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1.
Gene ; 766: 145022, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758579

RESUMO

BACKGROUND: A better understanding of the mechanism(s) underlying cardioembolic stroke can promote recovery and reduce the risk of recurrent embolisms. METHODS: Peripheral blood mononuclear cell (PBMC) gene expression datasets from cardioembolic patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database (GSE58294). The Limma software package was utilized to identify differentially-expressed genes (DEGs). Protein-protein interaction (PPI) analysis of the DEGs was performed using STRING. A weighted gene co-expression network analysis (WGCNA) was used to build a gene co-expression network. In vitro experiments assessed the effects on neutrophils exposed to oxygen and glucose-deprived (OGD) cortical neurons. An in vivo murine model of thromboembolic stroke was constructed through thrombin injection to examine effects on circulating neutrophils. Mechanistic in vitro studies were conducted using the proteasome inhibitor MG132, the p53-Mdm2 binding inhibitor Nutlin-3a, Mdm2 small-interfering RNA (siRNA), and Ctnnb1 siRNA. RESULTS: DEG analysis identified 44 upregulated and 66 downregulated genes in cardioembolic stroke PBMCs. PPI analysis of these DEGs yielded one eight-node protein module with ß-catenin (CTNNB1) as the central hub protein. Integration of the DEGs with WGCNA-derived hub genes revealed the key hub DEGs CTNNB1 and mouse double minute 2 (MDM2). Follow-up experiments revealed Mdm2, p53, and phospho-ß-catenin upregulation in neutrophils exposed to OGD neurons in vitro and following thromboembolic stroke in vivo. Mechanistic studies revealed that neutrophils transcriptionally upregulate Ctnnb1 expression to compensate for Mdm2/p53-mediated ß-catenin degradation induced by exposure to OGD neurons, thereby promoting neutrophil survival. CONCLUSION: Compensatory Ctnnb1 transcriptional upregulation in neutrophils induced by ischemic neuron exposure may be involved in promoting neutrophil survival following cardioembolic stroke.


Assuntos
Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Proteína Supressora de Tumor p53/genética , Regulação para Cima/genética , beta Catenina/genética , Animais , Células Cultivadas , Regulação para Baixo/genética , Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Coração/fisiopatologia , Humanos , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Transcrição Genética/genética , Ativação Transcricional/genética
2.
Nat Commun ; 11(1): 5196, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060592

RESUMO

Pericytes play essential roles in blood-brain barrier (BBB) integrity and dysfunction or degeneration of pericytes is implicated in a set of neurological disorders although the underlying mechanism remains largely unknown. However, the scarcity of material sources hinders the application of BBB models in vitro for pathophysiological studies. Additionally, whether pericytes can be used to treat neurological disorders remains to be elucidated. Here, we generate pericyte-like cells (PCs) from human pluripotent stem cells (hPSCs) through the intermediate stage of the cranial neural crest (CNC) and reveal that the cranial neural crest-derived pericyte-like cells (hPSC-CNC PCs) express typical pericyte markers including PDGFRß, CD146, NG2, CD13, Caldesmon, and Vimentin, and display distinct contractile properties, vasculogenic potential and endothelial barrier function. More importantly, when transplanted into a murine model of transient middle cerebral artery occlusion (tMCAO) with BBB disruption, hPSC-CNC PCs efficiently promote neurological functional recovery in tMCAO mice by reconstructing the BBB integrity and preventing of neuronal apoptosis. Our results indicate that hPSC-CNC PCs may represent an ideal cell source for the treatment of BBB dysfunction-related disorders and help to model the human BBB in vitro for the study of the pathogenesis of such neurological diseases.


Assuntos
Isquemia Encefálica/metabolismo , Pericitos/metabolismo , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/patologia , Diferenciação Celular/genética , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Crista Neural/metabolismo , Células-Tronco Pluripotentes/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Recuperação de Função Fisiológica/genética , Acidente Vascular Cerebral/patologia , Transcriptoma
4.
Life Sci ; 260: 118418, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931799

RESUMO

AIMS: Stroke is a devastating event with a limited choice of intervention. Benzoinum is frequently used to treat stroke in traditional Chinese medicine. Our team has found that the neuroprotection of benzoinum may related to angiogenesis, but the exact biological mechanism is unclear. The objective of this study was to explore its biological mechanism of angiogenesis in cerebral ischemia model rats. MAIN METHODS: First, network pharmacology and molecular docking were performed to predict the possible targets and mechanisms of benzoinum in treating ischemic stroke. The best dose was then selected according to pharmacodynamic indexes such as those for neurological deficit, cerebral infarction rate, and brain histopathology in middle cerebral artery occlusion (MCAO) model rats. Finally, RT-PCR, Western Blot and immunohistochemical analysis were applied to verify the prediction results from molecular docking. KEY FINDINGS: Network pharmacology and molecular docking demonstrated that the targets of treating cerebral ischemia were PDE4D, ACE and TTR, and the mechanism may be related to the ACE-AngI-VEGF signaling pathway. Experimental verification results suggested that 0.50 g/kg and 1.00 g/kg benzoinum could significantly protect against neurological deficit and reduce cerebral infarction rate in the cerebral cortex and hippocampus in MCAO model rats. At an optimal dose, benzoinum could significantly up-regulate VEGF, SHH and ANG-1, yet down-regulate ACE expression in MCAO model rats. SIGNIFICANCE: Balsamic acid is the active ingredient of benzoinum that protects against ischemic stroke and the possible mechanism is related to the promotion of angiogenesis via regulating ACE-AngI-VEGF pathway.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Masculino , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Ribonuclease Pancreático/genética , Ribonuclease Pancreático/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Stroke ; 51(10): 3095-3106, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32933419

RESUMO

BACKGROUND AND PURPOSE: Poststroke tissue repair, comprised of macrophage-mediated clearance of myelin debris and pericyte-mediated fibrotic response within the infarct area, is an important process for functional recovery. Herein, we investigated the reciprocal interaction between pericytes and macrophages during poststroke repair and functional recovery. METHODS: We performed a permanent middle cerebral artery occlusion in both wild-type and pericyte-deficient PDGFRß (platelet-derived growth factor receptor ß) heterozygous knockout (Pdgfrb+/-) mice and compared histological changes and neurological functions between the 2 groups. We also examined the effects of conditioned medium harvested from cultured pericytes, or bone marrow-derived macrophages, on the functions of other cell types. RESULTS: Localization of PDGFRß-positive pericytes and F4/80-positive macrophages was temporally and spatially very similar following permanent middle cerebral artery occlusion. Intrainfarct accumulation of macrophages was significantly attenuated in Pdgfrb+/- mice. Intrainfarct pericytes expressed CCL2 (C-C motif ligand 2) and CSF1 (colony stimulating factor 1), both of which were significantly lower in Pdgfrb+/- mice. Cultured pericytes expressed Ccl2 and Csf1, both of which were significantly increased by PDGF-BB and suppressed by a PDGFRß inhibitor. Pericyte conditioned medium significantly enhanced migration and proliferation of bone marrow-derived macrophages. Poststroke clearance of myelin debris was significantly attenuated in Pdgfrb+/- mice. Pericyte conditioned medium promoted phagocytic activity in bone marrow-derived macrophages, also enhancing both STAT3 (signal transducer and activator of transcription 3) phosphorylation and expression of scavenger receptors, Msr1 and Lrp1. Macrophages processing myelin debris produced trophic factors, enhancing PDGFRß signaling in pericytes leading to the production of ECM (extracellular matrix) proteins and oligodendrogenesis. Functional recovery was significantly attenuated in Pdgfrb+/- mice, parallel with the extent of tissue repair. CONCLUSIONS: A reciprocal interaction between pericytes and macrophages is important for poststroke tissue repair and functional recovery.


Assuntos
Infarto da Artéria Cerebral Média/metabolismo , Macrófagos/metabolismo , Pericitos/metabolismo , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/metabolismo , Cicatrização/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Meios de Cultivo Condicionados , Infarto da Artéria Cerebral Média/patologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Pericitos/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Acidente Vascular Cerebral/patologia
6.
Stroke ; 51(10): 3138-3141, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32819195

RESUMO

BACKGROUND AND PURPOSE: Increased expression of α-Syn (α-Synuclein) is known to mediate secondary brain damage after stroke. We presently studied if α-Syn knockdown can protect ischemic brain irrespective of sex and age. METHODS: Adult and aged male and female mice were subjected to transient middle cerebral artery occlusion. α-Syn small interfering RNA (siRNA) was administered intravenous at 30 minutes or 3 hour reperfusion. Poststroke motor deficits were evaluated between day 1 and 7 and infarct volume was measured at day 7 of reperfusion. RESULTS: α-Syn knockdown significantly decreased poststroke brain damage and improved poststroke motor function recovery in adult and aged mice of both sexes. However, the window of therapeutic opportunity for α-Syn siRNA is very limited. CONCLUSIONS: α-Syn plays a critical role in ischemic brain damage and preventing α-Syn protein expression early after stroke minimizes poststroke brain damage leading to better functional outcomes irrespective of age and sex.


Assuntos
Encéfalo/patologia , Infarto da Artéria Cerebral Média/genética , Acidente Vascular Cerebral/genética , alfa-Sinucleína/metabolismo , Fatores Etários , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos , RNA Interferente Pequeno , Recuperação de Função Fisiológica , Fatores Sexuais , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , alfa-Sinucleína/genética
7.
Stroke ; 51(9): 2770-2777, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32811388

RESUMO

BACKGROUND AND PURPOSE: Stroke is a common cause of death and a leading cause of disability and morbidity. Stroke risk assessment remains a challenge, but circulating biomarkers may improve risk prediction. Controversial evidence is available on the predictive ability of troponin concentrations and the risk of stroke in the community. Furthermore, reports on the predictive value of troponin concentrations for different stroke subtypes are scarce. METHODS: High-sensitivity cardiac troponin I (hsTnI) concentrations were assessed in 82 881 individuals (median age, 50.7 years; 49.7% men) free of stroke or myocardial infarction at baseline from 9 prospective European community cohorts. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for overoptimism. Follow-up was based upon linkage with national hospitalization registries and causes of death registries. RESULTS: Over a median follow-up of 12.7 years, 3033 individuals were diagnosed with incident nonfatal or fatal stroke (n=1654 ischemic strokes, n=612 hemorrhagic strokes, and n=767 indeterminate strokes). In multivariable regression models, hsTnI concentrations were associated with overall stroke (hazard ratio per 1-SD increase, 1.15 [95% CI, 1.10-1.21]), ischemic stroke (hazard ratio, 1.14 [95% CI, 1.09-1.21]), and hemorrhagic stroke (hazard ratio, 1.10 [95% CI, 1.01-1.20]). Adding hsTnI concentrations to classical cardiovascular risk factors (C indices, 0.809, 0.840, and 0.736 for overall, ischemic, and hemorrhagic stroke, respectively) increased the C index significantly but modestly. In individuals with an intermediate 10-year risk (5%-20%), the net reclassification improvement for overall stroke was 0.038 (P=0.021). CONCLUSIONS: Elevated hsTnI concentrations are associated with an increased risk of incident stroke in the community, irrespective of stroke subtype. Adding hsTnI concentrations to classical risk factors only modestly improved estimation of 10-year risk of stroke in the overall cohort but might be of some value in individuals at an intermediate risk.


Assuntos
Miocárdio/metabolismo , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/metabolismo , Troponina I/metabolismo , Biomarcadores , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros , Fatores de Risco
8.
Proc Natl Acad Sci U S A ; 117(34): 20764-20775, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32764143

RESUMO

The identification of precision blood biomarkers which can accurately indicate damage to brain tissue could yield molecular diagnostics with the potential to improve how we detect and treat neurological pathologies. However, a majority of candidate blood biomarkers for neurological damage that are studied today are proteins which were arbitrarily proposed several decades before the advent of high-throughput omic techniques, and it is unclear whether they represent the best possible targets relative to the remainder of the human proteome. Here, we leveraged mRNA expression data generated from nearly 12,000 human specimens to algorithmically evaluate over 17,000 protein-coding genes in terms of their potential to produce blood biomarkers for neurological damage based on their expression profiles both across the body and within the brain. The circulating levels of proteins associated with the top-ranked genes were then measured in blood sampled from a diverse cohort of patients diagnosed with a variety of acute and chronic neurological disorders, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, Alzheimer's disease, and multiple sclerosis, and evaluated for their diagnostic performance. Our analysis identifies several previously unexplored candidate blood biomarkers of neurological damage with possible clinical utility, many of which whose presence in blood is likely linked to specific cell-level pathologic processes. Furthermore, our findings also suggest that many frequently cited previously proposed blood biomarkers exhibit expression profiles which could limit their diagnostic efficacy.


Assuntos
Biomarcadores/metabolismo , Lesões Encefálicas/diagnóstico , Doenças do Sistema Nervoso/metabolismo , Adulto , Idoso , Doença de Alzheimer/metabolismo , Biomarcadores/sangue , Encéfalo/metabolismo , Lesões Encefálicas/sangue , Biologia Computacional/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Doenças do Sistema Nervoso/sangue , Neuropatologia/métodos , Proteoma/metabolismo , Acidente Vascular Cerebral/metabolismo
9.
Neuroepidemiology ; 54(5): 370-374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32791504

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) causes the coronavirus disease 2019 (COVID-19). It quickly became pandemic, and so did a new concern about COVID-19 infections increasing the risk for cerebrovascular diseases. There is an association between COVID-19 illness in people and acute stroke. Several chemical, mechanical, and/or inflammatory central nervous system pathologies are proposed to explain how this viral infection might induce acute cerebrovascular disease. Timely available evaluation and/or intervention is imperative for patients with concerns about acute cerebrovascular issues.


Assuntos
Betacoronavirus , Encéfalo/virologia , Circulação Cerebrovascular/fisiologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/virologia , Betacoronavirus/metabolismo , Encéfalo/metabolismo , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/virologia , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Pneumonia Viral/metabolismo , Acidente Vascular Cerebral/metabolismo
10.
Yakugaku Zasshi ; 140(8): 1007-1012, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741858

RESUMO

We previously showed that increased permeability of the blood-brain barrier (BBB) after ischemic stroke enables extravasation of nano-sized liposomes and accumulation in the ischemic region, and that delivery of neuroprotective agents using liposomal drug delivery systems (DDS) is applicable for treating cerebral ischemia/reperfusion (I/R) injury. However, entry of liposomes into the brain parenchyma was limited in the early stages after I/R possibly due to microvascular dysfunction induced by pathological progression. As such, new approaches to overcome the BBB are needed. Leukocytes can pass through inflamed BBB in I/R region due to membrane proteins displayed on their surface. We thus hypothesized that incorporation of leukocyte membrane proteins onto liposomal membranes would impart leukocyte-mimicking functions to liposomes and that leukocyte-mimetic liposomes (LM-Lipo) may pass through inflamed endothelial cells and BBB, similar to leukocytes. LM-Lipo prepared using intermembrane protein transfer from human leukemia cells showed significantly increased association to inflamed human umbilical vein endothelial cells relative to plain liposomes. Moreover, LM-Lipo passed through inflamed endothelial cell layer by regulating intercellular junctions. These results suggest that imparting leukocyte-like properties to liposomes via intermembrane protein transfer would be an effective strategy to overcome inflamed endothelial barriers. In this review, we describe our findings on ischemic stroke treatment using liposomal DDS and the potential of LM-Lipo to overcome inflamed endothelial barriers.


Assuntos
Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Leucócitos , Lipossomos/metabolismo , Proteínas de Membrana/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Humanos , Permeabilidade , Transporte Proteico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
11.
J Stroke Cerebrovasc Dis ; 29(8): 104941, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689643

RESUMO

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health threat. Some COVID-19 patients have exhibited widespread neurological manifestations including stroke. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19. COVID-19-associated coagulopathy is increasingly recognized as a result of acute infection and is likely caused by inflammation, including inflammatory cytokine storm. Recent studies suggest that axonal transport of SARS-CoV-2 to the brain can occur via the cribriform plate adjacent to the olfactory bulb that may lead to symptomatic anosmia. The internalization of SARS-CoV-2 is mediated by the binding of the spike glycoprotein of the virus to the angiotensin-converting enzyme 2 (ACE2) on cellular membranes. ACE2 is expressed in several tissues including lung alveolar cells, gastrointestinal tissue, and brain. The aim of this review is to provide insights into the clinical manifestations and pathophysiological mechanisms of stroke in COVID-19 patients. SARS-CoV-2 can down-regulate ACE2 and, in turn, overactivate the classical renin-angiotensin system (RAS) axis and decrease the activation of the alternative RAS pathway in the brain. The consequent imbalance in vasodilation, neuroinflammation, oxidative stress, and thrombotic response may contribute to the pathophysiology of stroke during SARS-CoV-2 infection.


Assuntos
Betacoronavirus/patogenicidade , Encéfalo/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Encefalite Viral/fisiopatologia , Pneumonia Viral/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Betacoronavirus/metabolismo , Coagulação Sanguínea , Encéfalo/metabolismo , Encéfalo/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Encefalite Viral/epidemiologia , Encefalite Viral/metabolismo , Encefalite Viral/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Mediadores da Inflamação/metabolismo , Estresse Oxidativo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/metabolismo , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/virologia , Vasodilatação , Virulência
12.
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
13.
Medicine (Baltimore) ; 99(28): e20921, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664088

RESUMO

Inflammation is an important pathophysiological process after an acute stroke (AS). Pro- and anti-inflammatory molecules (cytokines and interleukins) are the key players during this mechanism. Emerging evidence indicate that these molecules can serve as biomarkers of stroke progression and outcome and as novel therapeutics agents. The aim of this study is to explore the temporal changes in these molecules and validate them as biomarker of AS progression and neurological outcome.The "Cytokine Registry In Stroke Patients (CRISP)" is a prospective cohort study of 600 AS patients presenting to the tertiary hospital with-in 24 h of the onset of symptoms. Plasma cytokines and interleukins will be collected at admission and 24 h after and will be measured using enzyme-linked immunosorbent assay (ELISA) to evaluate the difference in their variation among different gender, race and ethnicity and their association with various neurological outcomes. The primary exposures are biological sex (male, female) and race/ethnicity. Confounding variables include age, vascular risk factors, infarct size, stroke onset to presentation time, and identified stroke etiologies. Matched controls will be used for the comparison and evaluation of the difference among gender and race/ethnicities.CRISP is a prospective observational study that investigates the role and relationship of molecular biomarkers identifying specific and relevant targets pertinent for monitoring the progression and outcome in AS patients.Trial Registration: The study is registered on ClinicalTrial.gov: https://clinicaltrials.gov/ (NCT03297827).


Assuntos
Isquemia Encefálica/metabolismo , Citocinas/sangue , Interleucinas/sangue , Acidente Vascular Cerebral/metabolismo , Doença Aguda , Biomarcadores/sangue , Isquemia Encefálica/fisiopatologia , Protocolos Clínicos/normas , Progressão da Doença , Ensaio de Imunoadsorção Enzimática/métodos , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Inflamação/metabolismo , Masculino , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
14.
Sci Rep ; 10(1): 9400, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523084

RESUMO

Pamoic acid is a potent ligand for G protein Coupled Receptor 35 (GPR35) and exhibits antinociceptive property. GPR35 activation leads to increased energy utilization and the expression of anti-inflammatory genes. However, its role in brain disorders, especially in stroke, remains unexplored. Here we show in a mouse model of stroke that GPR35 activation by pamoic acid is neuroprotective. Pharmacological inhibition of GPR35 reveals that pamoic acid reduces infarcts size in a GPR35 dependent manner. The flowcytometric analysis shows the expression of GPR35 on the infiltrating monocytes/macrophages and neutrophils in the ischemic brain. Pamoic acid treatment results in a preferential increment of noninflammatory Ly-6CLo monocytes/macrophages in the ischemic brain along with the reduced neutrophil counts. The neuroprotective effect of GPR35 activation depends on protein kinase B (Akt) and p38 MAPK. Together we conclude that GPR35 activation by pamoic acid reprograms Ly-6CLo monocytes/macrophages to relay a neuroprotective signal into the ischemic brain.


