Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.522
Filtrar
1.
Wiad Lek ; 73(4): 657-661, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32731692

RESUMO

OBJECTIVE: The aim: Investigate the effect of Lys198Asn polymorphism of the EDN1 gene on ischemic atherothrombotic stroke characteristics. PATIENTS AND METHODS: Materials and methods: Venous blood of 170 patients with ischemic atherothrombotic stroke (IAS) and 124 patients without cerebrovascular pathology, who made up the control group, used for the study. Lys198Asn (rs5370) polymorphism of the EDN1 gene was determined by the polymerase chain reaction method followed by restriction fragment length analysis. Statistical analysis was performed using SPSS-17.0. The values of Р < 0.05 were considered reliable. RESULTS: Results: An association between the Lys198Asn polymorphism of the EDN1 gene and the IAS development was detected. For Asn/Asn genotype carriers, the risk of IAS developing is 4 times higher than that of homozygotes for the major allele. The association of this polymorphism with the arterial pool, whose atherothrombotic changes lead to the development of IAS, was found in individuals with BMI < 25 kg/m2. Lys198Asn polymorphism also affects the severity of IAS in persons with hypertension and non-smokers. CONCLUSION: Conclusion: The Lys198Asn polymorphism of the EDN1 gene influences some characteristics of ischemic stroke.


Assuntos
Endotelina-1/genética , Acidente Vascular Cerebral , Alelos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética
2.
Biochem Biophys Res Commun ; 528(3): 413-419, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: covidwho-436643

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
3.
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
4.
PLoS One ; 15(6): e0235122, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584873

RESUMO

The MGP single nucleotide polymorphism (SNP) rs1800801 has previously been associated with recurrent ischemic stroke in a Spanish cohort. Here, we tested for association of this SNP with ischemic stroke recurrence in a North American Caucasian cohort. Acute ischemic stroke patients admitted between 10/2009 and 12/2016 at three hospitals within a large healthcare system in the northeastern United States that were enrolled in a healthcare system-wide exome sequencing program were retrospectively reviewed. Patients with recurrent stroke within 1 year after index event were compared to those without recurrence. Of 9,348 suspected acute ischemic strokes admitted between 10/2009 and 12/2016, 1,727 (18.5%) enrolled in the exome-sequencing program. Among those, 1,068 patients had exome sequencing completed and were eligible for inclusion. Recurrent stroke within the first year of stroke was observed in 79 patients (7.4%). In multivariable analysis, stroke prior to the index stroke (OR 9.694, 95% CI 5.793-16.224, p ≤ 0.001), pro-coagulant status (OR = 3.563, 95% CI 1.504-8.443, p = 0.004) and the AA genotype of SNP rs1800801 (OR = 2.408, 95% CI 1.079-4.389, p = 0.004) were independently associated with recurrent stroke within the first year. The AA genotype of the MGP SNP rs1800801 is associated with recurrence within the first year after ischemic stroke in North American Caucasians. Study of stroke subtypes and additional populations will be required to determine if incorporation of allelic status at this SNP into current risk scores improves prediction of recurrent ischemic stroke.


Assuntos
Isquemia Encefálica/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas da Matriz Extracelular/genética , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Sequenciamento Completo do Exoma
5.
Medicine (Baltimore) ; 99(21): e20206, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481290

RESUMO

In last decades, many scholars have studied the relationship between aldehyde dehydrogenase 2 (ALDH2) rs671 and ischemic stroke (IS), however, the results obtained from these studies were inconclusive. The purpose of this study was to investigate the association between rs671 and the risk of IS by systematically review.Two researchers independently screened relevant published literatures, derived data and estimated the risk of bias of the research in Pubmed, Embase, Ovid, China National Knowledge Infrastructure (CNKI), Cochrane Library and China Biomedical Literature Database throughout March 29, 2020. All statistical analyses were performed with the Stata 12.0 software. The data of the study was analyzed using fixed and random effects models. The results were expressed by odds ratio (OR) and 95% confidence interval (95%CI).A total of 10 articles were included this study. The total number of samples for all studies was 5265, including 2762 cases and 2503 controls. Statistical results indicated statistical differences between ALDH2 rs671 polymorphism and IS under dominant model (AA vs. AG + GG) and allelic model (A vs G), ORs (95% CI) were 1.66 (1.27-2.17) (P = .00) and 1.34 (1.05-1.71) (P = .02), respectively. But there was no statistical difference under recessive model (AA + AG vs GG), OR (95% CI) was 1.40 (0.99-1.97), P = .06.ALDH2 rs671 polymorphism was related to IS risk for Chinese population and the A allele of rs671 may be a risk factor of IS.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Isquemia Encefálica/diagnóstico , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética , Revisões Sistemáticas como Assunto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de Risco , Sensibilidade e Especificidade , Acidente Vascular Cerebral/patologia
6.
Mol Genet Genomics ; 295(5): 1173-1185, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32474671

