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1.
J Biomed Nanotechnol ; 15(12): 2401-2412, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748020

RESUMO

Ischemic strokes are caused by decreased blood flow into the brain, due to narrowed cerebral arteries. In the ischemic brain, high-mobility group box 1 (HMGB1) is released into extracellular spaces and induces inflammatory reactions. In this study, HMGB1 small interfering RNA (siRNA) was delivered into ischemic brains by intravenous administration using rabies virus glycoprotein (RVG) peptide-decorated exosomes. A fusion protein of RVG and Lamp2b was expressed in 293T cells. Since Lamp2b is an exosome membrane-integral protein, RVG-Lamp2b is integrated into the exosomes, producing RVG-decorated exosomes (RVG-Exo). HMGB1-siRNA was loaded into RVG-Exo and unmodified exosomes (Unmod-Exo) by electroporation. The exosomes were homogenous with a size of less than 50 nm and a negative surface charge. In vitro delivery assays showed that RVG-Exo showed higher efficiency to Neuro2A cells than Unmod-Exo. Also, HMGB1 levels were reduced more effectively by RVG-Exo/HMGB1-siRNA. In vivo delivery efficiency and therapeutic effects of RVG-Exo/HMGB1-siRNA were evaluated in a middle cerebral artery occlusion (MCAO) model. RVG-Exo/HMGB1-siRNA, Unmod-Exo/HMGB1-siRNA, and PEI25k/HMGB1-siRNA were administrated into the MCAO model intravenously through the tail vein. The results showed that HMGB1, tumor necrosis factor-α (TNF-α), and apoptosis levels in the brain were reduced in the RVG-Exo/HMGB1-siRNA group more efficiently than the other groups. In addition, the infarct size was decreased in the RVG-Exo/HMGB1 group more effectively than the other groups. These results suggest that RVG-Exo with HMGB1-siRNA may have potential as a therapeutic system for the treatment of ischemic strokes.


Assuntos
Isquemia Encefálica , Exossomos , Proteína HMGB1/genética , Acidente Vascular Cerebral , Encéfalo , Isquemia Encefálica/genética , Isquemia Encefálica/terapia , Humanos , RNA Interferente Pequeno , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/terapia
2.
Medicine (Baltimore) ; 98(43): e17438, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651847

RESUMO

Recent genome-wide association studies (GWAS) indicated that polymorphisms in ADAMTS7 were associated with artery disease caused by atherosclerosis. However, the correlation between the ADAMTS7 polymorphism and plaque stability remains unclear. The objective of this study was to evaluate the association between 2 ADAMTS7 variants rs3825807 and rs7173743 and ischemic stroke or atherosclerotic plaque vulnerability.This research is an observational study. Patients with ischemic stroke and normal control individuals admitted to Beijing Tiantan Hospital from May 2014 to October 2017 were enrolled. High-resolution magnetic resonance imaging was used to distinguish vulnerable and stable carotid plaques. The ADAMTS7 SNPs were genotyped using TaqMan assays on real-time PCR system. The multivariate logistic regression analyses were used to adjust for multiple risk factors between groups.Three hundred twenty-six patients with ischemic stroke (189 patients with vulnerable plaque and 81 patients with stable plaque) and 432 normal controls were included. ADAMTS7 polymorphisms of both rs7173743 and rs3825807 were associated with carotid plaque vulnerability but not the prevalence of ischemic stroke. The T/T genotype of rs7173743 [odds ratio (OR) = 1.885, 95% confidence interval (CI) = 1.067-3.328, P = .028] and A/A genotype of rs3825807 (OR = 2.146, 95% CI = 1.163-3.961, P = .013) were considered as risk genotypes for vulnerable plaque susceptibility.In conclusion, ADAMTS7 variants rs3825807 and rs7173743 are associated with the risk for carotid plaque vulnerability.