Assuntos
Isquemia Encefálica/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isquemia Encefálica/tratamento farmacológico , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/metabolismo , Modelos Animais de Doenças , Ligantes , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Naftóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo
15.
Stroke ; 51(7): 2208-2218, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32521221

RESUMO

BACKGROUND AND PURPOSE: The therapeutic use of transcranial direct current stimulation (tDCS), an adjuvant tool for stroke, induces long-term changes in cortical excitability, for example, the secretion of activity-dependent growth factors. We assessed the proper therapeutic configuration of high-definition tDCS (HD-tDCS) in the subacute stage of ischemic stroke and its underlying expression profiling of growth factors to propose a new method for ensuring better therapeutic effects. METHODS: Male C57BL/6J mice were subjected to middle cerebral artery occlusion, after which repetitive HD-tDCS (20 minutes, 55 µA/mm2, charge density 66 000 C/m2) was applied from subacute phases of their ischemic insult. Behavioral tests assessing motor and cognitive functions were used to determine suitable conditions and HD-tDCS stimulation sites. Gene expression profiling of growth factors and their secretion and activation were analyzed to shed light on the underlying mechanisms. RESULTS: Anodal HD-tDCS application over the contralesional cortex, especially the motor cortex, was more effective than ipsilesional stimulation in attenuating motor and cognitive deficits. In the HD-tDCS application over the contralesional motor cortex, positive changes in Bmp8b, Gdf5, Il4, Pdgfa, Pgf, and Vegfb were observed in the ipsilesional site. The expression of GDF5 (growth/differentiation factor 5) and PDGFA (platelet-derived growth factor subunit A) tended to similarly increase in both ipsi- and contralesional striata. However, higher expression levels of GDF5 and PDGFA and their receptors were observed in the peri-infarct regions of the striatum after HD-tDCS, especially in PDGFA expression. A higher number of proliferating or newly formed neuronal cells was detected in ipsilesional sites such as the subventricular zone. CONCLUSIONS: Application of anodal HD-tDCS over the contralesional cortex may enhance beneficial recovery through the expression of growth factors, such as GDF5 and PDGFA, in the ipsilesional site. Therefore, this therapeutic configuration may be applied in the subacute stage of ischemic stroke to ameliorate neurological impairments.


Assuntos
Lateralidade Funcional/fisiologia , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Estimulação Transcraniana por Corrente Contínua , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Fator 5 de Diferenciação de Crescimento/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Derivado de Plaquetas/biossíntese , Acidente Vascular Cerebral/metabolismo
16.
Life Sci ; 256: 117992, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32569781

RESUMO

AIMS: C1q/tumor necrosis factor-related protein-1 (CTRP1) is a newly identified adiponectin paralog that modulates metabolism and inflammation. However, the cerebral function of CTRP1 remains unknown. This study aimed to determine its role and mechanism in cerebral ischemia and reperfusion injury. MAIN METHODS: Serum level of CTRP1 as well as high-sensitivity C reactive protein (hs-CRP) in stroke patients was measured by ELISA assay. The levels of TNF-α, IL-1ß, and IL-6 were analyzed using ELISA kits. Quantitative RT-PCR, western blot analysis were conducted to detect indicated genes. KEY FINDINGS: CTRP1 was significantly upregulated in sera from patients with stroke and positive correlation with hs-CRP. CTRP1 was significantly upregulated in BV2 microglia exposed to oxygen and glucose deprivation and reperfusion (OGD/R). Knockdown of CTRP1 by si-CTRP1 transfection markedly enhanced OGD/R-induced autophagy and accelerated the inflammatory response in BV2 cells, as indicated by increased expression of LC3-II/LC3-I and beclin1, as well as increased concentration of the proinflammatory cytokines TNF-α, IL-1ß, and IL-6. However, recombinant CTRP1 or overexpression of CTRP1 attenuated OGD/R-induced autophagy and inflammatory response in BV2 cells. Further study demonstrated that knockdown of CTRP1 decreased, while recombinant CTRP1 increased the phosphorylation of Akt and mTOR in BV2 cells. IGF-1, which activates PI3-kinase and MEK1/2, abolished the promotive effect of si-CTRP1, while inhibition of Akt with A6730 reversed the inhibitory effect of recombinant CTRP1 on BV2 cells autophagy and inflammation response. SIGNIFICANCE: CTRP1 inhibited microglia autophagy and inflammation response by regulating the Akt/mTOR pathway.