RESUMO

Genome-wide association studies (GWASs) have identified more than 20 genetic loci as risk predictors associated with stroke. However, these studies were generally performed for single-trait and failed to consider the pleiotropic effects of these risk genes among the multiple risk factors for stroke. In this study, we applied a novel metaCCA method followed by gene-based VEGAS2 analysis to identify the risk genes for stroke that may overlap between seven correlated risk factors (including atrial fibrillation, hypertension, coronary artery disease, heart failure, diabetes, body mass index, and total cholesterol level) by integrating seven corresponding GWAS data. We detected 20 potential pleiotropic genes that may be associated with multiple risk factors of stroke. Furthermore, using gene-to-trait pathway analysis, we suggested six potential risk genes (FUT8, GMIP, PLA2G6, PDE3A, SMARCA4, SKAPT) that may affect ischemic or hemorrhage stroke through multiple intermediate factors such as MAPK family. These findings provide novel insight into the genetic determinants contributing to the concurrent development of biological conditions that may influence stroke susceptibility, and also indicate some potential therapeutic targets that can be further studied for the prevention of cerebrovascular disease.


Assuntos
Biologia Computacional/métodos , Redes Reguladoras de Genes , Acidente Vascular Cerebral/genética , Algoritmos , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Fatores de Risco
7.
Arterioscler Thromb Vasc Biol ; 40(7): 1777-1786, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32460577

RESUMO

OBJECTIVE: The aim of this study was to investigate if there is a causal relationship between circulating levels of TIM-1 (T-cell immunoglobulin and mucin domain 1) and incidence of stroke. Approach and Results: Plasma TIM-1 was analyzed in 4591 subjects (40% men; mean age, 57.5 years) attending the Malmö Diet and Cancer Study. Incidence of stroke was studied in relation to TIM-1 levels during a mean of 19.5 years follow-up. Genetic variants associated with TIM-1 (pQTLs [protein quantitative trait loci]) were examined, and a 2-sample Mendelian randomization analysis was performed to explore the role of TIM-1 in stroke using summary statistics from our pQTLs and the MEGASTROKE consortium. A total of 416 stroke events occurred during follow-up, of which 338 were ischemic strokes. After risk factor adjustment, TIM-1 was associated with increased incidence of all-cause stroke (hazards ratio for third versus first tertile, 1.44 [95% CI, 1.10-1.87]; P for trend, 0.004), and ischemic stroke (hazards ratio, 1.42 [95% CI, 1.06-1.90]; P for trend, 0.011). Nineteen independent lead SNPs, located in three genomic risk loci showed significant associations with TIM-1 (P<5×10-8). A 2-sample Mendelian Randomization analysis suggested a causal effect of TIM-1 on stroke (ß=0.083, P=0.0004) and ischemic stroke (ß=0.102, P=7.7×10-5). CONCLUSIONS: Plasma level of TIM-1 is associated with incidence of stroke. The genetic analyses suggest that this could be a causal relationship.


Assuntos
Receptor Celular 1 do Vírus da Hepatite A/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Biomarcadores/sangue , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Receptor Celular 1 do Vírus da Hepatite A/sangue , Humanos , Incidência , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Locos de Características Quantitativas , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Suécia/epidemiologia , Fatores de Tempo
8.
Gene ; 752: 144786, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32439379

RESUMO

AIM: Ischemic stroke (IS) is multifactorial disease and therefore different genes and proteins play a role in its development. Haptoglobin (Hp) removes free hemoglobin and protects from iron-induced oxidative damage, inflammatory response, atherosclerosis and cerebrovascular diseases. The aim of this study was to investigate Hp genetic variants in patients with carotid atherosclerotic lesions and IS. MATERIAL AND METHODS: A total of 121 subjects with IS participated in the study, 81 male and 40 female. RESULTS: Among 121 patients with IS, 79 had diffuse atherosclerotic plaques and stenosis. Hp genotype was statistically significantly associated with CDFI neck carotid artery stenosis findings (p = 0.006). Patients with Hp1-2 genotype had statistically significantly larger odds for atherosclerotic changes compared to those with Hp1-1 genotype, as well as those with Hp2-2 genotype. CONCLUSION: This study has shown an association of the Hp2-2 genotype and atherosclerosis in patients with IS, indicating Hp2-2 genotype as a genetic biomarker for precision medicine and personalized healthcare.


