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1.
BMC Neurol ; 19(1): 289, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729962

RESUMO

BACKGROUND: Ischemia-reperfusion (I/R)-induced vascular dysfunction is the main factor to acute ischemic stroke. Sirt3 is one of the sirtuin family members, which plays an important role in the development of neurological diseases. METHODS: In this study, we constructed I/R injury model on HBMEC cells and induced the overexpression of Sirt3 in model cells. Meanwhile, the p38 activator U-46619 was used to examine the connection between Sirt3 and p38. We also examined the level of endothelial associated proteins, including occluding, ZO-1 and claudin-4 by using qRT-PCR and western blot. RESULTS: Our findings indicated that overexpression of Sirt3 decreased the permeability of model cells and promoted in the growth of endothelial cells. However, the activation of p38 could antagonize the function of Sirt3 in HBMEC cells. Moreover, Our results indicated a positive correlation between Sirt3 and inter-endothelial junction proteins. Importantly, PPAR-γ agonist and inhibitor were utilized to investigate the role of PPAR-γ in Sirt3 mediated cell function. Sirt3 was targeted by PPAR-γ in model cells. CONCLUSIONS: Taken together, this research not only demonstrated PPAR-γ might benefit to the growth of endothelial cell though activating Sirt3 but also indicated its potential value in the treatment for ischemic stroke.


Assuntos
Permeabilidade Capilar/fisiologia , Células Endoteliais/metabolismo , PPAR gama/metabolismo , Sirtuína 3/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Linhagem Celular , Humanos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
2.
Life Sci ; 237: 116919, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610200

RESUMO

AIMS: Stroke-prone spontaneously hypertensive rats (SHRSP) show significantly lower body weight than normotensive Wistar-Kyoto rats (WKY). Our hypotheses are as follows: weight loss of the skeletal muscle is related to hypertension-related diseases, and muscle hypotrophy is useful as a therapeutic target for hypertension and hypertension-related diseases. In this study, we aimed to investigate the pathophysiological characteristics of muscle hypotrophy in SHRSP to determine the therapeutic target molecule(s). MAIN METHODS: The difference in skeletal muscles in the lower leg between WKY and SHRSP was evaluated mainly through weight/tibial length, histological, gene expression, and protein expression analyses. KEY FINDINGS: SHRSP had a significantly lower weight/tibial length in soleus and gastrocnemius, but not in plantaris and tibialis anterior, indicating that muscles consisting of a relatively high amount of slow muscle fiber were affected. This result was confirmed by the histological analysis of soleus, showing that type I fiber mainly decreased the fiber size. Microarray and protein expression analyses showed that the muscle-specific ubiquitin ligase, muscle RING finger 1 (MuRF1), but not atrogin-1, was highly expressed in soleus, but not in plantaris, in SHRSP. TNF-like weak inducer of apoptosis receptor (TWEAKR) was predicted as a MuRF1 up-regulator by Ingenuity Pathway Analysis and immunostained only in type II fiber in WKY but in both type I and II fibers in SHRSP. SIGNIFICANCE: TWEAKR is a type II-specific receptor in the skeletal muscle. Ectopic TWEAKR expression in type I fiber of SHRSP is most likely involved in slow muscle-specific hypotrophy through MuRF1 overexpression.


Assuntos
Hipertensão/patologia , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Músculo Liso Vascular/patologia , Atrofia Muscular/patologia , Acidente Vascular Cerebral/patologia , Receptor de TWEAK/metabolismo , Animais , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Liso Vascular/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Receptor de TWEAK/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
3.
Life Sci ; 237: 116915, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610207

RESUMO

AIMS: The objective of the study was to determine whether ß-caryophyllene (BCP) exerts a neuroprotective effect in cerebral ischemia-reperfusion (I/R) injury by inhibiting microglial activation and modulating their polarization via the TLR4 pathway. MAIN METHODS: Wild-type (WT) and TLR4 knockout (KO) C57BL/6J mice were subjected to cerebral I/R injury and neurologic dysfunction, cerebral infarct volume, brain edema, microglia activation and polarization, and TLR4 expression were determined. In vitro, primary microglia were stimulated with LPS and IFN-γ or IL-4 to induce polarization of microglia toward M1 or M2 phenotypes. KEY FINDINGS: BCP reduced cerebral infarct volume, brain edema, and neurologic deficits in WT mice after I/R. The optimal dose of BCP, 72 mg/kg body weight, inhibited microglial activation and reduced the secretion of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 by microglia of WT mice. BCP inhibited the level of TLR4 in WT mice, and partially reduced neurologic deficits, infarct volume, and brain edema in TLR4 KO mice. Importantly, BCP reduced the number of activated M1-type microglia and increased the number of M2-type microglia in the ipsilateral cortex of both WT and TLR4 KO mice. In vitro, BCP decreased the secretion of proinflammatory cytokines induced by LPS plus IFN-γ, downregulated the level of TLR4 protein, and polarized microglia towards the M2 phenotype. SIGNIFICANCES: The decrease in TLR4 activity mediated, at least in part, the anti-inflammatory effects of BCP and its ability to shift microglia polarization from the M1 to M2 phenotype.


Assuntos
Isquemia Encefálica/prevenção & controle , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos/farmacologia , Acidente Vascular Cerebral/prevenção & controle , Receptor 4 Toll-Like/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
4.
Nat Neurosci ; 22(11): 1892-1902, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31611708

RESUMO

Blood vessels in the CNS form a specialized and critical structure, the blood-brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells with peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizure, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders.


Assuntos
Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Células Endoteliais/metabolismo , Esclerose Múltipla/metabolismo , Convulsões/metabolismo , Acidente Vascular Cerebral/metabolismo , Transcriptoma/genética , Animais , Biotina/metabolismo , Encéfalo/metabolismo , Infarto da Artéria Cerebral Média , Ácido Caínico , Camundongos , Camundongos Transgênicos , Esclerose Múltipla/induzido quimicamente , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Permeabilidade , Toxina Pertussis , Convulsões/induzido quimicamente , Transdução de Sinais
5.
Comput Biol Chem ; 83: 107116, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31561071

RESUMO

According to the Trial of Org 10172 in Acute Stroke Treatment, ischemic stroke is classified into five subtypes. However, the predictive biomarkers of ischemic stroke subtypes are still largely unknown. The utmost objective of this study is to map, construct and analyze protein-protein interaction (PPI) networks for all subtypes of ischemic stroke, and to suggest the predominant biological pathways for each subtypes. Through 6285 protein data retrieved from PolySearch2 and STRING database, the first PPI networks for all subtypes of ischemic stroke were constructed. Notably, F2 and PLG were identified as the critical proteins for large artery atherosclerosis (LAA), lacunar, cardioembolic, stroke of other determined etiology (SOE) and stroke of undetermined etiology (SUE). Gene ontology and DAVID analysis revealed that GO:0030193 regulation of blood coagulation and GO:0051917 regulation of fibrinolysis were the important functional clusters for all the subtypes. In addition, inflammatory pathway was the key etiology for LAA and lacunar, while FOS and JAK2/STAT3 signaling pathways might contribute to cardioembolic stroke. Due to many risk factors associated with SOE and SUE, the precise etiology for these two subtypes remained to be concluded.


Assuntos
Isquemia Encefálica/classificação , Mapas de Interação de Proteínas , Proteínas/análise , Acidente Vascular Cerebral/classificação , Biomarcadores/análise , Biomarcadores/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Bases de Dados de Proteínas , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Ligação Proteica , Proteínas/genética , Proteínas/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo
6.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514409

RESUMO

Hypertension is the most common modifiable risk factor for stroke, and understanding the underlying mechanisms of hypertension and hypertension-related stroke is crucial. 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE), which plays an important role in vasoconstriction, autoregulation, endothelial dysfunction, angiogenesis, inflammation, and blood-brain barrier integrity, has been linked to hypertension and stroke. 20-HETE can promote hypertension by potentiating the vascular response to vasoconstrictors; it also can reduce blood pressure by inhibition of sodium transport in the kidney. The production of 20-HETE is elevated after the onset of both ischemic and hemorrhagic strokes; on the other hand, subjects with genetic variants in CYP4F2 and CYP4A11 that reduce 20-HETE production are more susceptible to stroke. This review summarizes recent genetic variants in CYP4F2, and CYP4A11 influencing 20-HETE production and discusses the role of 20-HETE in hypertension and the susceptibility to the onset, progression, and prognosis of ischemic and hemorrhagic strokes.


Assuntos
Ácidos Hidroxieicosatetraenoicos/metabolismo , Hipertensão/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Progressão da Doença , Humanos , Modelos Biológicos , Polimorfismo Genético
7.
Ann Hematol ; 98(12): 2673-2681, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31478061

RESUMO

Sickle cell anemia (SCA) is an autosomal recessive monogenic disease with significant clinical variability. Cerebrovascular disease, particularly ischemic stroke, is one of the most severe complications of SCA in children. This study aimed to investigate the influence of genetic variants on the levels of fetal hemoglobin (Hb F) and biochemical parameters related with chronic hemolysis, as well as on ischemic stroke risk, in ninety-one unrelated SCA patients, children of sub-Saharan progenitors. Our results show that a higher Hb F level has an inverse relationship with the occurrence of stroke, since the group of patients who suffered stroke presents a significantly lower mean Hb F level (5.34 ± 4.57% versus 9.36 ± 6.48%; p = 0.024). Furthermore, the co-inheritance of alpha-thalassemia improves the chronic hemolytic pattern, evidenced by a decreased reticulocyte count (8.61 ± 3.58% versus 12.85 ± 4.71%; p < 0.001). In addition, our findings have confirmed the importance of HBG2 and BCL11A loci in the regulation of Hb F expression in sub-Saharan African SCA patients, as rs7482144_A, rs11886868_C, and rs4671393_A alleles are significantly associated with a considerable increase in Hb F levels (p = 0.019, p = 0.026, and p = 0.028, respectively). Concerning KLF1, twelve different variants were identified, two of them novel. Seventy-three patients (80.2%) presented at least one variant in this gene. However, no correlation was observed between the presence of these variants and Hb F level, severity of hemolysis, or stroke occurrence, which is consistent with their in silico-predicted minor functional consequences. Thus, we conclude that the prevalence of functional KLF1 variants in a sub-Saharan African background does not seem to be relevant to SCA clinical modulation.


Assuntos
Grupo com Ancestrais do Continente Africano , Anemia Falciforme , Isquemia Encefálica , Hemoglobina Fetal , Regulação da Expressão Gênica , Acidente Vascular Cerebral , Adolescente , Anemia Falciforme/complicações , Anemia Falciforme/etnologia , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Isquemia Encefálica/etnologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Criança , Pré-Escolar , Feminino , Hemoglobina Fetal/biossíntese , Hemoglobina Fetal/genética , Loci Gênicos , Humanos , Masculino , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo
8.
Med Sci Monit ; 25: 5934-5941, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31397429

RESUMO

BACKGROUND The impact of low-density lipoprotein cholesterol (LDL-C) levels on outcomes in patients with non-diabetic acute ischemic stroke remains uncertain. The objective of this study was to explore whether LDL-C could refine outcomes after acute ischemic stroke in patients with non-diabetic acute ischemic stroke. MATERIAL AND METHODS A multi-center, retrospective, clinical-based study was conducted within eight hospitals between January 2015 and August 2016. Adjusted odds ratio (aOR) was used for measurement of unfavorable outcome which was evaluated by the modified Rankin Scale (mRS) score at 6 months after acute ischemic stroke, estimated categorically according to multivariate logistic regression. RESULTS A total of 1614 participants with non-diabetic acute ischemic stroke were enrolled, of which 376 patients (23.3%) had unfavorable neurologic outcomes at 6 months. After multivariate analysis comparing 4 LDL-C levels by quartiles (Q), we found that compared to Q1 (LDL-C level ≤2.41 mmol/L), there was a significant association between the frequency of unfavorable outcomes and levels of LDL-C (Q3: 2.95-3.54 mmol/L) for all participants (adjusted odds ratio [aOR]=0.63; 95% CI: 0.44-0.92, P=0.016) and patients with first ever strokes (aOR=0.52; 95% CI: 0.31-0.87, P=0.013). CONCLUSIONS Compared to lower LDL-C levels, non-diabetic patients with LDL-C levels in Q3 (2.95-3.54 mmol/L), were less likely to have unfavorable functional outcomes at 6 months after acute ischemic stroke. Managing HDL-C is one of the most important steps for the recovery of acute ischemic stroke.


Assuntos
LDL-Colesterol/efeitos adversos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , China , LDL-Colesterol/metabolismo , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
9.
J Stroke Cerebrovasc Dis ; 28(10): 104299, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31371141

RESUMO

Cognitive dysfunction is the most common nonphysical impairment in the stroke survivors. This impairment has a negative impact on patients' quality of life affects their daily living activities. Both pharmacological and nonpharmacological interventions are employed to improve cognitive impairment. Recently, nonpharmacological interventions have attracted great attention. Cognitive rehabilitation is considered as a therapeutic strategy to improve and maintain cognitive skills in patients with stroke. Enriched environment (EE), as a cognitive rehabilitation strategy, has been shown to facilitate physical, cognitive, as well as social abilities. Moreover, EE has been shown to increase endogenous growth factors. Growth factors have pivotal role in neurogenesis, synaptogenesis, as well as brain remodeling through neuron development, differentiation, and survival. In addition, administration of exogenous growth factors prevents cognitive dysfunction. Here, we review preclinical and clinical evidence of cognitive rehabilitation and role of growth factors in treating poststroke cognitive impairment.


Assuntos
Isquemia Encefálica/reabilitação , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Terapia Cognitivo-Comportamental , Disfunção Cognitiva/reabilitação , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/terapia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/psicologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/psicologia , Resultado do Tratamento
10.
Blood ; 134(13): 1037-1045, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31431443

RESUMO

With timely and effective treatment, most patients with thrombotic thrombocytopenic purpura (TTP) survive the acute TTP episode. In addition to the risk of relapse, TTP survivors have higher all-cause mortality than the general population and increased rates of chronic morbidities, including hypertension, depression, and mild cognitive impairment. We conducted this retrospective-prospective cohort study to determine the incidence and prevalence of stroke after recovery from acute TTP and to test the hypothesis that lower ADAMTS13 activity after recovery from TTP is associated with an increased risk of stroke during remission. Of 170 consecutive patients treated for TTP at The Johns Hopkins Hospital from 1995 through 2018, 14 (8.2%) died during the index episode and 19 were observed for less than 1 month after recovery. Of the remaining 137 patients, 18 (13.1%) developed stroke unrelated to an acute TTP episode over a median observation period of 3.08 years, which is fivefold higher than the expected prevalence of 2.6% from an age- and sex-matched reference population (P = .002). ADAMTS13 activity during remission was measured in 52 patients and was >70% in 44.2%, 40% to 70% in 23.1%, 10% to 39% in 25%, and <10% in 7.7%. Stroke after recovery from acute TTP occurred in 0% (0 of 22) of patients with normal remission ADAMTS13 activity (>70%) and in 27.6% (8 of 29) of patients with low ADAMTS13 activity (≤70%; P = .007). In conclusion, stroke is common after recovery from TTP and is associated with reduced ADAMTS13 activity during remission.


Assuntos
Proteína ADAMTS13/metabolismo , Púrpura Trombocitopênica Trombótica/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Fatores Etários , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Púrpura Trombocitopênica Trombótica/metabolismo , Estudos Retrospectivos , Fatores Sexuais , Acidente Vascular Cerebral/metabolismo , Resultado do Tratamento
11.
Postgrad Med ; 131(7): 423-437, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31382796

RESUMO

Hyperglycemia on hospital admission is a common phenomenon in acute ischemic stroke patients and represents an independent predictor of poor clinical outcome with or without acute recanalization therapies (systemic thrombolysis or mechanical thrombectomy). Effective restoration of normoglycemia is considered to be beneficial, but conclusive evidence from randomized controlled clinical trials and specific recommendations are lacking. In addition, aggressive glucose control can be complicated by hypoglycemia leading to early neurological deterioration. We conducted a systematic literature review with the aim of addressing several questions: timing of glucose control, target range, type of insulin delivery, duration and practicability of glucose-lowering protocols. Special issues regarding mechanical thrombectomy and glycemic variability can then be investigated in future trials which are also being considered.


Assuntos
Isquemia Encefálica/terapia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Acidente Vascular Cerebral/terapia , Glicemia/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Hospitalização , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hipoglicemia/induzido quimicamente , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismo , Trombectomia , Terapia Trombolítica
12.
Biomed Pharmacother ; 117: 109155, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387178

RESUMO

Stroke is a leading cause of mortality and disability globally. Cerebral ischaemia-reperfusion (I/R) injury is characterized by significant inflammation and extensive cell death. Multiple signaling pathways play essential roles in the process, and identifying the unclear crucial regulators of these pathways may provide promising targets for treatment. CASP8 and FADD-like apoptosis regulator (CFLAR) is expressed in multiple organs to regulate inflammation. Here, we reported that CFLAR expression was markedly reduced in brain samples of mice with middle cerebral artery occlusion (MCAO) stroke. Furthermore, CFLAR knockdown markedly elevated the neurological deficit, brain water content and the infarct volume. In addition, significantly promoted inflammation and endoplasmic reticulum (ER) stress was detected in brain tissues of mice after MCAO, as evidenced by the promoted expression of p-IκBα, p-nuclear factor (NF)-κB (p65), glucose-regulated protein 78 (GRP78), PKR-like ER kinase (PERK), activating transcription factor-6 (ATF-6) and cleaved Caspase-12. Notably, MCAO-induced cerebral I/R injury was markedly alleviated in mice over-expressing CFLAR through suppressing inflammation and ER stress. Furthermore, our in vitro results indicated that oxygen-glucose deprivation (OGD)-induced cell death was evidently ameliorated by CFLAR over-expression. In contrast, the cell death triggered by OGD was accelerated by CFLAR knockdown in vitro through enhancing Caspase-3 cleavage, and this effect was obviously ameliorated by the blockage of ER stress using 4-phenyl butyric acid (4-PBA). Collectively, these results demonstrated that CFLAR could be considered as a novel candidate to develop effective therapeutic treatment against cerebral I/R injury.


Assuntos
Isquemia Encefálica/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Inflamação/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Apoptose/fisiologia , Encéfalo/metabolismo , Linhagem Celular , Células HEK293 , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/metabolismo
13.
BMC Neurol ; 19(1): 177, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345181

RESUMO

BACKGROUND: Insulin resistance (IR) in relation to diabetes is a risk factor for ischemic stroke (IS), whereas less is known about non-diabetic IR and outcome after IS. METHODS: In non-diabetic IS (n = 441) and controls (n = 560) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), IR was investigated in relation to IS severity and functional outcome. IR was evaluated acutely and after 3 months using the Homeostasis model assessment of IR (HOMA-IR). Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS). Functional outcome was evaluated using the modified Rankin Scale (mRS) after 3 months, 2 and 7 years. Associations were evaluated by logistic regression. RESULTS: Higher acute and 3-month HOMA-IR was observed in IS compared to the controls (both p < 0.001) and in severe compared to mild IS (both p < 0.05). High acute HOMA-IR was associated with poor outcome (mRS 3-6) after 3 months and 7 years [crude Odds ratios (ORs), 95% confidence intervals (CIs) 1.50, 1.07-2.11 and 1.59, 1.11-2.30, respectively], but not after 2 years. These associations lost significance after adjustment for all covariates including initial stroke severity. In the largest IS subtype (cryptogenic stroke), acute HOMA-IR was associated with poor outcome after 2 years also after adjustment for age and stroke severity (OR 2.86, 95% CI 1.01-8.12). CONCLUSIONS: In non-diabetic IS patients, HOMA-IR was elevated and related to stroke severity, but after adjustment for IS severity, the associations between HOMR-IR and poor outcome lost significance. This could suggest that elevated IR mostly is a part of the acute IS morbidity. However, in the subgroup of cryptogenic stroke, the associations with poor outcome withstood correction for stroke severity.


Assuntos
Isquemia Encefálica/metabolismo , Resistência à Insulina , Acidente Vascular Cerebral/metabolismo , Estudos de Casos e Controles , Feminino , Homeostase , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco
14.
Food Funct ; 10(8): 4725-4738, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31304955

RESUMO

Antrodia camphorata is a well-known traditional Chinese mushroom used as a functional food and nutraceutical in Taiwan and China. The aim of this study was to explore the protective effects and mechanism(s) of the ethyl acetate crude extract of A. camphorata (EtOAc-AC) and its active constituent ergostatrien-7,9(11),22-trien-3ß-ol (EK100) in an acute ischemic stroke (AIS) murine model. Treating mice with induced AIS injury by using EtOAc-AC (0.3-0.6 g kg-1, p.o.) and EK100 (60 and 120 mg kg-1, p.o.) 2 h after AIS induction significantly increased the tracking distance and reduced brain infarction. Both EtOAc-AC and EK-100 reduced the expression levels of p65NF-κB and caspase 3 near the peri-infarct cortex and promoted the expression of neurogenesis-associated protein doublecortin (DCX) near the hippocampus, accompanied by glycogen synthase kinase 3 (GSK-3) inhibition and ß-catenin upregulation. Signaling pathway analysis revealed that the advantageous effects of EtOAc-AC and EK-100 involved triggering the activation of PI3K/Akt and inhibition of GSK-3. Our findings suggest that EtOAc-AC and its active constituent EK100 display anti-inflammatory and anti-apoptotic activities. Both EtOAc-AC and EK100 reduce ischemic brain injury by decreasing p65NF-κB and caspase 3 expression, and they promote neurogenesis (DCX) and neuroprotection (Bcl2) by activating the PI3k/Akt-associated GSK3 inhibition and ß-catenin activation.


Assuntos
Antrodia/química , Isquemia Encefálica/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Ergosterol/análogos & derivados , Neurogênese/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Caspase 3/genética , Caspase 3/metabolismo , Cateninas/genética , Cateninas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Ergosterol/administração & dosagem , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
15.
Cell Mol Neurobiol ; 39(8): 1151-1163, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31270712

RESUMO

Ischemic stroke often causes motor and cognitive deficits. Deregulated glia gap junction communication, which is reflected by increased protein levels of glial fibrillary acidic protein (GFAP) and connexin 43 (Cx43), has been observed in ischemic hippocampus and has been associated with cognitive impairment in animal stroke models. Here, we tested the hypothesis that reactive astrocytes-mediated loss of synaptophysin (SYP) and CREB-regulated transcription coactivator 1 (CRTC1) contribute to dysfunction in glia gap junction communication and memory impairment after ischemic stroke. Male Sprague-Dawley rats were subjected to a 90-min middle cerebral artery occlusion (MCAO) with 7-day reperfusion. Fluorocitrate (1 nmol), the reversible inhibitor of the astrocytic tricarboxylic acid cycle, was injected into the right lateral ventricle of MCAO rats once every 2 days starting immediately before reperfusion. The Morris water maze was used to assess memory in conjunction with western blotting and immunostaining to detect protein expression and distribution in the hippocampus. Our results showed that ischemic stroke caused significant memory impairment accompanied by increased protein levels of GFAP and Cx43 in hippocampal tissue. In addition, the levels of several key memory-related important proteins including SYP, CRTC1, myelin basic protein and high-mobility group-box-1 were significantly reduced in the hippocampal tissue. Of note, inhibition of reactive astrocytes with fluorocitrate was shown to significantly reverse the above noted changes induced by ischemic stroke. Taken together, our findings demonstrate that inhibiting reactive astrocytes with fluorocitrate immediately before reperfusion may protect against ischemic stroke-induced memory impairment through the upregulation of CRTC1 and SYP.


Assuntos
Astrócitos/metabolismo , Citratos/farmacologia , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/fisiopatologia , Acidente Vascular Cerebral/metabolismo , Sinaptofisina/metabolismo , Fatores de Transcrição/genética , Regulação para Cima/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Conexina 43/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Proteína HMGB1/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Ratos Sprague-Dawley , Acidente Vascular Cerebral/fisiopatologia , Fatores de Transcrição/metabolismo
16.
Med Sci Monit ; 25: 4869-4876, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257360

RESUMO

BACKGROUND We assessed the relationship between body mass index and results of rehabilitation in stroke patients. MATERIAL AND METHODS The study was carried out at the Clinical Rehabilitation Ward with Early Neurological Rehabilitation Unit at the Clinical Hospital. The examinations were performed 3 times. Based on inclusion and exclusion criteria, 128 subjects were qualified for the first examination, the second examination involved 114 subjects, and 100 stroke patients participated in the third examination. Body mass was examined with an accuracy of 0.1 kg, using a Tanita MC-780 MA body composition analyser. Body mass index (BMI) was calculated for all of the subjects. Effects of rehabilitation were assessed with the Barthel index and Ashworth scale. RESULTS Higher functional status in daily life, measured with the Barthel scale, was found in patients with normal body mass, compared to the overweight and obese subjects (examination I, II, and II). Exam I showed that before rehabilitation the overweight patients obtained significantly higher results in assessment of upper limbs, based on the Ashworth scale (mean=0.35±0.54) compared to the obese patients (mean=0.03±0.32) and those with normal body weight (mean=0.24±0.75). CONCLUSIONS Following hospital-based rehabilitation, patients with normal body mass achieved greater functional efficiency. The findings also show a trend towards normalization of BMI. The positive effect of rehabilitation was sustained for 3 months (Exam III), which may contribute to decreased risk of cardiovascular diseases and complications such as stroke.


Assuntos
Reabilitação do Acidente Vascular Cerebral/métodos , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Peso Corporal , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso , Polônia , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Resultado do Tratamento
17.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356182

RESUMO

Acute cerebral ischemia triggers local and systemic immune response. The aims of this project was to assess the blood serum concentration of the markers of inflammation and markers of the blood brain barrier damage on the first day of ischemic stroke, and the mutual correlations between these marker levels. Patients with first-in-life stroke were analysed according to: plasma concentration of the following markers on the first day of stroke: interleukin 2 (IL-2) and interleuki 6 (IL-6), S100B, tumor necrosis factor-α (TNF-α), progranulin (GRN), neuron specific enolase (NSE), urokinase-type plasminogen activator (uPA), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), C-reactive protein (CRP), leucocyte and thrombocyte counts; their neurological status on the first day of stroke (NIHSS) and their functional status at 30 days following stroke (mRS). The study included 138 patients with mean age: 73.11 ± 11.48. Patients with a higher score on the NIHSS showed significantly higher concentrations of TNF-α, white blood cells (WBC), CRP, NSE, IL-6 and S100B. Patients with a higher score on the modified Rankin Score (mRS) showed significantly higher concentrations of WBC, CRP, GRN, IL-6, S100B. Factors with an independent influence on the neurological status on the first day of stroke were: sex, WBC, total blood platelet (PLT) count, CRP, S100B and IL-6 levels. Atrial fibrillation, leukocyte count, CRP, NSA, uPA, IL-6 and S100B showed an independent impact on the functional status on the 30th day of stroke. Patients with symptomatic atherosclerosis, as compared to others, were older (P = 0.003) and had higher levels of CRP, IL-6, and S100B. In each case, the differences were statistically significant. We conclude that the concentration of Il-6 and S100B on the first day of stroke are important for both the neurological status and the functional status in the acute period of the disease. Increased CRP and leukocyte count are associated with a worse prognosis regarding the course of acute stroke. The expression of pro-inflammatory agents and markers of blood-brain barrier damage in the acute phase of stroke seem to be more prominent in patients with symptomatic atherosclerosis than in patients with no clinical features of atherosclerosis. The expression of inflammatory parameters may indicate the importance of the inflammatory process starting during the early days of ischemic stroke, for the post-stroke neurological deficit.


Assuntos
Biomarcadores/sangue , Barreira Hematoencefálica/patologia , Isquemia Encefálica/patologia , Inflamação/patologia , Acidente Vascular Cerebral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/sangue , Aterosclerose/metabolismo , Aterosclerose/patologia , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/sangue , Isquemia Encefálica/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína C-Reativa/metabolismo , Feminino , Humanos , Inflamação/sangue , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Fosfopiruvato Hidratase/metabolismo , Prognóstico , Estudos Prospectivos , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Life Sci ; 231: 116517, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150684

RESUMO

Our previous study indicated that microRNA 145 (miR-145) and its predicated target, erythropoietin-producing hepatoma (EPH) receptor A4 (EPHA4), was closely associated with ischemic stroke. In this study, we aimed to further explore their function in a model of oxygen-glucose deprivation (OGD). The expression of miR-145 in the blood of 44 patients with ischemic stroke and 37 normal controls was detected by qRT-PCR. After transfection with either the wild- or mutant-type pGL3-promoter EPHA4 3'UTR into the miR-145 mimic and miR-145 inhibitor, a dual-luciferase reporter assay was performed to explore the interaction between miR-145 and EPHA4. qRT-PCR and Western blot were performed to further explore the effects of miR-145 on EPHA4 expression after an miR-145 mimic, an miR-145 inhibitor or LV-sh-EPHA4 was transfected into cerebral cortical neurons. The expression of miR-145 was significantly upregulated in the blood of patients with ischemic stroke compared to that of normal controls. Dual-luciferase reporter assay, qRT-PCR and Western blot results indicated that miR-145 indeed targets EPHA4 through its 3'-UTR and regulates the expression level of EPHA4 at both the mRNA and protein levels. Moreover, the OGD model was successfully constructed, and miR-145 exerted a protective effects in cell viability in the OGD model by downregulating EPHA4. The expression of LOC105376244 could be regulated by the miR-145-EPHA4 interaction. MiR-145 exerted a protective effects in cell viability in the OGD model by downregulating EPHA4, which suggested their potential roles in ischemic stroke and requires further research.


Assuntos
Isquemia Encefálica/metabolismo , Córtex Cerebral/citologia , MicroRNAs/genética , Neurônios/citologia , Receptor EphA4/metabolismo , Idoso , Apoptose/efeitos dos fármacos , Isquemia Encefálica/patologia , Hipóxia Celular/fisiologia , Sobrevivência Celular/genética , Córtex Cerebral/metabolismo , Regulação para Baixo , Feminino , Glucose/metabolismo , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Neurônios/metabolismo , Oxigênio/metabolismo , Cultura Primária de Células , RNA Mensageiro/metabolismo , Acidente Vascular Cerebral/metabolismo
19.
Neural Plast ; 2019: 1460890, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191635

RESUMO

Stroke remains a leading cause of disability worldwide. Recently, we have established an animal model of stroke that results in delayed impairment in spatial memory, allowing us to better investigate cognitive deficits. Young and aged brains show different recovery profiles after stroke; therefore, we assessed aged-related differences in poststroke cognition. As neurotrophic support diminishes with age, we also investigated the involvement of brain-derived neurotrophic factor (BDNF) in these differences. Young (3-6 months old) and aged (16-21 months old) mice were trained in operant touchscreen chambers to complete a visual pairwise discrimination (VD) task. Stroke or sham surgery was induced using the photothrombotic model to induce a bilateral prefrontal cortex stroke. Five days poststroke, an additional cohort of aged stroke animals were treated with intracerebral hydrogels loaded with the BDNF decoy, TrkB-Fc. Following treatment, animals underwent the reversal and rereversal task to identify stroke-induced cognitive deficits at days 17 and 37 poststroke, respectively. Assessment of sham animals using Cox regression and log-rank analyses showed aged mice exhibit an increased impairment on VD reversal and rereversal learning compared to young controls. Stroke to young mice revealed no impairment on either task. In contrast, stroke to aged mice facilitated a significant improvement in reversal learning, which was dampened in the presence of the BDNF decoy, TrkB-Fc. In addition, aged stroke control animals required significantly less consecutive days and correction trials to master the reversal task, relative to aged shams, an effect dampened by TrkB-Fc. Our findings support age-related differences in recovery of cognitive function after stroke. Interestingly, aged stroke animals outperformed their sham counterparts, suggesting reopening of a critical window for recovery that is being mediated by BDNF.


Assuntos
Cognição/fisiologia , Recuperação de Função Fisiológica/fisiologia , Reversão de Aprendizagem/fisiologia , Acidente Vascular Cerebral/psicologia , Animais , Aprendizagem por Discriminação/fisiologia , Modelos Animais de Doenças , Masculino , Camundongos , Receptor trkB/metabolismo , Acidente Vascular Cerebral/metabolismo
20.
Cell Mol Life Sci ; 76(16): 3117-3140, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165904

RESUMO

Stroke is a leading cause of death and disability worldwide. However, after years of in-depth research, the pathophysiology of stroke is still not fully understood. Increasing evidence shows that matrix metalloproteinases (MMPs) and "a disintegrin and metalloproteinase" (ADAMs) participate in the neuro-inflammatory cascade that is triggered during stroke but also in recovery phases of the disease. This review covers the involvement of these proteins in brain injury following cerebral ischemia which has been widely studied in recent years, with efforts to modulate this group of proteins in neuroprotective therapies, together with their implication in neurorepair mechanisms. Moreover, the review also discusses the role of these proteins in specific forms of neurovascular disease, such as small vessel diseases and intracerebral hemorrhage. Finally, the potential use of MMPs and ADAMs as guiding biomarkers of brain injury and repair for decision-making in cases of stroke is also discussed.


Assuntos
Proteínas ADAM/metabolismo , Metaloproteinases da Matriz/metabolismo , Acidente Vascular Cerebral/patologia , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Doenças de Pequenos Vasos Cerebrais/metabolismo , Doenças de Pequenos Vasos Cerebrais/patologia , Humanos , Hemorragias Intracranianas/metabolismo , Hemorragias Intracranianas/patologia , Acidente Vascular Cerebral/metabolismo
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