Assuntos
Autofagia/fisiologia , Microglia/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Adulto , Animais , Linhagem Celular , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Acidente Vascular Cerebral/metabolismo
17.
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.
BMC Neurol ; 20(1): 250, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32563250

RESUMO

BACKGROUND: Post-stroke depression (PSD) is a mood disorder characterized by depression and anhedonia caused by stroke. Metabolomics identified metabolites associated with PSD, but previous studies are based on gas chromatography (GC)/mass spectrometry (MS). This study aimed to perform a liquid chromatography (LC)-MS-based metabolomics study of the plasma metabolite profiles between patients with PSD and controls. METHODS: This was a prospective study of patients with stroke enrolled between July and December 2017 at the Second Affiliated Hospital of Nanchang University. Patients were grouped as Hamilton Depression Rating Scale > 7 (PSD) or < 7 (controls). Metabonomics profiling of plasma sampled was conducted by LC-MS. By combining multivariable and univariable statistical analyses, significant differential metabolites between the two groups were screened. The threshold for significant differences was VIP ≥1 and P < 0.05. Log2FC is the logarithm of the mean ratio between the two groups. RESULTS: There were no significant difference with respect to age, NIHSS score, and MMSE between the two groups (all P > 0.05). There were six differential metabolites between the PSD and stroke groups, of which three metabolites were increased and three were decreased. Compared with the control group, p-chlorophenylalanine (Log2FC = 1.37, P = 0.03), phenylacetyl glutamine (Log2FC = 0.21, P = 0.048), and DHA (Log2FC = 0.77, P = 0.01) levels were higher in the PSD group, while betaine (trimethylglycine) (Log2FC = - 0.79, P = 0.04), palmitic acid (Log2FC = - 0.51, P = 0.001), and MHPG-SO4 (Log2FC = - 2.37, P = 0.045) were decreased. CONCLUSION: Plasma metabolomics showed that amino acid metabolism (phenylacetyl glutamine, p-chlorophenylalanine, trimethylglycine), lipid metabolism (DHA, palmitic acid, trimethylglycine), and oxidative stress (DHA, palmitic acid, trimethylglycine) were associated with PSD. These results could help to reveal the pathophysiological mechanism of PSD and eventually identify treatment targets.


Assuntos
Aminoácidos/metabolismo , Depressão/metabolismo , Metabolismo dos Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Acidente Vascular Cerebral/complicações , Idoso , Depressão/etiologia , Feminino , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/psicologia
19.
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
20.
Brain Behav Immun ; 87: 115-119, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32360439

RESUMO

OBJECTIVE: Acute stroke remains a medical emergency even during the COVID-19 pandemic. Most patients with COVID-19 infection present with constitutional and respiratory symptoms; while others present with atypical gastrointestinal, cardiovascular, or neurological manifestations. Here we present a series of four patients with COVID-19 that presented with acute stroke. METHODS: We searched the hospital databases for patients that presented with acute stroke and concomitant features of suspected COVID-19 infection. All patients who had radiographic evidence of stroke and PCR-confirmed COVID-19 infection were included in the study. Patients admitted to the hospital with PCR- confirmed COVID-19 disease whose hospital course was complicated with acute stroke while inpatient were excluded from the study. Retrospective patient data were obtained from electronic medical records. Informed consent was obtained. RESULTS: We identified four patients who presented with radiographic confirmation of acute stroke and PCR-confirmed SARS-CoV-2 infection. We elucidate the clinical characteristics, imaging findings, and the clinical course. CONCLUSIONS: Timely assessment and hyperacute treatment is the key to minimize mortality and morbidity of patients with acute stroke. Stroke teams should be wary of the fact that COVID-19 patients can present with cerebrovascular accidents and should dawn appropriate personal protective equipment in every suspected patient. Further studies are urgently needed to improve current understandings of neurological pathology in the setting of COVID-19 infection.


Assuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Acidente Vascular Cerebral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/metabolismo , Feminino , Hospitalização , Humanos , Masculino , Pandemias , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/metabolismo , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações
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