Assuntos
Aterosclerose/genética , Isquemia Encefálica/genética , Haptoglobinas/genética , Estenose das Carótidas/genética , Feminino , Genótipo , Haptoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/genética , Polimorfismo Genético/genética , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genética
9.
Medicine (Baltimore) ; 99(20): e19808, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443287

RESUMO

BACKGROUND: The interleukin-10 (IL-10)-819T/C polymorphism has been indicated to be correlated with ischemic stroke susceptibility, but this relationship remains controversial. A meta-analysis was conducted to investigate the potential association between IL-10-819T/C polymorphism and ischemic stroke risk. METHODS: Databases including Pubmed, Embase, and CNKI were searched. Data were extracted and odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: Eight case-control studies with 1832 cases and 1520 controls were included in this meta-analysis. IL-10-819T/C polymorphism may decrease the risk of ischemic stroke (C vs T: OR = 1.01, 95% CI: 0.91-1.12; CC vs TT: OR = 0.91, 95% CI: 0.73-1.14; CT vs TT: OR = 1.10, 95% CI: 0.95-1.28; CC + CT vs TT: OR = 1.06, 95% CI: 0.92-1.22; CC vs CT + TT: OR = 0.91, 95% CI: 0.75-1.11). In the stratified analysis by sample size, and case-control matched status, significant associations were still not observed in all genetic models. In the subgroup meta-analysis based on source of controls, IL-10-819T/C polymorphism had decreased ischemic stroke risk for recessive model in population-based controls' subgroup (CC vs CT + TT: OR = 0.69, 95% CI: 0.50-0.95), but not in the hospital-based controls' subgroup. In the stratified analysis based on ethnicity, IL-10-819T/C polymorphism had decreased ischemic stroke risk for recessive model in Asian populations (CC vs CT + TT: OR = 0.78, 95% CI: 0.62-0.99), but not in Caucasian populations. CONCLUSIONS: In conclusion, the results suggest that the IL-10-819T/C polymorphism is not associated with ischemic stroke risk. Larger scale studies are needed for confirmation.


Assuntos
Isquemia Encefálica/genética , Interleucina-10/genética , Acidente Vascular Cerebral/genética , Isquemia Encefálica/complicações , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único
10.
Nat Commun ; 11(1): 2175, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358547

RESUMO

Cerebral small vessel disease is a major cause of stroke and dementia, but its genetic basis is incompletely understood. We perform a genetic study of three MRI markers of the disease in UK Biobank imaging data and other sources: white matter hyperintensities (N = 42,310), fractional anisotropy (N = 17,663) and mean diffusivity (N = 17,467). Our aim is to better understand the disease pathophysiology. Across the three traits, we identify 31 loci, of which 21 were previously unreported. We perform a transcriptome-wide association study to identify associations with gene expression in relevant tissues, identifying 66 associated genes across the three traits. This genetic study provides insights into the understanding of the biological mechanisms underlying small vessel disease.


Assuntos
Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/genética , Acidente Vascular Cerebral/genética , Adulto , Idoso , Biomarcadores , Doenças de Pequenos Vasos Cerebrais/complicações , Feminino , Regulação da Expressão Gênica/genética , Ontologia Genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Transcriptoma/genética
11.
Nat Commun ; 11(1): 2488, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427863

RESUMO

Neovascularization and vascular remodeling are functionally important for brain repair after stroke. We show that neutrophils accumulate in the peri-infarct cortex during all stages of ischemic stroke. Neutrophils producing intravascular and intraparenchymal neutrophil extracellular traps (NETs) peak at 3-5 days. Neutrophil depletion reduces blood-brain barrier (BBB) breakdown and enhances neovascularization at 14 days. Peptidylarginine deiminase 4 (PAD4), an enzyme essential for NET formation, is upregulated in peri-ischemic brains. Overexpression of PAD4 induces an increase in NET formation that is accompanied by reduced neovascularization and increased BBB damage. Disruption of NETs by DNase 1 and inhibition of NET formation by genetic ablation or pharmacologic inhibition of PAD increases neovascularization and vascular repair and improves functional recovery. Furthermore, PAD inhibition reduces stroke-induced STING-mediated production of IFN-ß, and STING knockdown and IFN receptor-neutralizing antibody treatment reduces BBB breakdown and increases vascular plasticity. Collectively, our results indicate that NET release impairs vascular remodeling during stroke recovery.