Assuntos
Estenose das Carótidas/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética , Proteína ADAMTS7/sangue , Estenose das Carótidas/epidemiologia , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia
3.
Adv Exp Med Biol ; 1193: 195-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368105

RESUMO

Cerebral stroke is one of the leading causes of mortality and disability worldwide. The prevalence of cerebral stroke is the result of the synergistic effect of genetic susceptibility and numerous vascular risk factors, including hypertension, diabetes, excessive alcohol intake, obesity, and dyslipidemia. Mitochondrial aldehyde dehydrogenase (ALDH2) is a vital enzyme metabolizing various acetaldehyde and toxic aldehydes. The ALDH2 enzymatic activity is severely decreased in the individuals with ALDH2*2 gene mutation, especially in East Asians. Increasing epidemiological surveys have revealed that ALDH2 genetic polymorphism is closely associated with the increasing incidence of cardiovascular risk factors and cerebral stroke. Evidence from experimental studies has also suggested that ALDH2 facilitates the clearance of reactive aldehydes and reduces the size of cerebral infarct. Therefore, targeting ALDH2 may represent a promising avenue for protection against stroke injury. This review will mainly focus on clinical and epidemiological evidence and the underlying molecular mechanisms involved in the protective effect of ALDH2 in stroke-related injury.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Acidente Vascular Cerebral/genética , Predisposição Genética para Doença , Humanos , Polimorfismo Genético
4.
Medicine (Baltimore) ; 98(29): e16457, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335702

RESUMO

The impact of genetic polymorphisms on the occurrence of recurrent ischemic stroke (RIS) is not fully understood. This study was aimed to examine the relationships among the 106PEAR1 and 168PTGS1 polymorphisms and RIS.This was a single-center, retrospective, case-control study of patients seen in consultation between March 2016 and December 2016 at the Shandong Provincial Hospital. The 106PEAR1 (G>A) and 168PTGS1 (-842A>G) polymorphisms were determined by fluorescence in situ hybridization.There were 56 patients with RIS and 137 with initial stroke. Compared with the initial group, the RIS group showed lower LDL-C levels (P = .04). 168PTGS1 (-842A>G) did not meet the Hardy-Weinberg equilibrium. The AA genotype of the 106PEAR1 (G>A) polymorphism was more frequent in the RIS group (17.9% vs 5.8%, P = .009). The A allele also showed a higher frequency than the G allele in the RIS group (P = .02). The multivariable logistic regression analysis showed that 106PEAR1 (G>A) (OR = 3.24, 95%CI: 1.04-10.14, P = .04) and lipid-lowering agents (OR = 9.18, 95%CI: 4.48-18.84, P < .001) were independently associated with RIS.The polymorphism at 106PEAR1 (G>A) was independently associated with RIS in Chinese patients. The assessment of genetic polymorphisms in the prediction of RIS warrants further investigation in order to improve patient management and prognosis after a first ischemic stroke.


Assuntos
Isquemia Encefálica , Ciclo-Oxigenase 1/genética , Receptores de Superfície Celular/genética , Acidente Vascular Cerebral , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Recidiva , Estudos Retrospectivos , Medição de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética
5.
Rev Assoc Med Bras (1992) ; 65(6): 772-774, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31340302

RESUMO

The essential thrombocythemia is one of the seven described forms of myeloproliferative neoplasms. It is characterized by megakaryocytic hyperplasia with consequent thrombocytosis maintained in the peripheral blood, favoring the occurrence of thrombo-hemorrhagic phenomena. We present the case of an 81-year-old woman with a history of ischemic stroke in the context of a sustained thrombocytosis, which led to a spinal study and a search for the V617F mutation in the JAK2 gene, which was positive. The patient started cytoreductive therapy with hydroxyurea with favorable current evolution.


Assuntos
Acidente Vascular Cerebral/etiologia , Trombocitemia Essencial/complicações , Idoso de 80 Anos ou mais , Feminino , Humanos , Janus Quinase 2/genética , Mutação , Fatores de Risco , Acidente Vascular Cerebral/genética , Trombocitemia Essencial/genética
6.
Yonsei Med J ; 60(7): 659-666, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250580

