vascular endothelial growth factor (VEGF), AngII in the rat brain tissue were detected by Western blotting. Results Naoluoxintong improved neural functional in the model rats, reduced the scores of neural functional deficit, blood stasis syndrome and Qi deficiency syndrome, and restored rCBF simultaneously. Meanwhile, Naoluoxintong high- and middle-dose groups were better than any other model groups in terms of pathological changes, and the up-regulation of Wnt5a mRNA expression in these two groups was the most obvious. However, it had no significant effect on GSK3ß mRNA in the model rats. Expression levels of ß-catenin, VEGF, AngII protein were obviously up-regulated in Naoluoxintong high- and middle-dose groups. Conclusion Naoluoxintong can improve the rCBF with the aid of promoting cerebral vascular regeneration, which might be related to high expression of pro-angiogenic factors that are affected by Wnt signal path activation.


Assuntos
Vasos Sanguíneos , Isquemia Encefálica , Encéfalo , Qi , Animais , Vasos Sanguíneos/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/genética , Ratos , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética
7.
Hum Cell ; 33(4): 1046-1055, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772229

RESUMO

Acute ischemic stroke is a devastating disease with very limited therapeutics. Growing appreciation of dysregulated autophagy contributes to the progression of brain ischemic injury, making it to be an appealing intervention target. In terms of its well-characterized consequences, the signal molecules required for autophagy activation are rather poorly defined. Here, we found the induction of chloride channel-3 (ClC-3) directly activated autophagy, which played an important role in limiting cerebral ischemia/reperfusion (I/R) injury. Further mechanism exploration discovered that the up-regulation of ClC-3 was critical for the interaction of Beclin1 and Vps34. After ClC-3 knockdown using adeno-associated virus vectors in vivo, the autophagy activation was partially inhibited through disrupting the formation of Beclin1 and Vps34 complex. Consistent with these observations, ClC-3 knockdown could also significantly aggravated cerebral I/R injury through suppressing autophagy in vivo, which further confirmed the neuroprotective roles of ClC-3. Collectively, we provided an novel evidence for ClC-3 serving as a crucial regulator of autophagy; and our results indicated that the induction of ClC-3 may serve as a self-protective mechanism against cerebral I/R injury.


Assuntos
Autofagia/genética , Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/prevenção & controle , Canais de Cloreto/metabolismo , Canais de Cloreto/fisiologia , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Fármacos Neuroprotetores , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/prevenção & controle , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/prevenção & controle , Animais , Masculino , Ratos Sprague-Dawley , Regulação para Cima/genética
8.
J Stroke Cerebrovasc Dis ; 29(9): 104942, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807413

RESUMO

BACKGROUND AND OBJECTIVES: Studies implicate the lung in moderating systemic immune activation via effects on circulating leukocytes. In this study, we investigated whether targeted expression of the antioxidant extracellular superoxide dismutase (SOD3) within the lung would influence post-ischemic peripheral neutrophil activation and CNS reperfusion injury. METHODS: Adult, male mice expressing human SOD3 within type II pneumocytes were subjected to 15 min of transient global cerebral ischemia. Three days post-reperfusion, lung and brain tissue was collected and analyzed by immunohistochemistry for inflammation and injury markers. In vitro motility and neurotoxicity assays were conducted to ascertain the direct effects of hSOD3 on PMN activation. Results were compared against C57BL/6 age and sex-matched controls. RESULTS: Relative to wild-type controls, hSOD3 heterozygous mice exhibited a reduction in lung inflammation, blood-brain barrier damage, and post-ischemic neuronal injury within the hippocampus and cortex. PMNs harvested from hSOD3 mice were also resistant to LPS priming, slower-moving, and less toxic to primary neuronal cultures. CONCLUSIONS: Constitutive, focal expression of hSOD3 is neuroprotective in a model of global cerebral ischemia-reperfusion injury. The underlying mechanism of SOD3-dependent protection is attributable in part to effects on the activation state and toxic potential of circulating neutrophils. These results implicate lung-brain coupling as a determinant of cerebral ischemia-reperfusion injury and highlight post-stroke lung inflammation as a potential therapeutic target in acute ischemic cerebrovascular injuries.