Assuntos
Encéfalo/metabolismo , Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Acidente Vascular Cerebral/metabolismo , Remodelação Vascular , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Modelos Animais de Doenças , Armadilhas Extracelulares/genética , Humanos , Interferon beta/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína-Arginina Desiminase do Tipo 4/genética , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Acidente Vascular Cerebral/genética
12.
BMC Neurol ; 20(1): 167, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32357846

RESUMO

BACKGROUND: Stroke-like episodes (SLEs) in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with m.3243A > G mutation usually develop in the cerebral cortex. Few reports have documented SLEs in the cerebellum. The clinical neuroimaging features of cerebellar SLEs have not been fully investigated. We report distinctive features of cerebellar stroke-like lesions (SLLs) in a case of MELAS with m.3243A > G mutation. CASE PRESENTATION: A 47-year-old Japanese man with type-2 diabetes presented to our hospital with acute onset of aphasia. A brain MRI obtained on admission (day 1) showed increased diffusion-weighted imaging (DWI)/fluid-attenuated inversion recovery (FLAIR) signal in the left anterolateral temporal lobe, which subsequently spread along the cortex posteriorly accompanied by a new lesion in the right anterior temporal lobe. The patient was initially treated with acyclovir and subsequently with immunotherapy. However, on day 45, cerebellar ataxia developed. The brain MRI showed extensive increased DWI/FLAIR signals in the cerebellum along the folia without involvement of deep cerebellar nucleus or cerebellar peduncle; SLLs were incongruent with a vascular territory, similarly to classic cerebral SLLs. Apparent diffusion coefficient (ADC) map did not show reduction in ADC values in the affected folia. Genomic analysis revealed m.3243A > G mutation (heteroplasmy in leukocytes, 17%), confirming the diagnosis of MELAS. After the treatment with taurine (12,000 mg/day), L-arginine (12,000 mg/day), vitamin B1 (100 mg/day), and carnitine (3000 mg/day), the patient became able to follow simple commands, and he was transferred to a rehabilitation center on day 146. The follow-up MRI showed diffuse brain atrophy, including the cerebellum. CONCLUSIONS: SLLs develop in the cerebellum in MELAS with m.3243A > G mutation. The neuroimaging similarities to cerebral SLLs suggest the presence of the common pathophysiological mechanisms underlying both SLEs, which include microangiopathy and increased susceptibility of the cortex to metabolic derangements.


Assuntos
Cerebelo , Síndrome MELAS , Acidente Vascular Cerebral , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Cerebelo/fisiopatologia , Humanos , Síndrome MELAS/complicações , Síndrome MELAS/diagnóstico por imagem , Síndrome MELAS/genética , Síndrome MELAS/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologia
13.
Stroke ; 51(6): 1835-1843, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32397936