RESUMO

PURPOSE: To investigate associations for polymorphisms in ß-carotene 9',10'-oxygenase (BCO2, rs10431036 and rs11214109), proprotein convertase subtilisin kexin type 9 (PCSK9, rs11583680), and tribbles pseudokinase 1 (TRIB1, rs17321515 and rs2954029), as well as lifestyle factors, with ischemic stroke (IS). MATERIALS AND METHODS: This nested case-control study included 161 patients with IS and 483 matched control individuals. We collected medical reports, lifestyle details, and blood samples from individuals and used the PCR-ligase detection reaction method to genotype single nucleotide polymorphisms (SNPs). RESULTS: The GA+AA genotype of rs10431036 (p<0.001) and rs17321515 (p=0.003), the CT+TT genotype of rs11214109 (p=0.005), and the TA+AA genotype of rs2954029 (p=0.006) in dominant models increased the risk of IS. In additive models, the GG genotype of rs17321515 (p=0.005) and the TT genotype of rs2954029 (p=0.008) increased the risk of IS. Adequate intake of fruits/vegetables reduced the risk of IS (p=0.005). Although there was no interaction between genes and fruits/vegetables, people with inadequate intake of fruits/vegetables who carried a risk genotype had a higher risk of IS than those only having inadequate fruits/vegetables intake or those only carrying a risk genotype. Also, the haplotypes AC, AT, and GT (comprising rs10431036 and rs11214109) and GT (comprising rs2954029 and rs17321515) were found to be associated with an increased risk of IS (p<0.05). CONCLUSION: Polymorphisms in BCO2 and TRIB1 and fruits/vegetables intake were associated with IS. These results provide the theoretical basis for gene screening to prevent chronic cerebrovascular diseases.


Assuntos
Isquemia Encefálica/complicações , Dioxigenases/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estilo de Vida , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Acidente Vascular Cerebral/genética , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Acidente Vascular Cerebral/complicações
7.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(3. Vyp. 2): 11-17, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184620

RESUMO

To study the interaction of polymorphic markers of matrix metalloproteinases (MMP) and chronic stress in the development of stroke associated with hypertension. MATERIAL AND METHODS: A total of 830 patients, including 303 patients with ischemic stroke associated with essential hypertension (EH) and 527 patients with EH without stroke, were examined. The study of metalloproteinases SNP was carried out using real-time PCR. The functional significance and influence of polymorphic loci on gene expression was studied using of HaploReg (v4.1) (http://archive.broadinstitute.org) and GTEx-portal (http://www.gtexportal.org). RESULTS AND CONCLUSION: An association of the genotype GG (rs11568818) of MMP7 with a high risk of stroke in patients exposed to regular stress (OR=1.71) was observed. It was found that allele 5A and genotype 5A/5A (rs3025058) of MMP3 had a protective effect on the development of stroke in patients without regular stress in the anamnesis (OR=0.73 and OR=0.60, respectively). Those SNPs are localized in the region of histone proteins H3K4me1 and H3K4me3, in the region of hypersensitivity to DNase-1, in the region of binding of regulatory proteins and transcription factors. The polymorphic locus rs11568818 is associated with the expression level of MMP7.


Assuntos
Predisposição Genética para Doença , Acidente Vascular Cerebral , Estudos de Casos e Controles , Hipertensão Essencial , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética
8.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(3. Vyp. 2): 18-23, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184621

RESUMO

AIM: To study genetic characteristics of the population of the Moscow region and analyze the association of rs1801133 and rs1801131 of MTHFR with the risk of ischemic stroke (IS). MATERIAL AND METHODS: A sample of 170 and 115 patients with atherothrombotic and cardioembolic subtypes of IS and 360 residents of the Moscow region without IS were examined. MTHFR alleles were determined by a multiplex real-time polymerase chain reaction. RESULTS AND CONCLUSION: No association between the frequencies of MTHFR alleles and the risk of ischemic stroke was found. The comparison of allele frequencies with those in Caucasian populations published in the dbSNP (NCBI) and 1000 Genomes Project databases revealed significant differences for rs1801133 from the EUR 1000 Genomes Project. The allele frequency data for MTHFR could increase the accuracy and reliability of the individual risk calculation for multifactorial diseases in the Russian population.


Assuntos
Isquemia Encefálica , Predisposição Genética para Doença , Acidente Vascular Cerebral , Isquemia Encefálica/genética , Frequência do Gene , Genoma Humano , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Moscou , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Federação Russa , Acidente Vascular Cerebral/genética
9.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(3. Vyp. 2): 62-67, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184626