Assuntos
Células Epiteliais Alveolares/enzimologia , Isquemia Encefálica/enzimologia , Encéfalo/metabolismo , Neurônios/metabolismo , Ativação de Neutrófilo , Neutrófilos/metabolismo , Pneumonia/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Superóxido Dismutase/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/imunologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Imunidade Inata , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/patologia , Neutrófilos/imunologia , Pneumonia/enzimologia , Pneumonia/genética , Pneumonia/imunologia , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Transdução de Sinais , Superóxido Dismutase/genética
9.
Stroke ; 51(9): 2810-2816, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32811390

RESUMO

BACKGROUND AND PURPOSE: Identification of acute ischemic stroke (AIS) cause is crucial for guidance of secondary prevention. Previous studies have yielded inconsistent results regarding possible correlations between AIS cause and thrombus composition, as assessed by semiquantitative histological analysis. Here, we performed a correlation analysis between AIS cause and AIS thrombus cellular composition and content, as assessed using quantitative biochemical assays. METHODS: Homogenates of 250 patients with AIS thrombi were prepared by mechanical grinding. Platelet, red blood cell, and leukocyte content of AIS thrombi were estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. AIS cause was defined as cardioembolic, noncardioembolic, or embolic stroke of undetermined source, according to the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment). RESULTS: Cardioembolic thrombi were richer in DNA (35.8 versus 13.8 ng/mg, P<0.001) and poorer in GPVI (0.104 versus 0.117 ng/mg, P=0.045) than noncardioembolic ones. The area under the receiver operating characteristic curve of DNA content to discriminate cardioembolic thrombi from noncardioembolic was 0.72 (95% CI, 0.63-0.81). With a threshold of 44.7 ng DNA/mg thrombus, 47% of thrombi from undetermined cause would be classified as cardioembolic with a specificity of 90%. CONCLUSIONS: Thrombus DNA content may provide an accurate biomarker for identification of cardioembolic thrombi in patients with AIS with embolic stroke of undetermined source. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03268668.


Assuntos
Isquemia Encefálica/genética , DNA/genética , Embolia/genética , Cardiopatias/genética , Trombose Intracraniana/genética , Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Plaquetas/patologia , Isquemia Encefálica/sangue , Diagnóstico Diferencial , Embolia/complicações , Feminino , Cardiopatias/complicações , Humanos , Trombose Intracraniana/sangue , Trombose Intracraniana/etiologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Sensibilidade e Especificidade , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia
10.
Stroke ; 51(9): e238-e241, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32781942

RESUMO

BACKGROUND AND PURPOSE: Approximately 8% of Blacks have sickle cell trait (SCT), and there are conflicting reports from recent cohort studies on the association of SCT with ischemic stroke (IS). Most prior studies focused on older populations, with few data available in young adults. METHODS: A population-based case-control study of early-onset IS was conducted in the Baltimore-Washington region between 1992 and 2007. From this study, 342 Black IS cases, ages 15 to 49, and 333 controls without IS were used to examine the association between SCT and IS. Each participant's SCT status was established by genotyping and imputation. For analysis, χ2 tests and logistic regression models were performed with adjustment for potential confounding variables. RESULTS: Participants with SCT (n=55) did not differ from those without SCT (n=620) in prevalence of hypertension, previous myocardial infarction, diabetes mellitus, and current smoking status. Stroke cases had increased prevalence in these risk factors compared with controls. We did not find an association between SCT and early-onset IS in our overall population (odds ratio=0.9 [95% CI, 0.5-1.7]) or stratified by sex in males (odds ratio=1.26 [95% CI, 0.56-2.80]) and females (odds ratio=0.67 [95% CI, 0.28-1.69]). CONCLUSIONS: Our data did not find evidence of increased risk of early-onset stroke with SCT.


