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1.
Clin Chim Acta ; 565: 119962, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39244142

RESUMO

BACKGROUND: Little is known about the association between serum neuron-specific enolase (NSE) concentration and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. This study aims to investigate if serum NSE concentration is related to the clinical features of anti-NMDAR encephalitis. METHODS: Serum NSE levels were detected in 58 anti-NMDAR encephalitis cases, 58 matched healthy controls and 58 matched disease controls. Demographic features, clinical symptoms, cerebrospinal fluid parameters and brain MRI indexes of the cases were evaluated. RESULTS: Serum NSE concentrations were significant higher in case group than those in healthy controls and disease controls (both p < 0.001). Serum NSE concentrations in patients with mRS≥3 one year after onset were obviously higher than in those with mRS<3 (p < 0.001). Patients with status epilepticus or central hypoventilation had higher serum NSE levels than those without (p = 0.003 and p = 0.006). Serum NSE concentrations in cases with brain lesions or brain atrophy were significant higher than in those without (p = 0.001 and p < 0.001, respectively). Serum NSE concentrations were found to be significant higher in cases with limited response to treatment compared to those with favourable therapy outcomes (p < 0.001). Spearman's correlation analysis showed a significant positive association between serum NSE concentration and mRS score at the most critical time (max mRS) (r = 0.575, p < 0.001) and one year after onset (r = 0.705, p < 0.001). Cox regression results reflected that high serum NSE level was an independent predictor of poor prognosis in anti-NMDAR encephalitis group (p = 0.001), and the ROC curve threshold value was 15.72 ng/ml. CONCLUSIONS: Serum NSE concentrations in anti-NMDAR encephalitis cases are higher than those in controls. It can be used to predict the brain damage degree and prognosis of anti-NMDAR encephalitis cases.

2.
Nat Commun ; 14(1): 3945, 2023 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-37402721

RESUMO

Accumulation of amyloid beta protein (Aß) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aß and produce disease-modifying mediators. Herein, we report that Aß40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.


Assuntos
Doença de Alzheimer , Angiopatia Amiloide Cerebral , Camundongos , Animais , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Camundongos Transgênicos , Angiopatia Amiloide Cerebral/patologia , Encéfalo/metabolismo , Macrófagos/metabolismo , Doença de Alzheimer/metabolismo
3.
J Neurochem ; 164(2): 172-192, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36334306

RESUMO

Acute ischemic stroke (AIS) induces cerebral endothelial cell death resulting in the breakdown of the blood-brain barrier (BBB). Endothelial cell autophagy acts as a protective mechanism against cell death. Autophagy is activated in the very early stages of ischemic stroke and declines after prolonged ischemia. Previous studies have shown that Rubicon can inhibit autophagy. The current study aimed to investigate whether continuous long-term ischemia can inhibit autophagy in endothelial cells after ischemic stroke by regulating the function of Rubicon and its underlying mechanism. Wild-type male C57BL/6J mice were subjected to transient middle cerebral artery occlusion (tMCAO). ROCK1, ROCK2, and NOX2 inhibitors were injected into male mice 1 h before the onset of tMCAO. Disease severity and BBB permeability were evaluated. bEnd.3 cells were cultured in vitro and subjected to oxygen-glucose deprivation (OGD). bEnd.3 cells were pretreated with or without ROCK1, ROCK2, or NOX2 inhibitors overnight and then subjected to OGD. Cell viability and permeability were also evaluated. The expression of Rubicon, ROCK1, and autophagy-related proteins were analyzed. Increased BBB permeability was correlated with Rubicon expression in tMCAO mice and Rubicon was upregulated in endothelial cells subjected to OGD. Autophagy was inhibited in endothelial cells after long-term OGD treatment and knockdown of Rubicon expression restored autophagy and viability in endothelial cells subjected to 6-h OGD. ROCK1 inhibition decreased the interaction between Beclin1 and Rubicon and restored cell viability and autophagy suppressed by 6-h OGD treatment in endothelial cells. Additionally, ROCK1 inhibition suppressed Rubicon, attenuated BBB disruption, and brain injury induced by prolonged ischemia in 6-h tMCAO mice. Prolonged ischemia induced the death of brain endothelial cells and the breakdown of the BBB, thus aggravating brain injury by increasing the interaction of ROCK1 and Rubicon with Beclin1 while inhibiting canonical autophagy. Inhibition of ROCK1 signaling in endothelial cells could be a promising therapeutic strategy to prolong the therapeutic time window in AIS.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , AVC Isquêmico , Masculino , Camundongos , Animais , Células Endoteliais/metabolismo , AVC Isquêmico/metabolismo , Proteína Beclina-1/metabolismo , Camundongos Endogâmicos C57BL , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Lesões Encefálicas/metabolismo , Autofagia
4.
Front Neurol ; 12: 621555, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33967935

RESUMO

Background: The inflammasome represents a highly pro-inflammatory mechanism. It has been identified that inflammasome was activated after ischemic stroke. However, the impact of inflammasomes on stroke outcomes remains contradictory. The participating molecules and the functioning arena of post-stroke inflammasome activation are still elusive. Methods: In the present study, blood samples from stroke patients were collected and analyzed with flow cytometry to evaluate the correlation of inflammasome activation and stroke outcomes. A stroke model was established using male C57/Bl6 mice with transient middle cerebral artery occlusion (tMCAO, 1 h). The dynamics of inflammasome components, cell type, and location of inflammasome activation and the therapeutic effects of inhibiting post-stroke inflammasome executors were evaluated. Results: We found that a high level of inflammasome activation might indicate detrimental stroke outcomes in patients and mice models. Post-stroke inflammasome activation, especially NLRP3, cleaved Caspase-1, cleaved Caspase-11, IL-1ß, IL-18, and GSDMD, peaked at 3-5 days and declined at 7 days with the participation of multiple components in mice. Macrophage that infiltrated into the ischemic lesion was the main arena for post-stroke inflammasome activation among myeloid cells according to the data of mice. Among all the members of the Caspase family, Caspase-1 and -11 served as the main executing enzymes. Inhibiting Caspase-1/-11 signaling efficiently suppressed DAMPs-induced macrophage inflammasome activation and displayed neuroprotection to stroke models including infarct size (Control: 48.05 ± 14.98; Cas1.i: 19.34 ± 12.21; Cas11.i: 21.43 ± 14.67, P < 0.001) and neurological deficit score (0 d-Control: 2.20 ± 0.63; 0 d-Cas1.i: 2.20 ± 0.63; 0 d-Cas11.i: 2.20 ± 0.63; 1 d-Control: 2.50 ± 0.53; 1 d-Cas1.i: 1.50 ± 0.71; 1 d-Cas11.i: 2.00 ± 0.67; 2 d-Control: 2.30 ± 0.48; 2 d-Cas1.i: 1.30 ± 0.48; 2 d-Cas11.i: 1.50 ± 0.53; 3 d-Control: 2.00 ± 0.67; 3 d-Cas1.i: 1.20 ± 0.42; 3 d-Cas11.i: 1.30 ± 0.48, P < 0.001). Conclusions: Taken together, inflammasome activation played a detrimental role in stroke pathology. Targeting post-stroke inflammasome executing enzymes fitting in the dynamics of macrophages might obtain potential and efficient therapeutic effects.

5.
J Neuroinflammation ; 18(1): 90, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33845849

RESUMO

BACKGROUND: A high-salt diet (HSD) is one of the major risk factors for acute ischemic stroke (AIS). As a potential mechanism, surplus salt intake primes macrophages towards a proinflammatory phenotype. In this study, whether HSD could blunt the efferocytic capability of macrophages after ischemic stroke, thus exacerbating post-stroke neural inflammation, was investigated. METHODS: Wild-type male C57BL/6 mice were fed with fodder containing 8% sodium chloride for 4 weeks and subjected to transient middle cerebral occlusion (tMCAO). Disease severity, macrophage polarization as well as efferocytic capability were evaluated. Bone marrow-derived macrophages were cultured in vitro, and the impact of high salinity on their efferocytic activity, as well as their expression of phagocytic molecules, were analyzed. The relationships among sodium concentration, macrophage phenotype, and disease severity in AIS patients were explored. RESULTS: HSD-fed mice displayed increased infarct volume and aggravated neurological deficiency. Mice fed with HSD suffered exacerbated neural inflammation as shown by higher inflammatory mediator expression and immune cell infiltration levels. Infiltrated macrophages within stroke lesions in HSD-fed mice exhibited a shift towards proinflammatory phenotype and impaired efferocytic capability. As assessed with a PCR array, the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a receptor relevant to phagocytosis, was downregulated in high-salt-treated bone marrow-derived macrophages. Enhancement of TREM2 signaling restored the efferocytic capacity and cellular inflammation resolution of macrophages in a high salinity environment in vitro and in vivo. A high concentration of urine sodium in AIS patients was found to be correlated with lower TREM2 expression and detrimental stroke outcomes. CONCLUSIONS: HSD inhibited the efferocytic capacity of macrophages by downregulating TREM2 expression, thus impeding inflammation resolution after ischemic stroke. Enhancing TREM2 signaling in monocytes/macrophages could be a promising therapeutic strategy to enhance efferocytosis and promote post-stroke inflammation resolution.


Assuntos
Dieta , Regulação para Baixo/efeitos dos fármacos , AVC Isquêmico , Macrófagos/efeitos dos fármacos , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/biossíntese , Receptores Imunológicos/metabolismo , Cloreto de Sódio na Dieta/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Inflamação/metabolismo , AVC Isquêmico/complicações , AVC Isquêmico/patologia , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Fagocitose , Receptores Imunológicos/genética
6.
Medicine (Baltimore) ; 100(48): e27996, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-35049207

RESUMO

RATIONALE: Intravascular large B-cell lymphoma (IVLBCL) is a rare form of large B-cell non-Hodgkin lymphoma. The diagnosis is challenging and frequently made at biopsy. Here we reported a case of IVLBCL limited to the central nervous system (CNS) presenting with progressive dementia and acute stroke, who was diagnosed by brain biopsy. PATIENT CONCERNS: A 47-year-old woman was transferred to our hospital with a 6-month history of rapidly progressive dementia, and left limb weakness and numbness for 3 days. She was successively misdiagnosed with inflammatory demyelinating disease and stroke. Her condition deteriorated with elevated lactate dehydrogenase and multiple hyperintense lesions on the brain. DIAGNOSIS: She was diagnosed with IVLBCL limited to the CNS by brain biopsy. INTERVENTIONS: Bone marrow puncture and incisional random skin biopsy were not found neoplastic cells. Computed tomography scans were normal with no evidence of disease outside the CNS. OUTCOMES: The patient died due to rapid clinical aggravation. LESSONS: IVLBCL limited to the CNS is an aggressive disease with high mortality. Making a timely and correct diagnosis is crucial for early appropriate treatment in IVLBCL patients.


Assuntos
Encéfalo/diagnóstico por imagem , Demência , Linfoma Difuso de Grandes Células B/diagnóstico , Acidente Vascular Cerebral , Biópsia , Demência/diagnóstico , Demência/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia
7.
Front Neurol ; 11: 117, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32180757

RESUMO

Objective: The aim of this retrospective study was to investigate the relationship between serum systemic autoantibodies and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods: Thirty-nine patients with anti-NMDAR encephalitis were examined for serum systemic autoantibodies (antinuclear antibodies, extractable nuclear antigen autoantibodies, rheumatoid factors, and anti-neutrophil cytoplasmic antibodies), in comparison with 39 neuromyelitis optica spectrum disorder (NMOSD) and 78 healthy controls. Clinical features, cerebrospinal fluid characteristics, and outcomes were compared between the two subgroups of anti-NMDAR patients with positive and negative systemic autoantibodies, respectively. Results: Anti-NMDAR encephalitis patients had higher frequency of positive serum systemic autoantibodies than healthy controls (23.1 vs. 2.6%, p = 0.001) and lower frequency than NMOSD (23.1 vs. 48.7%, p = 0.018). No patients were diagnosed comorbidities with non-organ-specific autoimmune diseases. Consciousness disturbance was more frequent in autoantibodies positive group than in the negative group (88.9 vs. 40.0%, p = 0.02). Autoantibody positive group had a poorer outcome than autoantibody negative group (55.6 vs. 86.7%, p = 0.043). There was a negative correlation between serum autoantibodies and outcomes in anti-NMDAR encephalitis patients (r = -0.325, p = 0.044). Conclusion: Our data demonstrated serum systemic autoantibodies were more frequent in anti-NMDAR encephalitis patients than in healthy controls and less frequent than NMOSD, which were associated with higher severity of disease.

8.
Stroke ; 51(2): 637-640, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31795900

RESUMO

Background and Purpose- The relationship between infarct dimensions and neurological progression in patients with acute pontine infarctions remains unclear. This study aimed to investigate the morphometric predictive value of magnetic resonance imaging for early neurological deterioration (END) in acute pontine infarction. Methods- We included all patients admitted to our department having an acute ischemic stroke in the pons. The ventrodorsal length multiplied by thickness was measured as parameters of infarct size. END was defined as an incremental increase in the National Institutes of Health Stroke Scale score by ≥1 point in motor power, or ≥2 points in the total score within the first week after admission. Results- We enrolled 407 patients, and 114 (28.0%) patients were diagnosed with END. Adjusted logistic regression analyses showed the maximum length multiplied by thickness was independently associated with END (odds ratio, 4.580 [95% CI, 2.909-7.210]). The sensitivity, specificity, and area under the curve were 77.2%, 79.2%, and 0.843, respectively, in the receiver operating characteristic curve analysis of maximum length multiplied by thickness for predicting END. Conclusions- These results suggest that the maximum length multiplied by thickness may be a possible predictor in the evaluation of progression with isolated acute pontine infarction. The extent of the pontine infarction along the conduction tract may contribute to deterioration.


Assuntos
Isquemia Encefálica/diagnóstico , Infartos do Tronco Encefálico/diagnóstico , Diagnóstico Precoce , Valor Preditivo dos Testes , Acidente Vascular Cerebral/diagnóstico , Idoso , Isquemia Encefálica/fisiopatologia , Infartos do Tronco Encefálico/fisiopatologia , Angiografia Cerebral/métodos , Imagem de Difusão por Ressonância Magnética/métodos , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco , Acidente Vascular Cerebral/fisiopatologia
9.
J Neuroinflammation ; 16(1): 242, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779652

RESUMO

BACKGROUND: Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear. METHODS: In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo. RESULTS: Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD. CONCLUSION: Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.


Assuntos
Astrócitos/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Animais , Astrócitos/metabolismo , Barreira Hematoencefálica/patologia , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/metabolismo , Exenatida/uso terapêutico , Infarto da Artéria Cerebral Média/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
CNS Neurosci Ther ; 25(12): 1299-1307, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31729181

RESUMO

Aging and aging-related CNS diseases are associated with inflammatory status. As an efficient amplifier of immune responses, inflammasome is activated and played detrimental role in aging and aging-related CNS diseases. Macrophage and microglia display robust inflammasome activation in infectious and sterile inflammation. This review discussed the impact of inflammasome activation in microglia/macrophage on senescence "inflammaging" and aging-related CNS diseases. The preventive or therapeutic effects of targeting inflammasome on retarding aging process or tackling aging-related diseases are also discussed.


Assuntos
Envelhecimento/patologia , Doenças do Sistema Nervoso Central/patologia , Inflamassomos , Macrófagos/patologia , Microglia/patologia , Animais , Humanos , Inflamação
11.
Curr Neurovasc Res ; 16(4): 340-347, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31549956

RESUMO

BACKGROUND AND OBJECTIVE: Vitamin D deficiency is internationally recognized among the potentially modifiable risk factors for ischemic cardio-cerebrovascular diseases. However, the association between vitamin D deficiency and stroke morbidity or mortality remains insufficiently known. Our aim is to investigate their relevance to 25-hydroxyvitamin D [25(OH) D] levels and clinical severity and outcome after 3 months in first-ever ischemic stroke. METHODS: Retrospective analysis of 356 consecutive patients in first-ever ischemic stroke between 2013 and 2015. Serum 25(OH) D levels were measured at baseline. Stroke severity was assessed at admission using the National Institutes of Health Stroke Scale (NIHSS) score. Functional outcome after 3 months of onset was evaluated using the modified Rankin scale (mRS). RESULTS: Among the 356 enrolled patients, HbA1c was higher in insufficiency/deficiency group than that in the sufficiency group (6.3 ± 1.7 vs. 5.9 ± 1.1, p =0.015). The hospital stay was longer in insufficiency/deficiency group than that in the sufficiency group (11 (8-17) vs. 9.5 (7-13), p = 0.035). There was a significant inversed trend between serum 25(OH) D levels and hospital stay (OR 0.960, P = 0.031), using logistic regression. CONCLUSION: 25(OH)D levels are associated with glucose homeostasis, 25(OH) D contributes to increase the length of hospital stay. Low serum 25-OHD level is an independent predictor for hospital stay in first-ever ischemic stroke. Vitamin D deficiency did not predict functional outcome in the span of 3 months.


Assuntos
Glicemia/metabolismo , Isquemia Encefálica/complicações , Homeostase/fisiologia , Acidente Vascular Cerebral/complicações , Vitamina D/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Vitamina D/sangue , Deficiência de Vitamina D/sangue
12.
Liver Cancer ; 8(3): 155-171, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31192153

RESUMO

BACKGROUND: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment. METHODS: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors. RESULTS: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given. CONCLUSIONS: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.

13.
FASEB J ; 33(3): 4376-4387, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30694693

RESUMO

Astrocytes mediate the destruction of the blood-brain barrier (BBB) during ischemic stroke (IS). IL-9 is a pleiotropic cytokine that we previously found to be highly expressed in peripheral blood mononuclear cells from patients with IS, and the presence of IL-9 receptors on astrocytes has been reported in the literature. Here, we detected the effect of IL-9 on astrocytes using an anti-IL-9-neutralizing antibody to treat rats with experimental stroke. Supernatants from astrocytes treated with or without oxygen-glucose deprivation and/or IL-9 were incubated with bEnd.3 cell monolayers after blocking the IL-9 receptor on the endothelium. Immunofluorescence staining and Western blot analyses were conducted to observe the change in tight junction proteins (TJPs) in bEnd.3 cells as well as the level of VEGF-A and possible signal pathways in astrocytes. We also applied middle cerebral artery occlusion (MCAO) models to determine the effect of anti-IL-9-neutralizing antibodies on IS. As a result, astrocyte-conditioned medium treated with IL-9 aggravated the disruption of the BBB accomplished by the degradation of TJPs in endothelial cells. In addition, IL-9 increased the level of VEGF-A in astrocytes, and blocking the effect of VEGF-A reversed the breakdown of the BBB. In the MCAO model, anti-IL-9-neutralizing antibody reduced the infarct volume and BBB destruction. Mechanistically, the anti-IL-9-neutralizing antibody repaired the damaged TJPs (zonula occludens 1, occludin, and claudin-5) and induced a decrease in VEGF-A expression in ischemic lateral brain tissue. In contrast, a local injection of recombinant murine IL-9 to the brain resulted in a marked up-regulation of VEGF-A in the striatum. In conclusion, anti-IL-9-neutralizing antibody can reduce the severity of IS partially by alleviating the destruction of the BBB via down-regulation of astrocyte-derived VEGF-A. This finding suggests that targeting IL-9 or VEGF-A could provide a new direction for the treatment of IS.-Tan, S., Shan, Y., Lin, Y., Liao, S., Zhang, B., Zeng, Q., Wang, Y., Deng, Z., Chen, C., Hu, X., Peng, L., Qiu, W., Lu, Z. Neutralization of IL-9 ameliorates experimental stroke by repairing the blood-brain barrier via down-regulation of astrocyte-derived vascular endothelial growth factor-A.


Assuntos
Astrócitos/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Interleucina-9/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Astrócitos/metabolismo , Hipóxia Celular , Células Cultivadas , Corpo Estriado/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Glucose/farmacologia , Hipóxia-Isquemia Encefálica , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Inflamação , Interleucina-9/administração & dosagem , Interleucina-9/imunologia , Interleucina-9/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética
14.
Brain Behav ; 8(4): e00946, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29670826

RESUMO

Objectives: The association of branch atherosclerotic disease (BAD) and diabetes mellitus (DM) in the territory of posterior circulation is rarely discussed. Intracranial BAD was divided into two different types: paramedian pontine arteries (PPA) disease (PPD) and lenticulostriate arteries (LSA) disease. The goal of the study was to evaluate the clinical characteristics of PPD and its association with hemoglobinA1c (HbA1c) in China. Materials and Methods: Radiologically confirmed PPD was defined as an isolated unilateral infarction extending to the ventral surface of the pons. Small deep cerebral infarctions are usually caused by two different pathological changes of arteries: BAD and lipohyalinotic degeneration (LD). We compared the vascular risk factors between BAD and LD in PPA territory. A total of 159 stroke patients were analyzed (PPD, n = 75; LD, n = 84). Patients with PPD were also categorized into two groups according to follow-up modified Rankin Scale (FmRS) scores. Logistic regression analyses were used for the evaluation of independent risk factors of PPD and prognosis. Results: Comparison between PPD and LD revealed statistical significance in fasting glucose, HbA1c, estimated glomerular filtration rate (eGFR), and uric acid (p = .011, p = .005, p = .027, p = .018, respectively). Compared with LD, PPD was only related to HbA1c (p = .011) in logistic regression analysis. There were statistically significant differences between the two groups based on the stratification of FmRS scores in fasting glucose, HbA1c, homocysteine, eGFR, and the occurrence of DM. After multivariate analysis, only HbA1c was related with poor prognosis of PPD (p = .002). Conclusions: The subtypes and prognosis of small deep brain infarcts are significantly influenced by elevated HbA1c level in PPA territory. DM might play an important role in the pathogenesis of PPD.


Assuntos
Artéria Basilar/diagnóstico por imagem , Infartos do Tronco Encefálico/diagnóstico por imagem , Diabetes Mellitus/metabolismo , Hemoglobinas Glicadas/metabolismo , Arteriosclerose Intracraniana/diagnóstico por imagem , Ponte/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Artérias/diagnóstico por imagem , Doença Cerebrovascular dos Gânglios da Base/diagnóstico por imagem , Doença Cerebrovascular dos Gânglios da Base/metabolismo , Glicemia/metabolismo , Infartos do Tronco Encefálico/metabolismo , China , Feminino , Humanos , Arteriosclerose Intracraniana/metabolismo , Modelos Logísticos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Ponte/irrigação sanguínea , Prognóstico , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/metabolismo
16.
Parkinsonism Relat Disord ; 47: 76-79, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29174172

RESUMO

BACKGROUND: Juvenile-onset parkinsonism is often caused by genetic factors. Mutations in several autosomal genes, including the F-box only protein 7 (FBXO7) gene, have been found in patients suffering from juvenile-onset parkinsonism with pyramidal signs. Only five types of FBXO7 mutations have been described. Here, we present a case report about a Chinese patient presenting with juvenile-onset parkinsonism likely caused by FBXO7 mutations. METHODS: The patient was a 32-year-old Chinese male. DNA samples were extracted from the patient and his parents. Exons in parkinsonism-related genes were amplified and sequenced. RESULTS: The patient began experiencing a progressive involuntary tremor in his left hand at 16 years of age, which was followed by the development of gait dysfunction, dysarthria, and rapid eye movement sleep behavior disorder. A neurological examination of the patient revealed cogwheel rigidity, bradykinesia, static and postural tremor and bilateral Babinski signs. The patient responded to dopaminergic therapies but was affected by psychiatric side effects. Further genetic analysis of the patient and his parents revealed compound heterozygous mutations of the FBXO7 gene (NM_012179.3) in the patient (a nonsense c.1408G > T (p.E470X) mutation and a missense c.152A > G (p.N51S) mutation coming from the patient's mother and father, respectively). CONCLUSIONS: This is the first case harboring FBXO7 mutations that presented with juvenile-onset parkinsonism in the Chinese population.


Assuntos
Proteínas F-Box/genética , Mutação/genética , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/fisiopatologia , Adulto , Humanos , Masculino , Exame Neurológico
17.
Clin Sci (Lond) ; 131(13): 1499-1513, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28550144

RESUMO

Interleukin (IL)-9 exerts a variety of functions in autoimmune diseases. However, its role in ischemic brain injury remains unknown. The present study explored the biological effects of IL-9 in ischemic stroke (IS). We recruited 42 patients newly diagnosed with IS and 22 age- and sex-matched healthy controls. The expression levels of IL-9 and percentages of IL-9-producing T cells, including CD3+CD4+IL-9+ and CD3+CD8+IL-9+ cells, were determined in peripheral blood mononuclear cells (PBMCs) obtained from patients and control individuals. We also investigated the effects of IL-9 on the blood-brain barrier (BBB) following oxygen-glucose deprivation (OGD) and the potential downstream signaling pathways. We found that patients with IS had higher IL-9 expression levels and increased percentages of IL-9-producing T cells in their PBMCs. The percentages of CD3+CD4+IL-9+ and CD3+CD8+IL-9+ T cells were positively correlated with the severity of illness. In in vitro experiments using bEnd.3 cells, exogenously administered IL-9 exacerbated the loss of tight junction proteins (TJPs) in cells subjected to OGD plus reoxygenation (RO). This effect was mediated via activation of IL-9 receptors, which increased the level of endothelial nitric oxide synthase (eNOS), as well as through up-regulated phosphorylation of signal transducer and activator of transcription 1 and 3 and down-regulated phosphorylated protein kinase B/phosphorylated phosphatidylinositol 3-kinase signaling. These results indicate that IL-9 has a destructive effect on the BBB following OGD, at least in part by inducing eNOS production, and raise the possibility of targetting IL-9 for therapeutic intervention in IS.


Assuntos
Barreira Hematoencefálica/imunologia , Interleucina-9/imunologia , Acidente Vascular Cerebral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Complexo CD3/sangue , Estudos de Casos e Controles , Hipóxia Celular/fisiologia , Células Cultivadas , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Expressão Gênica , Glucose/metabolismo , Fatores de Troca do Nucleotídeo Guanina/sangue , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Interleucina-9/sangue , Interleucina-9/genética , Interleucina-9/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/biossíntese , Proteínas Nucleares/sangue , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , Índice de Gravidade de Doença , Acidente Vascular Cerebral/patologia , Subpopulações de Linfócitos T/imunologia , Proteínas de Junções Íntimas/metabolismo , Transativadores/sangue , Transativadores/genética , Adulto Jovem
18.
Mol Cell Biochem ; 429(1-2): 45-58, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28110404

RESUMO

Atherosclerosis, a chronic inflammatory disease, is the major cause of life-threatening complications such as myocardial infarction and stroke. Endothelial cells (ECs) apoptosis plays a vital role in the initiation and progression of atherosclerosis. Although a subset of microRNAs (miRNAs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In the current study, we show that miRNA-150 (miR-150) expression was substantially up-regulated during the oxidized low-density lipoprotein (ox-LDL)-induced apoptosis in human umbilical cord vein endothelial cells (HUVECs). Forced expression of miR-150 enhanced apoptosis in ECs, whereas inhibition of miR-150 could partly alleviate apoptotic cell death mediated by ox-LDL. Further analysis identified ELK1 as a direct target of miR-150, and ELK1 knockdown abolished the anti-apoptotic effect of miR-150 inhibitor. These findings reveal a novel role of miR-150 in endothelial apoptosis and indicate a therapeutic potential of miR-150 for endothelial dysfunction and atherosclerosis.


Assuntos
Células Endoteliais/citologia , Lipoproteínas LDL/farmacologia , MicroRNAs/genética , Proteínas Elk-1 do Domínio ets/genética , Regiões 3' não Traduzidas , Apoptose , Células Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos
19.
BMC Neurol ; 16(1): 162, 2016 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-27601009

RESUMO

BACKGROUND: The underlying causes of minor stroke are difficult to assess. Here, we evaluate the reliability of the Chinese Ischemic Stroke Subclassification (CISS) system in patients with minor stroke, and compare it to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) system. METHODS: A total of 320 patients with minor stroke were retrospectively registered and categorized into different subgroups of the CISS and TOAST by two neurologists. Inter- and intra-rater agreement with the two systems were assessed with kappa statistics. RESULTS: The percentage of undetermined etiology (UE) cases in the CISS system was 77.3 % less than that in the TOAST system, which was statistically significant (P < 0.001). The percentage of large artery atherosclerosis (LAA) in the CISS system was 79.7 % more than that in the TOAST system, which was also statistically significant (P < 0.001). The kappa values for inter-examiner agreement were 0.898 (P = 0.031) and 0.732 (P = 0.022) for the CISS and TOAST systems, respectively. The intra-observer reliability indexes were moderate (0.569 for neurologist A, and 0.487 for neurologist B). CONCLUSIONS: The CISS and TOAST systems are both reliable in classifying patients with minor stroke. CISS classified more patients into known etiologic categories without sacrificing reliability.


Assuntos
Índice de Gravidade de Doença , Acidente Vascular Cerebral/classificação , Acidente Vascular Cerebral/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/complicações , Aterosclerose/diagnóstico , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações
20.
J Neuroinflammation ; 13(1): 147, 2016 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-27296014

RESUMO

BACKGROUND: Cholera toxin B subunit (CTB) has multifaceted immunoregulatory functions. Immunity plays an important role in the mechanism of stroke. However, little is known about whether CTB is beneficial for stroke. METHODS: CTB was administered intraperitoneally after ischemia to rats subjected to transient focal ischemia. Infarct volumes, body weight loss, and neurologic deficits were measured. Cytokines, microglia/macrophage activation, and transcriptional factors in the ischemic brain were tested. The mRNA expressions of IL-1ß and TNF-α were tested in the microglia/macrophage isolated from the ischemic hemisphere. γδT cells, IL-17-producing γδT cells, Th17 cells, and regulatory T (Treg) cells in the ischemic brain were tested. γδT cells and Treg cells in the peripheral blood were also evaluated. RESULTS: CTB reduced infarct volumes, neurologic deficits, and body weight loss after ischemia. At 24 h after ischemia, CTB downregulated the levels of IL-1ß, TNF-α, NF-kB p65, phosphorylated-ERK1/2, and microglia/macrophage activation and suppressed NF-kB binding activity, but did not affect the level of ERK1/2. The mRNA expressions of IL-1ß and TNF-α in the microglia/macrophage isolated from the ischemic hemisphere were suppressed after CTB therapy. In the ischemic hemisphere, CTB treatment reduced the levels of γδT cells, IL-17-producing γδT cells, and IL-17 at both 24 and 72 h after ischemia, while Th17 cells were not affected. After CTB treatment, the levels of Treg cells, TGF-ß, and IL-10 remained unchanged at 24 h and upregulated at 72 h after ischemia. Inactivation of Treg cells using anti-CD25 attenuated the increase of TGF-ß and IL-10 induced by CTB at 72 h after ischemia. In the peripheral blood, CTB increased Treg cells and suppressed γδT cells at 24 h after ischemia. And then at 72 h after ischemia, it increased Treg cells but did not impact γδT cells. CTB had no effect on cytokines, transcription factors, infiltrating γδT cells, and Treg cells in the brain of shams. In the peripheral blood of shams, CTB increased Treg cells at both 24 and 72 h, while it did not affect γδT cells. CONCLUSIONS: CTB decreased neurologic impairment and tissue injury after cerebral ischemia via its immunomodulatory functions, including inhibiting microglia/macrophage activation, suppressing γδT cells, and inducing production of Treg cells, thus regulating the secretion of related cytokines. Suppression of NF-kB and ERK1/2 pathways is involved in the neuroprotective mechanism of CTB.


Assuntos
Toxina da Cólera/uso terapêutico , Citocinas/metabolismo , Encefalite/tratamento farmacológico , Encefalite/etiologia , Infarto da Artéria Cerebral Média/complicações , Análise de Variância , Animais , Anti-Inflamatórios , Infarto Encefálico/etiologia , Toxina da Cólera/farmacologia , Citocinas/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaio de Desvio de Mobilidade Eletroforética , Citometria de Fluxo , Lateralidade Funcional , Infarto da Artéria Cerebral Média/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Microglia/efeitos dos fármacos , Microglia/patologia , Doenças do Sistema Nervoso/etiologia , RNA Mensageiro/metabolismo , Ratos , Fatores de Tempo
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