RESUMO

To study the association between polymorphic markers in the ACE, SERPINE1, FGB, F5, F7, F12, GP1BA, GPIIIa, MTHFR, CYP11B2, PON1, PON2, NOS2, NOS2, HIFla, LTA, ALOX5AP genes and clinical characteristics of acute and chronic forms of circulatory disorders of the brain. MATERIAL AND METHODS: The analysis of polymorphic variants in ACE, FGB, F5, F7, F12, GP1BA, GPIIIa, SERPINE1, MTHFR, CYP11B2, PON1, PON2, NOS2, NOS3, PDE4D, HIF1a, LTA, ALOX5AP in 81 patients with chronic cerebral ischemia (CCI) and 69 patients with ischemic stroke (IS), and their interrelation with clinical manifestations of disease were investigated. RESULTS AND CONCLUSION: The association between the T/T genotype of the PDE4D SNP 83C>T polymorphism and a rapid progression of hypertensive disease (GB) was revealed (OR=6.22, CI=1.86-20.79, p=0.0036) in the group of patients with CCI. The association of the allele D and the DD genotype of the ACE (I>D, rs1799752) with cardioembolic stroke (OR=2.67, 95% CI=1.23-5.8, p=0.02 and OR=7.14, 95% CI=1.72-29.69, p=0.0057) was found. When comparing subgroups of patients with different degrees of stenosis of brachiocephalic arteries (BCA), the association of the allele C and the TC genotype of the GP1BA (rs2243093, -5T/C) with BCA occlusion and expressed hemodynamically significant stenosis (>75%) was revealed (OR=3.39, 95% CI=1.12-10.25, p=0.03 and OR=4.44, 95% CI=1.27-15.54, p=0.023, respectively). Thus, polymorphic markers in PDE4D, ACE, GP1BA in combination with certain clinical characteristics are risk factors for the progression of CCI and development of IS.


Assuntos
Isquemia Encefálica , Predisposição Genética para Doença , Polimorfismo Genético , Acidente Vascular Cerebral , Arildialquilfosfatase/genética , Isquemia Encefálica/genética , Marcadores Genéticos , Testes Genéticos , Genótipo , Humanos , Fatores de Risco , Acidente Vascular Cerebral/genética
10.
Int J Mol Sci ; 20(12)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200484

RESUMO

Ischemic penumbra that surrounds a stroke-induced infarction core is potentially salvageable; however, mechanisms of its formation are not well known. Covalent modifications of histones control chromatin conformation, gene expression and protein synthesis. To study epigenetic processes in ischemic penumbra, we used photothrombotic stroke (PTS), a stroke model in which laser irradiation of the rat brain cortex photosensitized by Rose Bengal induces local vessel occlusion. Immunoblotting and immunofluorescence microscopy showed decrease in acetylation of lysine 9 in histone H3 in penumbra at 1, 4 or 24 h after PTS. This was associated with upregulation of histone deacetylases HDAC1 and HDAC2, but not HDAC4, which did not localize in the nuclei. HDAC2 was found in cell nuclei, HDAC4 in the cytoplasm and HDAC1 both in nuclei and cytoplasm. Histone acetyltransferases HAT1 and PCAF (p300/CBP associated factor) that acetylated histone H3 synthesis were also upregulated, but lesser and later. PTS increased localization of HDAC2 and HAT1 in astroglia. Thus, the cell fate in PTS-induced penumbra is determined by the balance between opposite tendencies leading either to histone acetylation and stimulation of gene expression, or to deacetylation and suppression of transcriptional processes and protein biosynthesis. These epigenetic proteins may be the potential targets for anti-stroke therapy.


Assuntos
Córtex Cerebral/metabolismo , Epigênese Genética , Histona Acetiltransferases/metabolismo , Código das Histonas , Histona Desacetilases/metabolismo , Trombose Intracraniana/genética , Acidente Vascular Cerebral/genética , Acetilação , Animais , Histona Acetiltransferases/genética , Histona Desacetilases/genética , Histonas/genética , Histonas/metabolismo , Trombose Intracraniana/complicações , Trombose Intracraniana/metabolismo , Masculino , Ratos , Ratos Wistar , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Regulação para Cima
11.
Dis Markers ; 2019: 2193835, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191743

RESUMO

Large artery atherosclerotic stroke (LAAS) is the most common ischemic stroke (IS) subtype, and microemboli may be clinically important for indicating increased risk of IS. The inflammatory process of atherosclerosis is well known, and lymphoid phosphatase (Lyp), which is encoded by the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene, plays an important role in the inflammatory response. Our study was intended to evaluate the relationship between PTPN22 gene and LAAS and microembolic signals (MES). Three loci of the PTPN22 gene (rs2476599, rs1217414, and rs2488457) were analyzed in 364 LAAS patients and 369 control subjects. A genotyping determination was performed using the TaqMan assay. The G allele of rs2488457 might be related to a higher risk for developing LAAS and MES (odds ratio (OR) = 1.456, 95% confidence interval (CI) 1.156-1.833, P = 0.001; OR = 1.652, 95% CI 1.177-2.319, P = 0.004, respectively). In the LAAS group, the prevalence of the GTG haplotype was higher (P < 0.001) and the prevalence of the GCC haplotype was lower (P = 0.001). An interaction analysis of rs2488457 with smoking showed that smokers with the CG/GG genotypes had a higher risk of LAAS, compared to nonsmokers with the rs2488457 CC genotype (OR = 2.492, 95% CI 1.510-4.114, P < 0.001). Our research indicated that the PTPN22 rs2488457 might be related to the occurrence of LAAS and MES in the Han Chinese population. In addition, the rs2488457 polymorphism and the environmental factor of smoking jointly influenced the susceptibility of LAAS.


Assuntos
Arteriosclerose Intracraniana/genética , Embolia Intracraniana/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Acidente Vascular Cerebral/genética , Idoso , Artérias Carótidas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/epidemiologia
12.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146325

RESUMO

Methylmalonic aciduria (MMA-uria) is seen in several inborn errors of metabolism (IEM) affecting intracellular cobalamin pathways. Methylmalonyl-CoA epimerase (MCE) is an enzyme involved in the mitochondrial cobalamin-dependent pathway generating succinyl-CoA. Homozygous mutations in the corresponding MCEE gene have been shown in children to cause MCE deficiency with isolated MMA-uria and a variable clinical phenotype. We describe a 78-year-old man with Parkinson's disease, dementia and stroke in whom elevated serum levels of methylmalonic acid had been evident for many years. Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin. Whole genome sequencing was performed, with data analysis targeted towards genes known to cause IEM. Compound heterozygous mutations were identified in the MCEE gene, c.139C>T (p.Arg47X) and c.419delA (p.Lys140fs), of which the latter is novel. To our knowledge, this is the first report of an adult patient with MCEE mutations and MMA-uria, thus adding novel data to the possible phenotypical spectrum of MCE deficiency. Although clinical implications are uncertain, it can be speculated whether intermittent hyperammonemia during episodes of metabolic stress could have precipitated the patient's ongoing neurodegeneration attributed to Parkinson's disease.


Assuntos
Demência/genética , Erros Inatos do Metabolismo/genética , Ácido Metilmalônico/sangue , Doença de Parkinson/genética , Fenótipo , Racemases e Epimerases/genética , Acidente Vascular Cerebral/genética , Idoso , Demência/complicações , Demência/patologia , Humanos , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/patologia , Mutação , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Racemases e Epimerases/deficiência , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia
13.
Artif Cells Nanomed Biotechnol ; 47(1): 1384-1395, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31174432

RESUMO

lncRNA ANRIL was reported to be closely related to ischaemic stroke (IS). In this study, we used oxygen-glucose deprivation (OGD) to stimulate rat adrenal medulla-derived pheochromocytoma cell line PC-12 to construct an in vitro IS cell model and investigated the role of ANRIL and the underlying mechanism. PC-12 cells were stimulated by OGD and/or transfected with pc-ANRIL, si-ANRIL, miR-127 mimic, miR-127 inhibitor, pEX-Mcl-1, sh-Mcl-1 and their negative controls. Cell viability, apoptosis, mRNA and protein expression was detected using CCK-8 assay, flow cytometry assay, qRT-PCR and western blot, respectively. Results showed that OGD-induced PC-12 cell injury and decreased ANRIL expression. ANRIL overexpression significantly reduced OGD-induced PC-12 cell injury evidenced by increasing cell viability and decreasing apoptosis, while ANRIL silence led to the opposite results. Meanwhile, dysregulation of ANRIL altered the expression of apoptotic proteins. Furthermore, ANRIL negatively regulated miR-127 expression. miR-127 overexpression significantly enhanced OGD-induced PC-12 cell injury. In addition, Mcl-1 expression was negatively regulated by miR-127, besides ANRIL up-regulated Mcl-1 expression by down-regulation of miR-127. Mcl-1 overexpression alleviated cell injury and miR-127 silence up-regulated Mcl-1 expression. In conclusion, lncRNA ANRIL alleviated OGD-induced PC-12 cell injury as evidenced. PI3K/AKT pathway might be involved in this regulating progression.