Assuntos
Isquemia Encefálica/epidemiologia , Isquemia Encefálica/genética , Traço Falciforme/epidemiologia , Traço Falciforme/genética , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Adolescente , Adulto , Afro-Americanos , Idade de Início , Baltimore/epidemiologia , Estudos de Casos e Controles , Complicações do Diabetes/epidemiologia , District of Columbia/epidemiologia , Feminino , Genótipo , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Resultados Negativos , Prevalência , Medição de Risco , Fumar/efeitos adversos , Adulto Jovem
11.
J Pharmacol Sci ; 144(2): 69-75, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32713799

RESUMO

The mechanism of the papaverine (PV) for the treatment of cerebral ischemia remains unclear. A total of 42 mice induced with focal cerebral ischemia were randomly divided into three groups: PV,baicalin (BA)and vehicle group. Both PV and BA could significantly reduce the ischemic infarct volume (P < 0.05). Pathway enrichment analysis was performed on MetaCore™ to search the molecular pathways associated with the gene expression profile of PV, compared with vehicle and BA. Compared with vehicle, we found that 60% of the top 10 pathways in PV group were related to immune response. The top 10 biological processes of the targeted pathways were mainly related to the multiple immunomodulatory process of neuro-vascular inflammation, including immune_Th17-deried cytokins, regulation of angiogenesis, cell adhesion_Leucocyte chemotaxis, antigen presentation, cell adhesion_synaptic contact, and inflammation related to Amphoterin signaling. Moreover, compared with BA, 17 pathways of PV were identified, and 58.82% (10/17) were also related to immune response, especially, half of the top 10 pathways with the lower p-value. In these top 10 pathways, 4 were the cytokine-mediated signaling pathways, which play key role in inflammation, like IL-17 signaling pathways with the activation of G-CSF,IL-23,RANKL, p38MAPK and NF-κB.These findings indicate that PV may be an efficacious pluripotent anti-inflammatory agent against cerebral ischemic-reperfusion injury by targeting on multiple immunomodulatory process of neuro-vascular inflammation.


Assuntos
Anti-Inflamatórios , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Fatores Imunológicos , Papaverina/farmacologia , Papaverina/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Inflamação , Interleucina-17/genética , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
12.
J Biol Regul Homeost Agents ; 34(3): 893-900, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32657103

RESUMO

Previous studies have shown that lncRNAs play crucial roles in cerebral ischemia/reperfusion injury. In this study, the function and possible mechanism of lncRNA HCP5 in cerebral ischemia/reperfusion injury was investigated. An oxygen glucose deprivation (OGD) model in N2a cells was used to simulate cerebral ischemia/reperfusion injury in vitro. The functional mechanism of lncRNA HCP5 was detected using Trypan blue staining, JC-1, MTT and dual luciferase reporter assays. The expression of apoptosis-related proteins (Bcl-2 and Bax) was measured by Western blot analysis. We found that lncRNA HCP5 was upregulated in N2a cells treated with OGD/R, and knockdown of lncRNA HCP5 enhanced cell viability and reduced cell death. In addition, miR-652-3p was found to act as a sponge for lncRNA HCP5. The overexpression of miR- 652-3p can prevent cerebral ischemic reperfusion injury, however, lncRNA HCP5 attenuated the protective effect of miR-652-3p in cerebral ischemic reperfusion injury. In conclusion, upregulation of lncRNA HCP5 may exacerbate cerebral ischemic reperfusion injury by sponging miR-652-3p.


Assuntos
Isquemia Encefálica , RNA Longo não Codificante/genética , Traumatismo por Reperfusão , Apoptose , Isquemia Encefálica/genética , Isquemia Encefálica/prevenção & controle , Humanos , MicroRNAs/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/prevenção & controle
13.
Stroke ; 51(8): 2514-2525, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32640942