RESUMO

Background and Purpose- oxLDL (oxidized low-density lipoprotein) has been known for its potential to induce endothelial dysfunction and used as a major serological marker of oxidative stress. Recently, LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a lectin-like receptor for oxLDL, has attracted attention in studies of neuronal apoptosis and stroke. We aim to investigate the impact of LOX-1-deficiency on spontaneous hypertension-related brain damage in the present study. Methods- We generated a LOX-1 deficient strain on the genetic background of stroke-prone spontaneously hypertensive rat (SHRSP), an animal model of severe hypertension and spontaneous stroke. In this new disease model with stroke-proneness, we monitored the occurrence of brain abnormalities with and without salt loading by multiple procedures including T2 weighted magnetic resonance imaging and also explored circulatory miRNAs as diagnostic biomarkers for cerebral ischemic injury by microarray analysis. Results- Both T2 weighted magnetic resonance imaging abnormalities and physiological parameter changes could be detected at significantly delayed timing in LOX-1 knockout rats compared with wild-type SHRSP, in either case of normal rat chow and salt loading (P<0.005 in all instances; n=11-20 for SHRSP and n=13-23 for LOX-1 knockout rats). There were no significant differences in the form of magnetic resonance imaging findings between the strains. A number of miRNAs expressed in the normal rat plasma, including rno-miR-150-5p and rno-miR-320-3p, showed significant changes after spontaneous brain damage in SHRSP, whereas the corresponding changes were modest or almost unnoticeable in LOX-1 knockout rats. There appeared to be the lessening of correlation of postischemic miRNA alterations between the injured brain tissue and plasma in LOX-1 knockout rats. Conclusions- Our data show that deficiency of LOX-1 has a protective effect on spontaneous brain damage in a newly generated LOX-1-deficient strain of SHRSP. Further, our analysis of miRNAs as biomarkers for ischemic brain damage supports a potential involvement of LOX-1 in blood brain barrier disruption after cerebral ischemia. Visual Overview- An online visual overview is available for this article.


Assuntos
Barreira Hematoencefálica , Isquemia Encefálica , Deleção de Genes , Hipertensão , Receptores Depuradores Classe E/deficiência , Acidente Vascular Cerebral , Animais , Barreira Hematoencefálica/lesões , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Isquemia Encefálica/sangue , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , MicroRNA Circulante , Hipertensão/sangue , Hipertensão/genética , Hipertensão/patologia , MicroRNAs/sangue , MicroRNAs/genética , Ratos , Ratos Endogâmicos SHR , Ratos Transgênicos , Receptores Depuradores Classe E/metabolismo , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
14.
Medicine (Baltimore) ; 99(15): e19472, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282698

RESUMO

High on-treatment platelet reactivity (HTPR) was suggested to be better correlated with recurrent ischemic events as compared with gene polymorphism, whereas most of the results were from white populations with acute coronary disease. The evidence is relatively limited regarding HTPR and its genetic determinants in predicting clinical outcomes of stroke among Chinese-Han patients.A prospective study including 131 Chinese-Han stroke patients treated with clopidogrel was analyzed. Platelet function was assessed by light transmission aggregometry (LTA)- adenosine diphosphate (ADP) method. HTPR was defined as 5 µM ADP induced platelet aggregation > 46%. CYP2C19 and P2Y12 genotype were detected using the PCR-RFLP method. The difference in the occurrence of the primary endpoint was analyzed according to platelet function and genetic status.Sixty-three (48.1%) subjects displayed HTPR after administering clopidogrel for 1 week. The prevalence of HTPR was significantly higher in CYP2C19 loss-of-function (LOF) alleles (2, 3) carriers vs wild-type homozygotes (71.7% vs 32.1%, P < .01), and logistic regression analysis showed that carriers of CYP2C19 LOF alleles were an independent risk factor of HTPR. Survival analysis indicated that patients with HTPR had an increased risk of primary endpoints (20.6% vs 7.3%, P = .04), whereas the presence of CYP2C19 LOF alleles or P2Y12 H2 haplotype did not increase the incidence of ischemic events. Cox regression analysis demonstrated that HTPR was an independent predictor of the primary composite endpoint (HR, 3.1; 95% CI, 1.07-8.99; P = .04).We identified a high prevalence of clopidogrel-HTPR in a cohort of Chinese-Han patients with acute ischemic stroke, and patients with HTPR may have an increased risk of recurrent ischemic stroke events. CYP2C19 LOF alleles are associated with HTPR but not with stroke prognosis. Further clinical trials with large samples are needed to confirm these findings.


Assuntos
Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Inibidores da Agregação de Plaquetas/uso terapêutico , Receptores Purinérgicos P2Y12/genética , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Plaquetária , Prognóstico , Estudos Prospectivos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/genética
15.
BMC Med Genet ; 21(1): 66, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228489