Assuntos
Isquemia Encefálica/complicações , Glucose/metabolismo , Oxigênio/metabolismo , RNA Longo não Codificante/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Animais , Regulação para Baixo/genética , MicroRNAs/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/genética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia
14.
Lipids Health Dis ; 18(1): 110, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077198

RESUMO

Genome-wide association study (GWAS) identified chromosome 12p13 rs12425791 and rs11833579 as susceptibility loci of ischemic stroke (IS) in a European population. However, conflicting results were obtained in subsequent replication analysis. miR-200c, located on chromosome 12p13, was found to have a neuroprotective effect on ischemia. Our aim of this study was to investigate the association of the rs12425791, rs11833579 and rs12904 in the binding site of miR-200c with the risk of IS. The rs12425791, rs11833579, and rs12904 were genotyped using a TaqMan allelic discrimination assay. The results were verified by Sanger sequencing. We found that the rs12904 AG/GG genotypes and G allele were associated with a decreased risk of IS (AG/GG vs. AA: adjusted OR = 0.64; 95% CI, 0.44-0.95; G vs. A: adjusted OR = 0.65; 95% CI, 0.46-0.93). The combined genotypes of the rs11833579AG/AA and rs12904AG/GG were also associated with a reduced risk of IS (OR = 0.65; 95% CI, 0.46-0.93). These findings suggest that the rs12904 may have a jointly protective effect against the risk of IS.


Assuntos
Isquemia Encefálica/genética , Predisposição Genética para Doença , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética , Sítios de Ligação , Cromossomos Humanos Par 12/genética , Feminino , Estudo de Associação Genômica Ampla , Haplótipos/genética , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Fatores de Risco
15.
Hum Cell ; 32(3): 316-325, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31127489

RESUMO

Cerebrovascular smooth muscle cell proliferation is the major contributor to cerebrovascular remodeling and stroke. Chloride channels have been suggested to play an important role in the regulation of smooth muscle cell proliferation. This study aims to investigate the effect of leucine-rich repeat-containing 8A (LRRC8A), an essential component of volume-sensitive chloride channels, on cerebrovascular smooth muscle cell proliferation. The data showed that LRRC8A expression was increased in mouse brain artery during angiotensin II (AngII)-induced cerebrovascular remodeling. Similarly, AngII also increased the expression of LRRC8A in human brain vascular smooth muscle cells (HBVSMCs). Knockdown of LRRC8A by siRNA significantly inhibited AngII-induced the proliferation, migration, and invasion in HBVSMCs. The inhibition of HBVSMCs proliferation by LRRC8A downregulation appeared to be involved in suppression of cell-cycle transition. AngII-induced the decrease in p21 and p27 expression and the increase in CDK4 and cyclin D1 expression were attenuated by LRRC8A downregulation. Moreover, inhibition of LRRC8A suppressed AngII-induced PI3K/AKT activation and reactive oxygen species generation, but had no effect on JNK, ERK, and p38 phosphorylation. In addition, activation of PI3K/AKT-signaling pathways with specific agonists significantly abolished the effect of LRRC8A deficiency on HBVSMC proliferation. This present study demonstrates that knockdown of LRRC8A ameliorates AngII-induced cerebrovascular smooth muscle cell proliferation via inhibiting PI3K/AKT pathway, suggesting that LRRC8A may be a novel molecular target in the treatment of vascular remodeling and stroke.


Assuntos
Angiotensina II/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/terapia , Remodelação Vascular
16.
Mol Med Rep ; 20(1): 735-744, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115561

RESUMO

The present study aimed to ascertain the potential roles and mechanisms of action of micro (mi)RNA­22 in ischemic stroke. The results indicated that miRNA­22 expression was downregulated in ischemic stroke rats model, compared with a control group. The downregulation of miRNA­22 upregulated the expression of inflammatory factors [including tumor necrosis factor­α, interleukin (IL)­1ß, IL­6 and IL­18]. It could also induce the expression of macrophage inflammatory protein (MIP­2), prostaglandin E2 (PGE2), cyclooxygenase­2 (COX­2) and inducible NO synthase (iNOS) in the in vitro model. By contrast, the overexpression of miRNA­22 downregulated the expression of inflammatory factors, and suppressed the expression of MIP­2, PGE2, COX­2 and iNOS in the in vitro model. The downregulation of miRNA­22 induced the protein expression of nuclear factor (NF)­κB and phosphorylated­p38 (p­p38) mitogen­activated protein kinase (MAPK) in the in vitro model. By comparison, the overexpression of miRNA­22 suppressed the protein expression of NF­κB and p­p38 in the in vitro model. Typically, LY2228820, the p38 inhibitor (3 nM) would mitigate the pro­inflammatory effects of anti­miRNA­22 in the in vitro model. These results suggested that miRNA­22 can alleviate ischemic stroke­induced inflammation in rats model or vitro model through p38 MAPK/NF­κB pathway suppression.