RESUMO

BACKGROUND AND PURPOSE: Stroke is a major cause of chronic neurological disability. There is considerable interest in understanding how acute transcriptome changes evolve into subacute and chronic patterns that facilitate or limit spontaneous recovery. Here we mapped longitudinal changes in gene expression at multiple time points after stroke in mice out to 6 months. METHODS: Adult C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Longitudinal transcriptome levels were measured at 10 time points after stroke from acute to recovery phases of ischemic stroke. Localization and the number of mononuclear phagocytes were determined in the postischemic brain. Whole-mount brain imaging was performed in asplenic mice receiving GFP+ (green fluorescent protein)-tagged splenocytes. RESULTS: Sustained stroke-induced mRNA abundance changes were observed in both hemispheres with 2989 ipsilateral and 822 contralateral genes significantly perturbed. In the hemisphere ipsilateral to the infarct, genes associated with immune functions were strongly affected, including temporally overlapping innate and adaptive immunity and macrophage M1 and M2 phenotype-related genes. The strong immune gene activation was accompanied by the sustained infiltration of peripheral immune cells at acute, subacute, and recovery stages of stroke. The infiltrated immune cells were found in the infarcted area but also in remote regions at 2 months after stroke. CONCLUSIONS: The study identifies that immune components are the predominant molecular signatures and they may propagate or continuously respond to brain injury in the subacute to chronic phase after central nervous system injury. The study suggests a potential immune-based strategy to modify injury progression and tissue remodeling in ischemic stroke, even months after the initiating event.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/imunologia , Movimento Celular/fisiologia , Imunidade Celular/fisiologia , Recuperação de Função Fisiológica/fisiologia , Transcrição Genética/fisiologia , Animais , Isquemia Encefálica/genética , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Am J Physiol Cell Physiol ; 319(3): C579-C588, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32608990

RESUMO

Identification of specific biomarkers for ischemic stroke is necessary due to their abilities to improve treatment outcomes. Many studies have demonstrated the involvement of microRNAs (miRNAs) in the pathogenesis and complications of ischemic stroke and patient outcomes. We found that the expression of miR-874-3p was downregulated in clinical samples of ischemic stroke. Thus the present study explored the potential role of miR-874-3p in ischemic stroke and related mechanisms. A mouse model of ischemic stroke was constructed by middle cerebral artery occlusion. The relationship among miR-874-3p, C-X-C motif chemokine ligand 12 (CXCL12), and the Wnt/ß-catenin pathway was explored by dual luciferase reporter assay and Western blot analysis. Angiogenesis and brain tissue apoptosis were evaluated by immunofluorescence staining and TUNEL staining, respectively. ELISA was introduced to measure levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, IL-8, and IL-10 in brain tissues. Primary hippocampal neuronal cells were isolated from the mouse model of ischemic stroke and incubated with human umbilical vein endothelial cells (HUVECs) for HUVEC tube formation. High expression of CXCL12 and low expression of miR-874-3p were confirmed in ischemic stroke. In addition, miR-874-3p was found to target and downregulate CXCL12, thus reducing TNF-α, IL-1, IL-6, and IL-8 levels, but enhancing IL-10 level. Collectively, upregulating miR-874-3p inhibits CXCL12 expression to promote angiogenesis and inhibit inflammation in ischemic stroke mice by activating the Wnt/ß-catenin pathway, which may provide a new direction of ischemic stroke treatment.


Assuntos
Quimiocina CXCL12/metabolismo , Inflamação/metabolismo , MicroRNAs/genética , Acidente Vascular Cerebral/metabolismo , Animais , Apoptose/fisiologia , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Camundongos , Neurônios/metabolismo , Acidente Vascular Cerebral/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
15.
J Stroke Cerebrovasc Dis ; 29(8): 104874, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689633

RESUMO

INTRODUCTION: Previous studies have reported the involvement of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the inflammatory activation and pathophysiology of Ischemic Stroke (IS). Variations in genes encoding the constituent proteins of NLRP3 inflammasome can alter the risk of IS. OBJECTIVE: We investigated the role of the NLRP3 inflammasome in the pathogenesis of IS by establishing associations between combined polymorphisms of caspase recruitment domain-containing protein 8 (CARD8) rs2043211 and NLRP3 rs10754558 and the susceptibility to IS in a Chinese population. METHODS: Single nucleotide polymorphisms (SNPs) in CARD8 rs2043211 and NLRP3 rs10754558 were analyzed using TaqMan SNP genotyping assays in patients with IS (n=234) and healthy controls (n=115). Logistic regression analysis was carried out to evaluate potential interactions between CARD8 and NLRP3. RESULTS: Compared with healthy controls, there were no significant differences in the minor allele frequency (MAF) and the genotype frequency of NLRP3 rs10754558 or CARD8 rs2043211 in patients with IS(P>0.05). After stratification by gender, there was an increased risk for IS in men carrying heterozygous CARD8 rs2043211 when a co-dominant genetic model was applied (P=0.021, OR=3.83[1.22-12.03]). Logistic regression analysis indicated that men carrying both CARD8 rs2043211 AT and NLRP3 rs10754558 CG had a significantly higher risk of IS (P=0.046, OR=7.116[1.033-49.044]). CONCLUSIONS: Nucleotide variations in the genes encoding NLRP3 inflammasome proteins may be important to IS, and men carrying CARD8 rs2043211 and NLRP3 rs10754558, both heterozygous, confer a higher risk of IS.


Assuntos
Isquemia Encefálica/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etnologia , Estudos de Casos e Controles , China/epidemiologia , Feminino , Frequência do Gene , Interação Gene-Ambiente , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Fenótipo , Medição de Risco , Fatores de Risco , Fatores Sexuais , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etnologia
16.
Biochem Biophys Res Commun ; 528(3): 413-419, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32513532

RESUMO

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.


Assuntos
Betacoronavirus/metabolismo , Isquemia Encefálica/virologia , Encéfalo/irrigação sanguínea , Diabetes Mellitus , Peptidil Dipeptidase A/biossíntese , Receptores Virais/biossíntese , Fumantes , Acidente Vascular Cerebral/virologia , Regulação para Cima , Animais , Betacoronavirus/patogenicidade , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ratos , Ratos Sprague-Dawley , Receptores Virais/genética , Fumaça/efeitos adversos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
Am J Physiol Cell Physiol ; 319(2): C381-C391, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32491927

RESUMO

Several microRNAs (miRNAs or miRs) regulate cerebral ischemic injury outcomes; however, little is known about the role of miR-539-5p during cerebral ischemic injury or the postischemic state. Cerebral ischemic injury was modeled in vitro by exposing human cortical neurons to oxygen-glucose deprivation (OGD) and in vivo by occluding the middle cerebral artery (MCAO) in a rat model. The effects of miR-539-5p, histone deacetylase 1 (HDAC1), and early growth response 2 (EGR2) on cerebral ischemia were investigated using gain- and loss-of-function experiments. We identified changes in miR-539-5p, HDAC1, EGR2, and phosphorylated c-Jun NH2-terminal kinase (JNK). The interaction among miR-539-5p, HDAC1, and EGR2 was determined by dual luciferase reporter gene assay, chromatin immunoprecipitation, and coimmunoprecipitation. We also investigated the effects on cell viability and apoptosis and changes in inflammatory cytokine expression and spatial memory on MCAO rats. miR-539-5p and EGR2 were poorly expressed, while HDAC1 was highly expressed in OGD-treated HCN-2 cells. miR-539-5p targeted HDAC1, while HDAC1 prevented acetylation of EGR2 resulting in its downregulation and subsequent activation of the JNK pathway. Overexpression of miR-539-5p or EGR2 or silencing HDAC1 improved viability and reduced apoptosis of OGD-treated HCN-2 cells in vitro. Furthermore, overexpression of miR-539-5p improved spatial memory, while decreasing cell apoptosis and inflammation in MCAO rats. Collectively, these data suggest that miR-539-5p targets HDAC1 to upregulate EGR2, thus blocking the JNK signaling pathway, by which cerebral ischemic injury is alleviated.