RESUMO

BACKGROUND: Ischemic Stroke (IS) is the most common neurological emergency disease and has become the second most frequent cause of death after coronary artery disease in 2015. Owing to its high fatality rate and narrow therapeutic time window, early identification and prevention of potential stroke is becoming increasingly important. METHODS: We used meta-analysis and bioinformatics mining to explore disease-related pathways and regulatory networks after combining messengerRNA (mRNA) and miRNA expression analyses. The purpose of our study was to screen for candidate target genes and microRNA(miRNA) for early diagnosis of potential stroke. RESULTS: Five datasets were collected from the Gene Expression Omnibus (GEO) database by systematical retrieval, which contained three mRNA datasets (102 peripheral blood samples in total) and two miRNA dataset (59 peripheral blood samples). Approximately 221 different expression(DE) mRNAs (155 upregulated and 66 downregulated mRNAs) and 185 DE miRNAs were obtained using the metaDE package and GEO2R tools. Further functional enrichments of DE-mRNA, DE-miRNA and protein-protein interaction (PPI) were performed and visualized using Cytoscape. CONCLUSION: Our study identified six core mRNAs and two regulated miRNAs in the pathogenesis of stroke, and we elaborated the intrinsic role of systemic lupus erythematosus (SLE) and atypical infections in stroke, which may aid in the development of precision medicine for treating ischemic stroke. However, the role of these novel biomarkers and the underlying molecular mechanisms in IS require further fundamental experiments and further clinical evidence.


Assuntos
Biomarcadores/análise , Isquemia Encefálica/genética , Acidente Vascular Cerebral/genética , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Biologia Computacional/métodos , Conjuntos de Dados como Assunto/estatística & dados numéricos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Estudos de Associação Genética/estatística & dados numéricos , Humanos , MicroRNAs/genética , RNA Mensageiro/genética , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia
16.
BMC Neurol ; 20(1): 159, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345264

RESUMO

BACKGROUND: Early neurological deterioration (END) is common in acute ischemic stroke (IS). However, the underlying mechanisms for END are unclear. The aim of this study was to evaluate the associations of 16 variants in clopidogrel-relevant genes and interactions among these variants with END in acute IS patients receiving clopidogrel treatment. METHODS: We consecutively enrolled 375 acute IS patients between June 2014 and January 2015. Platelet aggregation was measured on admission and after the 7-10 days of clopidogrel treatment. The 16 variants in clopidogrel-relevant genes were examined using mass spectrometry. The primary outcome was END within the 10 days of admission. Gene-gene interactions were analyzed by generalized multifactor dimensionality reduction (GMDR) methods. RESULTS: Among the 375 patients, 95 (25.3%) patients developed END within the first 10 days of admission. Among the 16 variants, only CYP2C19*2 (rs4244285) AA/AG was associated with END using single-locus analytical approach. GMDR analysis revealed that there was a synergistic effect of gene-gene interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 on the risk for END. The high-risk interactions among the three variants were associated with the higher platelet aggregation and independent predictor for END after adjusting for the covariates (hazard ratio: 2.82; 95% confidence interval: 1.36-7.76; P = 0.003). CONCLUSIONS: END is very common in patients with acute IS. The mechanisms leading to END are most likely multifactorial. Interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 may confer a higher risk for END. It was very important to modify clopidogrel therapy for the patients carrying the high-risk interactive genotypes. CLINICAL TRIAL REGISTRATION INFORMATION: The study described here is registered at http://www.chictr.org/ (unique Identifier: ChiCTR-OCH-14004724). The date of trial registration was May 30, 2014.


Assuntos
Isquemia Encefálica/genética , Clopidogrel/efeitos adversos , Citocromo P-450 CYP2C19/genética , Epistasia Genética/genética , Integrina beta3/genética , Agregação Plaquetária/genética , Receptores Purinérgicos P2Y12/genética , Recidiva , Acidente Vascular Cerebral/genética , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Clopidogrel/uso terapêutico , Genótipo , Humanos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico
17.
Stroke ; 51(5): 1587-1595, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312218