Assuntos
Isquemia Encefálica/genética , Inflamação/genética , MicroRNAs/genética , Acidente Vascular Cerebral/genética , Animais , Isquemia Encefálica/patologia , Ciclo-Oxigenase 2/genética , Dinoprostona/genética , Humanos , Imidazóis/farmacologia , Inflamação/patologia , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/patologia , Fator de Necrose Tumoral alfa/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
17.
J Stroke Cerebrovasc Dis ; 28(7): 1860-1865, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31064695

RESUMO

BACKGROUND AND PURPOSE: Previous studies have shown that common variants within CYP3A4 and CYP3A5 are associated with statin pharmacokinetics and the risk of cardiovascular disease. However, the association of variants in CYP3A4 and CYP3A5 with the prognosis of ischemic stroke remains undetermined. Therefore, we investigated this herein. METHODS: Four hundred thirty-three consecutive patients with acute ischemic stroke were recruited. The outcome at the 1-year follow-up was assessed using the modified Rankin Scale (mRS). Two variants, CYP3A4*1G and CYP3A5*3, were genotyped by the improved Multiple Ligase Detection Reaction platform. RESULTS: Binary logistic regression analysis showed that the CYP3A4*1G/*1G homozygote was associated with poor outcome at 1 year (mRS score ≥2) after adjustment for conventional factors in the additive model (odds ratio [OR] = 2.92; 95% confidence interval, 1.07-7.98; P = .037) and recessive model (OR = 3.37; 95% confidence interval, 1.26-9.04; P = .016). Subgroup analysis indicated that the CYP3A4*1G/*1G homozygote was associated with poor prognosis at 1 year among patients with stable high-intensity atorvastatin therapy (40-80 mg/d) after adjustment for conventional factors in the additive model (OR = 8.16; 95% confidence interval, 1.50-44.44; P = .015) and recessive model (OR = 9.06; 95% confidence interval, 1.72-47.64; P = .009). No significant association was identified between CYP3A5*3 and the 1-year outcome of patients with ischemic stroke. CONCLUSIONS: Our study findings suggest that the CYP3A4*1G/CYP3A4*1G genotype may be associated with poor prognosis at 1 year after acute ischemic stroke in the Han Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/genética , Citocromo P-450 CYP3A/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Atorvastatina/administração & dosagem , Atorvastatina/farmacocinética , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/enzimologia , Isquemia Encefálica/etnologia , China/epidemiologia , Citocromo P-450 CYP3A/metabolismo , Avaliação da Deficiência , Feminino , Frequência do Gene , Homozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Prevenção Secundária/métodos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/etnologia , Fatores de Tempo , Resultado do Tratamento
18.
J Biomed Sci ; 26(1): 27, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999900

RESUMO

BACKGROUND: Promoting post-stroke neurogenesis has long been proposed to be a therapeutic strategy for the enhancement of functional recovery after cerebral ischemic stroke. Despite numerous approaches have been widely reported the proliferation or differentiation of the neurogenic population therapeutic strategies by targeting adult neurogenesis not yet to be successfully clarified in clinical settings. Here, we hypothesized that alterations in microenvironment of the ischemic brain might impede the functional maturation of adult newly generated neurons that limits functional recovery after stroke. METHODS: The in vivo retroviral based labeling model was applied to directly birth-date and trace the maturation process of adult newly generating neurons after hypoxic challenge. A rehabilitation therapy procedure was adopted through the combination of task-specific motor rehabilitating training with environmental enrichment to promote functional recovery after stroke. In addition, a pharmacological or genetic suppression of HDAC6 was performed to evaluate the functional significance of HDAC6 in the pathology of ischemic stroke induced deficits. RESULTS: Serial morphological analyses at multiple stages along the maturation process showed significant retardation of the dendritic maturation on the newly generated neurons after stroke. Subsequent biochemical analyses revealed an aberrant nuclear translocation of HDAC6 that leads to the hyper-acetylation of α-tubulin (an indication of over-stabilized microtubules) after hypoxic challenge was observed at different time points after stroke. Furthermore, the mimicry experiments with either pharmacological or genetic suppression of HDAC6, phenocopied the stroke induced retardation in dendritic maturation of newly generating neurons in vivo. More importantly, we provide direct evidence showing the proper function of HDAC6 is required for rehabilitation therapy induced therapeutic benefits after stroke. CONCLUSION: Together, our current study unravels that dysfunction of HDAC6 contributes to stroke induced deficits in neurogenesis and provides an innovative therapeutic strategy that targets HDAC6 for promoting functional recovery toward the patients with stroke in clinic.


Assuntos
Isquemia Encefálica/genética , Desacetilase 6 de Histona/genética , Neurogênese/genética , Recuperação de Função Fisiológica/genética , Acidente Vascular Cerebral/genética , Animais , Isquemia Encefálica/fisiopatologia , Feminino , Desacetilase 6 de Histona/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/fisiopatologia
19.
Turk J Med Sci ; 49(2): 589-594, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30997974

RESUMO

Background/aim: We aimed to investigate the associations between endothelial nitric oxide synthase(eNOS) gene polymorphisms [G894T (rs1799983)], intron 4 (27-bpTR) variable number tandem repeat (VNTR) and T786C (rs2070744), and ischemic stroke in the Anatolian population. Materials and methods: This case-control study included 112 patients with "stroke of undetermined etiology" and 160 controls. Real-time polymerase chain reaction (RT-PCR) analysis was used to analyze these polymorphisms. Between-group frequencies of alleles and genotypes were compared using binary logistic regression analysis. Results: No significant difference was observed between the two groups in terms of the genotype and allele distributions of the eNOS G894T (rs1799983) polymorphism (P > 0.05). The a alleles and the 4b/a and 4a/a genotypes of the intron 4 (27-bpTR) VNTR polymorphism had significantly higher frequencies in the patient group than in the control group (OR: 2.715, P < 0.001; OR: 3.396, P < 0.001; OR: 10.631, P = 0.016, respectively). On the contrary, the TC genotype and C alleles of the T786C (rs2070744) polymorphism had a significantly lower frequency in the patient group than in the control group (OR: 0.244, P < 0.001, OR: 0.605, P = 0.006, respectively) Conclusion: Our findings indicate that the eNOS G894T and T786C [rs2070744] polymorphisms are not associated with the risk of ischemic stroke, whereas the intron 4 [27-bpTR] VNTR may be a risk factor in the Anatolian population.


Assuntos
Isquemia Encefálica/genética , Predisposição Genética para Doença/genética , Íntrons/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/enzimologia , Isquemia Encefálica/fisiopatologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Repetições Minissatélites/genética , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/fisiopatologia
20.
Pak J Biol Sci ; 22(2): 59-66, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30972987

RESUMO

BACKGROUND AND OBJECTIVE: The fibrinogen receptor the human platelet antigen (HPA1 and HPA3) have an essential role in Atherothrombosis. This study aimed to detect the association of αIIbß3 polymorphism with ischemic stroke in Sudanese patients and its association with the common risk factors. METHODOLOGY: This is a case-control study. Fifty atherosclerotic with ischemic stroke Sudanese patients were included in present study and were compared to apparently 50 healthy Sudanese subjects at the same ages. The ages of both groups were >18 years. About 5 mL of venous blood sample was taken from each patient and control. The laboratory analyses were done for HbA1c, lipid profile and DNA genotyping by polymerase chain reaction (PCR) followed by FokI and ScrFI digestion. RESULTS: The result showed that, the risk factors (TRI.G, HDL, HbA1C, and body mass index were associated with the increased risk of ischemic stroke). None of the cholesterol levels and LDL increased the risk of stroke. The risk of ischemic stroke was higher with B/B genotype in HPA3 (p-value 0.009) and A/B genotype in HPA1 (p-value 0.041) and HPA1 (p-value 0.041). CONCLUSION: The αIIbß3 polymorphism were with ischemic stroke in Sudanese patients.


Assuntos
Isquemia Encefálica/genética , Predisposição Genética para Doença/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Fibrinogênio/genética , Acidente Vascular Cerebral/genética , Adolescente , Estudos de Casos e Controles , LDL-Colesterol/genética , Feminino , Genótipo , Humanos , Masculino , Fatores de Risco
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