Assuntos
Isquemia Encefálica/genética , Histona Desacetilase 1/genética , MicroRNAs/genética , Animais , Apoptose/genética , Isquemia Encefálica/patologia , Citocinas/metabolismo , Progressão da Doença , Proteína 2 de Resposta de Crescimento Precoce/genética , Regulação da Expressão Gênica/genética , Glucose/metabolismo , Humanos , Inflamação/genética , Artéria Cerebral Média/lesões , Artéria Cerebral Média/patologia , Neurônios/metabolismo , Neurônios/patologia , Ratos
19.
Neurology ; 95(9): e1153-e1162, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32576634

RESUMO

OBJECTIVE: To determine whether mean platelet volume (MPV) and selected single nucleotide polymorphisms (SNPs) that have been associated with MPV in genome-wide association studies relate to stroke severity, functional outcome on discharge, and 1-year mortality in patients with ischemic stroke, we retrospectively analyzed 577 patients with first-ever ischemic stroke. METHODS: Genotyping of 3 SNPs (rs342293, rs1354034, rs7961894) was performed using a real-time PCR allelic discrimination assay. Multivariable regression was used to determine the association of MPV and MPV-associated SNPs with the NIH Stroke Scale (NIHSS) score on admission, modified Rankin Scale score on discharge, and data on 1-year mortality. RESULTS: Rs7961894, but not rs342293 or rs1354034 SNP, was independently associated with an MPV in the highest quartile (MPV Q4). MPV Q4 was associated with significantly greater admission NIHSS (p = 0.006), poor discharge outcome (p = 0.034), and worse 1-year mortality (p = 0.033). After adjustment for pertinent covariates, MPV Q4 remained independently associated with a greater admission NIHSS score (p = 0.025). The T>C variant of rs7961894 SNP was an independent marker of a lower 1-year mortality (hazard ratio, 0.30; 95% confidence interval, 0.13-0.70; p = 0.006) in the studied population. CONCLUSION: MPV is a marker of stroke severity and T>C variant of rs7961894 is independently associated with greater MPV in acute phase of ischemic stroke and relates to decreased 1-year mortality after stroke.


Assuntos
Isquemia Encefálica/sangue , Volume Plaquetário Médio , Acidente Vascular Cerebral/sangue , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/genética , Isquemia Encefálica/fisiopatologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Índice de Gravidade de Doença , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologia
20.
Adv Clin Exp Med ; 29(6): 649-659, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32558399

RESUMO

BACKGROUND: Ischemia/reperfusion (I/R) refers to situations where blood is perfused into ischemic or hypoxic tissues, potentially resulting in an inflammatory response and oxidative injury. OBJECTIVES: This study was conducted to explore the pathogenesis of I/R injury. MATERIAL AND METHODS: GSE82146 was extracted from the Gene Expression Omnibus, consisting of 15 complete global brain ischemia (CGBI) reperfusion hippocampus samples and 12 non-ischemic control (NIC) hippocampus samples. The differentially expressed genes (DEGs) between the CGBI and NIC samples were selected using LIMMA package, and were then analyzed with weighted gene co-expression network analysis (WGCNA). Using DAVID software, the DEGs in significant modules were run through enrichment analysis. The DEGs in significant modules were merged, and then a protein-protein interaction (PPI) network was built for them using Cytoscape software. After miRNAs and transcription factors (TFs) were predicted for the DEGs using the WebGestalt tool, a TF-miRNA-target regulatory network was built using Cytoscape software. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was conducted to detect the levels of key genes. RESULTS: There were 390 DEGs in the CGBI samples. Based on WGCNA, brown and turquoise modules were screened as CGBI-associated modules. In the PPI network, key nodes HSP90AA1 and HSPA5 were able to interact with each other. In the regulatory network, MYC, HSF1 and miR-22 had higher degree values. Moreover, HSPA5 was targeted by MYC in the regulatory network. In addition, upregulated HSPB1 and HMOX1, as well as downregulated NR4A2, were confirmed with qRT-PCR analysis. CONCLUSIONS: HSPB1, HMOX1 and NR4A2 were the key genes correlated with I/R injury. Additionally, HSP90AA1, HSPA5, MYC, HSF1, and miR-22 might be related to the pathogenesis of I/R injury.


Assuntos
Isquemia Encefálica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/genética , Biologia Computacional , MicroRNAs/genética , Ratos , Traumatismo por Reperfusão/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...