RESUMO

Background and Purpose- Women have worse stroke outcomes than men, especially after menopause. Few studies have focused on female-specific mechanisms, other than hormones. We investigated the role of the blood protein VTN (vitronectin) after ischemic stroke in mice. Methods- Adult male and female VTN knockout and wild-type littermates and C57BL/6 mice received a middle cerebral artery occlusion and the injured brain tissue analyzed 24 hours to 3 weeks later for cell loss and inflammation, as well as neurological function. Blood VTN levels were measured before and after stroke. Results- Intravenously injected VTN leaked extensively from bloodstream into brain infarct and penumbra by 24 hours after stroke. Strikingly, VTN was detrimental in female, but not male, mice, as shown by reduced brain injury (26.2±2.6% versus 13.4±3.8%; P=0.018; n=6 and 5) and forelimb dysfunction in female VTN knockout mice. Stroke increased plasma VTN 2- to 8-fold at 24 hours in females (36±4 versus 145±24 µg/mL; P<0.0001; n=10 and 7), but not males (62±8 versus 68±6; P>0.99; n=10 and 7), and returned to control levels by 7 days. Individually variable VTN levels at 24 hours correlated with stroke-induced brain injury at 7 days only in females. VTN promoted stroke-induced microglia/macrophage activation and leukocyte infiltration in females. Proinflammatory IL (interleukin)-6 greatly increased in the striatum at 24 hours in wild-type mice but was increased ≈60% less in female (739±159 versus 268±111; P=0.02; n=7 and 6), but not male (889±178 versus 1179±295; P=0.73; n=10 and 11), knockout mice. In individual wild-type females, plasma VTN levels correlated with striatal IL-6 expression at 24 hours. The female-specific effect of VTN-induced IL-6 expression following stroke was not due to gonadal hormones, as shown by ovariectomy and castration. Lastly, intrastriatal injection of IL-6 in female mice immediately before stroke reversed the VTN knockout phenotypes of reduced brain injury and microglia/macrophage activation. Conclusions- VTN plays a novel sexually dimorphic detrimental pathophysiological role in females and might ultimately be a therapeutic target to improve stroke outcomes in women.


Assuntos
Barreira Hematoencefálica/metabolismo , Infarto da Artéria Cerebral Média/genética , Inflamação/genética , Interleucina-6/genética , Vitronectina/genética , Animais , Fator Neurotrófico Ciliar/genética , Fator Neurotrófico Ciliar/metabolismo , Feminino , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Inflamação/metabolismo , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , RNA Mensageiro/metabolismo , Fatores Sexuais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Vitronectina/sangue , Vitronectina/metabolismo
18.
Cerebrovasc Dis ; 49(2): 170-176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32209797

RESUMO

OBJECTIVE: A multigenetic pro-inflammatory profile may increase stroke risk. We investigated whether a higher number of pro-inflammatory genetic variants are associated with ischaemic stroke risk and whether other risk factors further elevate this risk. METHODS: In a case-control study with 470 ischaemic stroke patients (cases) and 807 population controls, we investigated 23 haplotypes or alleles in 16 inflammatory genes (interleukin [IL]1A, IL1B, IL1 receptor antagonist, IL6, IL6 receptor, IL10, tumour necrosis factor-a; C-C motif chemokine ligand 2, C-C motif chemokine receptor 5, C-reactive protein (CRP), intercellular adhesion molecule 1, transforming growth factor ß1, E-Selectin, selenoprotein S, cluster determinant 14, histone deacetylase 9 [HDAC9]). We constructed an extended gene score (EGS) as the sum of all individual risk alleles and analysed its effect on stroke, just as its association and interaction with cardiovascular risk factors and infectious scores (IgG antibodies against 5 respectively IgA antibodies against 4 microbial antigens). RESULTS: Cases were less likely to carry the minor allele of IL10 rs1800872 and more likely to carry the HDAC9 allele rs11984041 and the pro-inflammatory haplotype of CRP, although the latter was not statistically significant in our study. Overall, cases tended to have more pro-inflammatory alleles and haplotypes than controls (mean ± SD 13.25 ± 2.25 and 13.04 ± 2.41, respectively). However, the EGS only slightly and not significantly increased the risk of stroke (OR 1.04, 95% CI 0.99-1.09). Its effect was neither associated with included risk factors nor with IgA and IgG infectious scores, and we found no significant interaction effects. CONCLUSION: A more pro-inflammatory genetic profile might increase stroke risk to some extent. This potential effect is most likely independent of established cardiovascular risk factors and the infectious burden of an individual.


Assuntos
Isquemia Encefálica/genética , Mediadores da Inflamação/análise , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Transcriptoma , Idoso , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Alemanha/epidemiologia , Haplótipos , Humanos , Masculino , Fenótipo , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico
19.
Gene ; 743: 144617, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32222535

RESUMO

Osteoprotegerin is involved in the progression of atherosclerosis. This study aimed to determine whether TNFRSF11B polymorphisms are associated with prognosis of large artery atherosclerosis (LAA) stroke. Three TNFRSF11B polymorphisms (rs2073617, rs2073618 and rs3134069) were genotyped in 1010 patients with LAA stroke. Short-term outcome was evaluated using the modified Rankin Scale score at 3-month after stroke onset. Long-term outcome was assessed using the stroke recurrence. We found that rs2073617G was associated with an increased risk of poor outcome of LAA stroke (additive model: odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.06-1.73). This association was also observed in rs3134069C (additive model: OR = 1.53, 95% CI = 1.10-2.12). Furthermore, when we combined these two polymorphisms according to the numbers of risk alleles (rs2073617G and rs3134069C), we found that the patients with 3-4 risk alleles were statistically significantly associated with an increased risk of poor outcome of LAA stroke (OR = 1.90, 95% CI = 1.10-3.28) compared with 0-2 risk alleles, and this increased risk was more evident among those with hypertension (OR = 2.02, 95% CI = 1.04-3.91), those without diabetes (OR = 2.02, 95% CI = 1.02-4.01) and those with smoking (OR = 2.43, 95% CI = 1.09-5.42). In silico analysis showed that rs2073617 and rs3134069 are located in various histone modification marked regions, DNase I hypersensitive sites and can change the binding of regulatory motifs. Moreover, rs2073617 is also located in the binding site of transcription factors. Our findings suggested that TNFRSF11B polymorphisms may be associated with an increased risk of short-term poor outcome of LAA stroke.


Assuntos
Artérias/patologia , Aterosclerose/complicações , Avaliação da Deficiência , Osteoprotegerina/genética , Acidente Vascular Cerebral/genética , Alelos , Aterosclerose/genética , Aterosclerose/patologia , Estudos de Casos e Controles , Simulação por Computador , Progressão da Doença , Feminino , Seguimentos , Código das Histonas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Recidiva , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia
20.
Croat Med J ; 61(1): 18-27, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32118374

RESUMO

AIM: To assess the role of human platelet antigens (HPA), P-selectin gene (SELP) polymorphisms, and HPA and SELP haplotypes with factor V (FV) R506Q in ischemic pediatric stroke (IPS) subtypes: cerebral sinovenous thrombosis (CSVT), perinatal (PAIS), and childhood (CAIS) arterial ischemic stroke. METHODS: This case-control study enrolled 150 children with confirmed IPS and 150 age- and sex-matched controls. FV R506Q and HPA-1 were genotyped with CVD StripAssay®, HPA-2 and HPA-3 with real-time polymerase chain reaction, SELP S290N, V599L, and T715P with high resolution melting analysis, and SELP N562D with sequence-specific polymerase chain reaction. RESULTS: HPA-1b allele (odds ratio [OR] 2.75, 95% confidence interval [CI] 1.02-7.42, P=0.048) and HPA-1a2a3b (OR 5.46, 95% CI 1.51-19.76, P=0.011), HPA-1b2a3a (OR 7.00, 95% CI 1.25-39.13, P=0.028), and HPA-1b2b3a (OR 11.39, 95% CI 1.39-92.95, P=0.024) haplotypes increased the risk for CSVT. HPA-3b allele was significantly associated with 2-fold lower risk for PAIS (OR 0.49, 95% CI 0.26-0.89, P=0.020) and CAIS (OR 0.47, 95% CI 0.26-0.86, P=0.014) and non-significantly associated with increased risk for CSVT (OR 6.43, 95% CI 0.83-50.00, P=0.022). HPA-1a2b3a haplotype was significantly associated with CAIS (OR 6.76, 95% CI 2.13-21.44, P=0.001). The inclusion of FV R506Q in SELP haplotype analysis increased the risk for PAIS 4-fold in QNDVT carriers (OR 8.14, 95% CI 0.93-71.33, P=0.060) compared with NDVT haplotype (OR 2.45, 95% CI 0.98-6.18, P=0.058), but the result was not significant. CONCLUSION: Individual HPAs, and particularly HPA haplotypes, are involved in IPS subtypes pathogenesis. A possible risk-inducing synergistic effect of SELP haplotypes with FV R506Q is restricted to PAIS only.


Assuntos
Antígenos de Plaquetas Humanas/genética , Isquemia Encefálica/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Adolescente , Alelos , Isquemia Encefálica/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , Fator V/genética , Feminino , Genótipo , Haplótipos , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Razão de Chances , Selectina-P/genética , Reação em Cadeia da Polimerase em Tempo Real , Acidente Vascular Cerebral/diagnóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA