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1.
Oxid Med Cell Longev ; 2021: 5633514, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457116

RESUMO

This study sought to perform integrative analysis of the immune/methylation/autophagy landscape on breast cancer prognosis and single-cell genotypes. Breast Cancer Recurrence Risk Score (BCRRS) and Breast Cancer Prognostic Risk Score (BCPRS) were determined based on 6 prognostic IMAAGs obtained from the TCGA-BRCA cohort. BCRRS and BCPRS, respectively, were used to construct a risk prediction model of overall survival and progression-free survival. Predictive capacity of the model was evaluated using clinical data. Analysis showed that BCRRS is associated with a high risk of stroke. In addition, PPI and drug-ceRNA networks based on differences in BCPRS were constructed. Single cells were genotyped through integrated scRNA-seq of the TNBC samples based on clustering results of BCPRS-related genes. The findings of this study show the potential regulatory effects of IMAAGs on breast cancer tumor microenvironment. High AUCs of 0.856 and 0.842 were obtained for the OS and PFS prognostic models, respectively. scRNA-seq analysis showed high expression levels of adipocytes and adipose tissue macrophages (ATMs) in high BCPRS clusters. Moreover, analysis of ligand-receptor interactions and potential regulatory mechanisms were performed. The LINC00276&MALAT1/miR-206/FZD4-Wnt7b pathway was also identified which may be useful in future research on targets against breast cancer metastasis and recurrence. Neural network-based deep learning models using BCPRS-related genes showed that these genes can be used to map the tumor microenvironment. In summary, analysis of IMAAGs, BCPRS, and BCRRS provides information on the breast cancer microenvironment at both the macro- and microlevels and provides a basis for development of personalized treatment therapy.


Assuntos
Autofagia , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Metilação de DNA , Análise de Célula Única/métodos , Acidente Vascular Cerebral/patologia , Microambiente Tumoral/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Terapia Combinada , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Genótipo , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Medição de Risco/métodos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapia , Taxa de Sobrevida , Transcriptoma
2.
Nutrients ; 13(8)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34445037

RESUMO

Among cardiovascular diseases (CVDs), a major cause of morbidity and mortality worldwide, coronary heart disease and stroke are the most well-known and extensively studied. The onset and progression of CVD is associated with multiple risk factors, among which, gut microbiota has received much attention in the past two decades. Gut microbiota, the microbial community colonizing in the gut, plays a prominent role in human health. In particular, gut dysbiosis is directly related to many acute or chronic dysfunctions of the cardiovascular system (CVS) in the host. Earlier studies have demonstrated that the pathogenesis of CVD is strongly linked to intestinal microbiota imbalance and inflammatory responses. Probiotics and prebiotics conferring various health benefits on the host are emerging as promising therapeutic interventions for many diseases. These two types of food supplements have the potential to alleviate the risks of CVD through improving the levels of several cardiovascular markers, such as total and low-density lipoprotein (LDL) cholesterol, high sensitivity C-reactive protein (hs-CRP), and certain cytokines involved in the inflammatory response. In this review, we focus mainly on the preventive effects of probiotics and prebiotics on CVD via rebalancing the structural and functional changes in gut microbiota and maintaining immune homeostasis.


Assuntos
Bactérias/crescimento & desenvolvimento , Doença das Coronárias/prevenção & controle , Intestinos/microbiologia , Prebióticos , Probióticos , Acidente Vascular Cerebral/prevenção & controle , Animais , Bactérias/imunologia , Doença das Coronárias/epidemiologia , Doença das Coronárias/imunologia , Doença das Coronárias/microbiologia , Disbiose , Microbioma Gastrointestinal , Fatores de Risco de Doenças Cardíacas , Interações Hospedeiro-Patógeno , Humanos , Intestinos/imunologia , Prebióticos/efeitos adversos , Prevalência , Probióticos/efeitos adversos , Fatores de Proteção , Medição de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/microbiologia
4.
J Stroke Cerebrovasc Dis ; 30(8): 105896, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34144337

RESUMO

OBJECTIVES: French national guidelines recommend searching for anti-SS-A antibodies during the second-line assessment of stroke in adults < 55 years of age in the absence of an identified etiology. We aimed to assess the impact of finding anti-SS-A antibodies during the etiological investigations of stroke in young adults. METHODS: Medical files from all patients ≤ 55 years of age admitted to a single stroke unit during a five-year period and for whom anti-SS-A antibodies were positive were retrospectively analyzed. RESULTS: Twelve patients were included (9 women; median age 48.5 years), with a rate of anti-SS-A antibody positivity of 1.6% (95% confidence interval [0.71-2.55] %; 12/735 admissions). The etiologies of the 12 ischemic events based on the TOAST classification were large-artery atherosclerosis (n = 1), cardioembolism (n = 1), small-vessel disease (n = 1), other determined etiology (n = 3), multiple etiology (n = 1), and no determined etiology (n = 5). A connective tissue disease (CTD) was discovered in 8/12 patients (1 primary Sjögren's Syndrome, 1 mixed CTD, 1 systemic sclerosis, 2 antiphospholipid syndromes, 1 undetermined CTD, 2 lupus). Anti-SSA antibodies were not directly responsible for the stroke in any of the 12 cases. A link between the autoimmune disease and the neurological vascular episode could be hypothesized for four patients, but it never influenced the therapeutic decision. CONCLUSIONS: Finding anti-SS-A antibodies during the etiological assessment of a stroke of young adults is rare. However, it may be worthwhile to refer the patient to a rheumatologist/an internist because CTD may be discovered and may require specific follow-up.


Assuntos
Anticorpos Antinucleares/sangue , Autoimunidade , Acidente Vascular Cerebral/sangue , Adulto , Fatores Etários , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/imunologia
5.
J Neuroimmunol ; 355: 577568, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862420

RESUMO

Stroke-induced immunosuppression contributes to the development of stroke-associated pneumonia (SAP). Experiments in mice demonstrated that apoptosis of IFN-γ producing cells and reduced IFN-γ secretion resulted in impaired immune responses and the development of pneumonia after middle cerebral artery occlusion (MCAo). In the present study, we investigated the efficacy of intratracheal IFN-γ treatment to prevent SAP and demonstrated that modest benefits on pulmonary cytokine response in IFN-γ treated stroke mice did not prevent spontaneously developing infections and even slightly reduced bacterial clearance of aspirated pneumococci. Our results suggest that pulmonary IFN-γ treatment is not an effective preventive measure for SAP.


Assuntos
Interferon gama/administração & dosagem , Infecções Pneumocócicas/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções Pneumocócicas/etiologia , Infecções Pneumocócicas/imunologia , Infecções Respiratórias/etiologia , Infecções Respiratórias/imunologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/imunologia , Resultado do Tratamento
6.
Immunity ; 54(4): 648-659.e8, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33667383

RESUMO

Loss of lymphocytes, particularly T cell apoptosis, is a central pathological event after severe tissue injury that is associated with increased susceptibility for life-threatening infections. The precise immunological mechanisms leading to T cell death after acute injury are largely unknown. Here, we identified a monocyte-T cell interaction driving bystander cell death of T cells in ischemic stroke and burn injury. Specifically, we found that stroke induced a FasL-expressing monocyte population, which led to extrinsic T cell apoptosis. This phenomenon was driven by AIM2 inflammasome-dependent interleukin-1ß (IL-1ß) secretion after sensing cell-free DNA. Pharmacological inhibition of this pathway improved T cell survival and reduced post-stroke bacterial infections. As such, this study describes inflammasome-dependent monocyte activation as a previously unstudied cause of T cell death after injury and challenges the current paradigms of post-injury lymphopenia.


Assuntos
Coinfecção/imunologia , Proteínas de Ligação a DNA/imunologia , Tolerância Imunológica/imunologia , Inflamassomos/imunologia , Transdução de Sinais/imunologia , Animais , Apoptose/imunologia , Infecções Bacterianas/imunologia , Queimaduras/imunologia , Queimaduras/microbiologia , Coinfecção/microbiologia , Humanos , Interleucina-1beta/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/microbiologia , Linfócitos T/imunologia
7.
Int Immunopharmacol ; 94: 107507, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33657523

RESUMO

Hemorrhagic transformation (HT) is a frequent complication of ischemic stroke after thrombolytic therapy and seriously affects the prognosis of stroke. Due to the limited therapeutic window and hemorrhagic complications, tissue plasminogen activator (t-PA) is underutilized in acute ischemic stroke. Currently, there are no clinically effective drugs to decrease the incidence of t-PA-induced HT. Hypoxia-inducible factor 1 (HIF-1) is an important transcription factor that maintains oxygen homeostasis and mediates neuroinflammation under hypoxia. However, the effect of HIF-1 on t-PA-induced HT is not clear. The aim of this study was to investigate the role of HIF-1 in t-PA-induced HT by applying YC-1, an inhibitor of HIF-1. In the present study, we found that HIF-1 expression was significantly increased in ischemic brain tissue after delayed t-PA treatment and was mainly localized in neurons and endothelial cells. Inhibition of HIF-1 by YC-1 improved infarct volume and neurological deficits. YC-1 inhibited matrix metalloproteinase protein expression, increased tight junction protein expression, and ameliorated BBB disruption and the occurrence of HT. Furthermore, YC-1 suppressed the release of inflammatory factors, neutrophil infiltration and the activation of the HMGB1/TLR4/NF-κB signaling pathway. These results demonstrated that inhibition of HIF-1 could protect BBB integrity by suppressing HMGB1/TLR4/NF-κB-mediated neutrophil infiltration, thereby reducing the risk of t-PA-induced HT. Thus, HIF-1 may be a potential therapeutic target for t-PA-induced HT.


Assuntos
Isquemia Encefálica/imunologia , Hemorragia Cerebral/imunologia , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Acidente Vascular Cerebral/imunologia , Tromboembolia/imunologia , Ativador de Plasminogênio Tecidual , Animais , Células Endoteliais/efeitos dos fármacos , Proteína HMGB1/imunologia , Indazóis/farmacologia , Masculino , NF-kappa B/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Ratos Sprague-Dawley , Receptor 4 Toll-Like/imunologia
8.
Front Immunol ; 12: 630430, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679775

RESUMO

C-reactive protein (CRP) is the best-known acute phase protein. In humans, almost every type of inflammation is accompanied by an increase of CRP concentration. Until recently, the only known physiological function of CRP was the marking of cells to initiate their phagocytosis. This triggers the classical complement pathway up to C4, which helps to eliminate pathogens and dead cells. However, vital cells with reduced energy supply are also marked, which is useful in the case of a classical external wound because an important substrate for pathogens is disposed of, but is counterproductive at internal wounds (e.g., heart attack or stroke). This mechanism negatively affects clinical outcomes since it is established that CRP levels correlate with the prognosis of these indications. Here, we summarize what we can learn from a clinical study in which CRP was adsorbed from the bloodstream by CRP-apheresis. Recently, it was shown that CRP can have a direct effect on blood pressure in rabbits. This is interesting in regard to patients with high inflammation, as they often become tachycardic and need catecholamines. These two physiological effects of CRP apparently also occur in COVID-19. Parts of the lung become ischemic due to intra-alveolar edema and hemorrhage and in parallel CRP increases dramatically, hence it is assumed that CRP is also involved in this ischemic condition. It is meanwhile considered that most of the damage in COVID-19 is caused by the immune system. The high amounts of CRP could have an additional influence on blood pressure in severe COVID-19.


Assuntos
Proteína C-Reativa/imunologia , COVID-19/imunologia , Infarto do Miocárdio/imunologia , SARS-CoV-2/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Morte Celular/imunologia , Hipóxia Celular/imunologia , Complemento C4/imunologia , Humanos , Coelhos
9.
Lupus ; 30(5): 775-784, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33554716

RESUMO

INTRODUCTION: Antiphospholipid syndrome (APS) is an autoimmune disorder manifested by thromboembolic events, recurrent spontaneous abortions and elevated titers of circulating antiphospholipid antibodies. In addition, the presence of antiphospholipid antibodies seems to confer a fivefold higher risk for stroke or transient ischemic attack. Although the major antigen of APS is ß2 glycoprotein I, it is now well established that antiphospholipid antibodies are heterogeneous and bind to various targets. Recently, antibodies to Annexin A2 (ANXA2) have been reported in APS. This is of special interest since data indicated ANXA2 as a key player in fibrinolysis. Therefore, in the present study we assessed whether anti-ANXA2 antibodies play a pathological role in thrombosis associated disease. MATERIALS AND METHODS: Mice were induced to produce anti-ANXA2 antibodies by immunization with ANXA2 (iANXA2) and control mice were immunized with adjuvant only. A middle cerebral artery occlusion stroke model was applied to the mice. The outcome of stroke severity was assessed and compared between the two groups. RESULTS: Our results indicate that antibodies to ANXA2 lead to a more severe stroke as demonstrated by a significant larger stroke infarct volume (iANXA2 133.9 ± 3.3 mm3 and control 113.7 ± 7.4 mm3; p = 0.017) and a more severe neurological outcome (iANXA2 2.2 ± 0.2, and control 1.5 ± 0.18; p = 0.03). CONCLUSIONS: This study supports the hypothesis that auto-antibodies to ANXA2 are an independent risk factor for cerebral thrombosis. Consequently, we propose screening for anti-ANXA2 antibodies should be more widely used and patients that exhibit the manifestations of APS should be closely monitored by physicians.


Assuntos
Anexina A2/imunologia , Síndrome Antifosfolipídica/imunologia , Autoanticorpos/imunologia , Trombose Intracraniana/metabolismo , Adulto , Animais , Anexina A2/administração & dosagem , Anexina A2/metabolismo , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/metabolismo , Autoanticorpos/metabolismo , Autoimunidade/imunologia , Modelos Animais de Doenças , Feminino , Fibrinólise/imunologia , Humanos , Infarto da Artéria Cerebral Média/imunologia , Infarto da Artéria Cerebral Média/fisiopatologia , Injeções Subcutâneas , Trombose Intracraniana/etiologia , Ataque Isquêmico Transitório/imunologia , Camundongos , Camundongos Endogâmicos BALB C/imunologia , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/imunologia , beta 2-Glicoproteína I/metabolismo
10.
BMC Neurol ; 21(1): 62, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568099

RESUMO

BACKGROUND: Persistent inflammation is an important driver of disease progression and affects prognosis. Some indicators of inflammation predict short-term outcomes. The relationship between prognosis, especially mortality, and persistent inflammation in massive stroke has not been studied, and this has been the subject of our research. METHODS: From April 1, 2017 to February 1, 2020, consecutive patients were prospectively enrolled. Clinical data, laboratory data, imaging data and follow-up infections morbidity were compared between 2 groups according to modified Rankin scale (mRS) scores (mRS < 3 and ≥ 3) at 1 month. The binomial logistic analysis was used to determine independent factors of 1-month prognosis. Short-term functional outcome, mortality and infection rates in massive stroke with and without persistent inflammation were compared. RESULTS: One hundred thirty-nine patients with massive stroke were included from 800 patients. We found that admission blood glucose levels (p = 0.005), proportions of cerebral hemispheric (p = 0.001), posterior circulatory (p = 0.035), and lacunar (p = 0.022) ischemia were higher in poor outcome patients; neutrophil-to-lymphocyte ratio (odd ratio = 1.87, 95%CI 1.14-3.07, p = 0.013) and blood glucose concentrations (odd ratio = 1.34, 95%CI 1.01-1.79, p = 0.043) can independently predict the short-term prognosis in massive stroke patients. We also found that the incidence of pulmonary infection (p = 0.009), one-month mortality (p = 0.003) and adverse outcomes (p = 0.0005) were higher in patients with persistent inflammation. CONCLUSIONS: This study suggested that persistent inflammation is associated with poor prognosis, 1-month mortality and the occurrence of in-hospital pulmonary infection and that higher baseline inflammation level predicts short-term poor outcomes in massive stroke.


Assuntos
Inflamação/imunologia , Recuperação de Função Fisiológica/imunologia , Acidente Vascular Cerebral/imunologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inflamação/etiologia , Inflamação/mortalidade , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidade
11.
Arterioscler Thromb Vasc Biol ; 41(3): 1218-1228, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472398

RESUMO

OBJECTIVE: COMP (cartilage oligomeric matrix protein) is abundantly expressed in the cardiovascular system, cartilage, and atherosclerotic plaques. We investigated if the total COMP (COMPtotal) and COMP neoepitope (COMPneo) with other cardiovascular markers and clinical parameters could identify symptomatic carotid stenosis. Approach and Results: Blood samples were collected from patients with symptomatic carotid stenosis (stenosis, n=50), patients with stroke without carotid stenosis but small plaques (plaque, n=50), and control subjects (n=50). COMPtotal and COMPneo were measured using an ELISA. Ninety-two cardiovascular disease markers were measured by the Olink CVD kit. The presence of native COMP and COMPneo was determined by immunohistochemistry. The concentration of COMPneo was higher and COMPtotal was lower in the stenosis group. When the concentration was compared between the stenosis and control groups, IL-1ra (interleukin-1 receptor antagonist protein), IL6 (interleukin-6), REN (Renin), MMP1 (matrix metalloproteinase-1), TRAIL-R2 (tumor necrosis factor-related apoptosis-inducing ligand receptor 2), ITGB1BP2 (integrin beta 1 binding protein 2), and COMPneo were predictive of stenosis. Conversely, KLK6 (kallikrein-6), COMPtotal, NEMO (nuclear factor-kappa-B essential modulator), SRC (Proto-oncogene tyrosine-protein kinase Src), SIRT2 (SIR2-like protein), CD40 (cluster of differentiation 40), TF (tissue factor), MP (myoglobin), and RAGE (receptor for advanced glycation end-products) were predictive of the control group. Model reproducibility was good with the receiver operating characteristic plot area under the curve being 0.86. When comparing the plaque group and stenosis group, COMPneo, GAL (galanin), and PTX3 (pentraxin-related protein PTX3) were predictive of stenosis. Model reproducibility was excellent (receiver operating characteristic plot area under the curve 0.92). COMPneo was detected in smooth muscle-, endothelial-, and foam-cells in carotid stenosis. CONCLUSIONS: Degradation of COMP may be associated with atherosclerosis progression and generation of a specific COMP fragment-COMPneo. This may represent a novel biomarker that together with COMPtotal and other risk-markers could be used to identify symptomatic carotid stenosis. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Estenose das Carótidas/sangue , Proteína de Matriz Oligomérica de Cartilagem/sangue , Proteína de Matriz Oligomérica de Cartilagem/imunologia , Epitopos/sangue , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Estenose das Carótidas/imunologia , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Epitopos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Placa Aterosclerótica/sangue , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/metabolismo , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/imunologia
12.
Brain Behav Immun ; 91: 649-667, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017613

RESUMO

For the last two decades, researchers have placed hopes in a new era in which a combination of reperfusion and neuroprotection would revolutionize the treatment of stroke. Nevertheless, despite the thousands of papers available in the literature showing positive results in preclinical stroke models, randomized clinical trials have failed to show efficacy. It seems clear now that the existing data obtained in preclinical research have depicted an incomplete picture of stroke pathophysiology. In order to ameliorate bench-to-bed translation, in this review we first describe the main actors on stroke inflammatory and immune responses based on the available preclinical data, highlighting the fact that the link between leukocyte infiltration, lesion volume and neurological outcome remains unclear. We then describe what is known on neuroinflammation and immune responses in stroke patients, and summarize the results of the clinical trials on immunomodulatory drugs. In order to understand the gap between clinical trials and preclinical results on stroke, we discuss in detail the experimental results that served as the basis for the summarized clinical trials on immunomodulatory drugs, focusing on (i) experimental stroke models, (ii) the timing and selection of outcome measuring, (iii) alternative entry routes for leukocytes into the ischemic region, and (iv) factors affecting stroke outcome such as gender differences, ageing, comorbidities like hypertension and diabetes, obesity, tobacco, alcohol consumption and previous infections like Covid-19. We can do better for stroke treatment, especially when targeting inflammation following stroke. We need to re-think the design of stroke experimental setups, notably by (i) using clinically relevant models of stroke, (ii) including both radiological and neurological outcomes, (iii) performing long-term follow-up studies, (iv) conducting large-scale preclinical stroke trials, and (v) including stroke comorbidities in preclinical research.


Assuntos
Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Isquemia Encefálica/tratamento farmacológico , Comorbidade , Modelos Animais de Doenças , Humanos , Imunidade/imunologia , Imunidade/fisiologia , Inflamação/imunologia , Neuroproteção/imunologia , Neuroproteção/fisiologia , Avaliação de Resultados em Cuidados de Saúde , Reperfusão/métodos , Reperfusão/tendências
13.
Platelets ; 32(3): 314-324, 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32896192

RESUMO

Platelets are increasingly being recognized for playing roles beyond thrombosis and hemostasis. Today we know that they mediate inflammation by direct interactions with innate immune cells or secretion of cytokines/chemokines. Here we review their interactions with neutrophils and monocytes/macrophages in infection and sepsis, stroke, myocardial infarction and venous thromboembolism. We discuss new roles for platelet surface receptors like GPVI or GPIb and also look at platelet contributions to the formation of neutrophil extracellular traps (NETs) as well as to deep vein thrombosis during infection, e.g. in COVID-19 patients.


Assuntos
Plaquetas/imunologia , COVID-19/imunologia , Infarto do Miocárdio/imunologia , Neutrófilos/imunologia , Sepse/imunologia , Acidente Vascular Cerebral/imunologia , Tromboembolia Venosa/imunologia , Plaquetas/patologia , COVID-19/genética , COVID-19/patologia , COVID-19/virologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Citocinas/genética , Citocinas/imunologia , Armadilhas Extracelulares/genética , Armadilhas Extracelulares/imunologia , Regulação da Expressão Gênica , Humanos , Inflamação , Macrófagos/imunologia , Macrófagos/patologia , Monócitos/imunologia , Monócitos/patologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Neutrófilos/patologia , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Complexo Glicoproteico GPIb-IX de Plaquetas/imunologia , Glicoproteínas da Membrana de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/imunologia , Sepse/genética , Sepse/patologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Tromboembolia Venosa/genética , Tromboembolia Venosa/patologia
14.
Rheumatology (Oxford) ; 60(8): 3770-3777, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-33331921

RESUMO

OBJECTIVE: We evaluated which aPL combinations increase the risk of future thrombosis in patients with SLE. METHODS: This prospective cohort study consisted of SLE patients who had been tested for all seven aPL (LA, aCL isotypes IgM, IgG and IgA, and anti-ß2-glycoprotein I isotypes IgM, IgG and IgA). Pooled logistic regression was used to assess the relationship between aPL and thrombosis. RESULTS: There were 821 SLE patients with a total of 75 048 person-months of follow-up. During the follow-up we observed 88 incident cases of thrombosis: 48 patients with arterial, 37 with venous and 3 with both arterial and venous thrombosis. In individual models, LA was the most predictive of any [age-adjusted rate ratio 3.56 (95% CI 2.01, 6.30), P < 0.0001], venous [4.89 (2.25, 10.64), P < 0.0001] and arterial [3.14 (1.41, 6.97), P = 0.005] thrombosis. Anti-ß2-glycoprotein I IgA positivity was a significant risk factor for any [2.00 (1.22, 3.3), P = 0.0065] and venous [2.8 (1.42, 5.51), P = 0.0029] thrombosis. Only anti-ß2-glycoprotein I IgA appeared to add significant risk to any [1.73 (1.04, 2.88), P = 0.0362] and venous [2.27 (1.13, 4.59), P = 0.0218] thrombosis among those with LA. We created an interaction model with four categories based on combinations of LA and other aPL to look at the relationships between combinations and the risk of thrombosis. In this model LA remained the best predictor of thrombosis. CONCLUSION: Our study demonstrated that in SLE, LA remained the best predictor of thrombosis and adding additional aPL did not add to the risk, with the exception of anti-ß2-glycoprotein I IgA.


Assuntos
Anticorpos Anticardiolipina/imunologia , Inibidor de Coagulação do Lúpus/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Trombose/imunologia , beta 2-Glicoproteína I/imunologia , Adulto , Anticorpos Antifosfolipídeos/imunologia , Estudos de Coortes , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Isquemia/epidemiologia , Isquemia/imunologia , Modelos Logísticos , Masculino , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/imunologia , Estudos Prospectivos , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/imunologia , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/imunologia , Trombose/epidemiologia , Trombose Venosa/epidemiologia , Trombose Venosa/imunologia
15.
Oxid Med Cell Longev ; 2020: 8880244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376583

RESUMO

Background: The goal of this study was to determine whether leukemia inhibitory factor (LIF) promotes anti-inflammatory activity after stroke in a sex-dependent manner. Methods: Aged (18-month-old) Sprague-Dawley rats of both sexes underwent sham surgery or permanent middle cerebral artery occlusion (MCAO). Animals received three doses of intravenous LIF (125 µg/kg) or PBS at 6, 24, and 48 h before euthanization at 72 h. Spleen weights were measured immediately following euthanization. Western blot was used to measure protein levels of CCL8, CD11b, CXCL9, CXCL10, IL-12 p40, IL-3, and the LIF receptor (LIFR) in spleen tissue. ELISA was used to measure IL-1ß, IL-6, TNFα, and IFNγ in spleen tissue. A Griess Assay was used to indirectly quantify NO levels via measurement of nitrite. Levels of cellular markers and inflammatory mediators were normalized to the baseline (sham) group from each sex. Statistical analysis was performed using two-way ANOVA and followed by Fisher's LSD post hoc test. Results: Aged female rats showed a significantly lower spleen weight after MCAO, but showed a significant increase in spleen size after LIF treatment. This effect was observed in aged male rats, but not to as great of an extent. CD11b levels were significantly higher in the spleens of MCAO+PBS males compared to their female counterparts, but there was no significant difference in CD11b levels between MCAO+LIF males and females. LIF significantly increased CXCL9 after LIF treatment in aged male and female rats. LIFR and IL-3 were upregulated after LIF treatment in aged females. Splenic nitrate increased after MCAO but decreased after LIF treatment in aged females. Splenic nitrate levels did not increase after MCAO but did increase after LIF treatment in aged males. The following cytokines/chemokines were not altered by sex or treatment: TNFα, IL-6, IL-12 p40, CCL8, IFNγ, and CXCL10. Conclusions: LIF treatment after permanent MCAO induces sex-dependent effects on the poststroke splenic response and the production of proinflammatory cytokines among aged rats.


Assuntos
Envelhecimento/imunologia , Fator Inibidor de Leucemia/imunologia , Caracteres Sexuais , Baço/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Quimiocinas/imunologia , Feminino , Interleucinas/imunologia , Masculino , Óxido Nítrico/imunologia , Ratos , Ratos Sprague-Dawley
16.
Front Immunol ; 11: 610696, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33343584

RESUMO

Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.


Assuntos
Proteína ADAMTS13/imunologia , COVID-19/imunologia , Armadilhas Extracelulares/imunologia , SARS-CoV-2/imunologia , Trombose/imunologia , Fator de von Willebrand/imunologia , Doença Aguda , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Isquemia Encefálica/virologia , COVID-19/patologia , Humanos , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/virologia , Trombose/patologia , Trombose/virologia , Microangiopatias Trombóticas/imunologia , Microangiopatias Trombóticas/patologia , Microangiopatias Trombóticas/virologia
17.
Eur Rev Med Pharmacol Sci ; 24(24): 13044-13048, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33378056

RESUMO

As a severe and highly contagious infection, coronavirus disease (COVID-19) affects all aspects of society and has become a global public health problem. Because of the complexity of the pathology of COVID-19, it is difficult to treat. An increasing number of reports have indicated that COVID-19 may have neurological complications, including stroke. The nervous system complications of COVID-19 have gradually attracted research attention. In this review, we summarize the latest findings related to COVID 19, elaborate on the possible mechanism of COVID 19 related onset of stroke, and summarize current treatment options because an improved understanding and appropriate treatments may improve the prognosis of patients with COVID-19-related stroke.


Assuntos
Anosmia/fisiopatologia , COVID-19/fisiopatologia , Cefaleia/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Distúrbios do Paladar/fisiopatologia , Enzima de Conversão de Angiotensina 2/metabolismo , Anticoagulantes/uso terapêutico , Transtornos da Coagulação Sanguínea/complicações , Transtornos da Coagulação Sanguínea/fisiopatologia , COVID-19/complicações , COVID-19/imunologia , COVID-19/terapia , Transtornos da Consciência/fisiopatologia , Citocinas/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Receptores de Coronavírus/metabolismo , Sistema Renina-Angiotensina , SARS-CoV-2 , Meias de Compressão , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapia , Terapia Trombolítica
18.
Front Immunol ; 11: 1931, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042113

RESUMO

Cerebral ischemia may cause irreversible neural network damage and result in functional deficits. Targeting neuronal repair after stroke potentiates the formation of new connections, which can be translated into a better functional outcome. Innate and adaptive immune responses in the brain and the periphery triggered by ischemic damage participate in regulating neural repair after a stroke. Immune cells in the blood circulation and gut lymphatic tissues that have been shaped by immune components including gut microbiota and metabolites can infiltrate the ischemic brain and, once there, influence neuronal regeneration either directly or by modulating the properties of brain-resident immune cells. Immune-related signalings and metabolites from the gut microbiota can also directly alter the phenotypes of resident immune cells to promote neuronal regeneration. In this review, we discuss several potential mechanisms through which peripheral and brain-resident immune components can cooperate to promote first the resolution of neuroinflammation and subsequently to improved neural regeneration and a better functional recovery. We propose that new insights into discovery of regulators targeting pro-regenerative process in this complex neuro-immune network may lead to novel strategies for neuronal regeneration.


Assuntos
Encéfalo/imunologia , Sistema Imunitário/imunologia , Regeneração Nervosa , Neuroimunomodulação , Neurônios/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Microbioma Gastrointestinal , Humanos , Sistema Imunitário/metabolismo , Sistema Imunitário/fisiopatologia , Neurônios/metabolismo , Recuperação de Função Fisiológica , Transdução de Sinais , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia
19.
Int J Mol Sci ; 21(19)2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33049931

RESUMO

Genetic determinants play important role in the complex processes of inflammation and immune response in stroke and could be studied in different ways. Inflammation and immunomodulation are associated with repair processes in ischemic stroke, and together with the concept of preconditioning are promising modes of stroke treatment. One of the important aspects to be considered in the recovery of patients after the stroke is a genetic predisposition, which has been studied extensively. Polymorphisms in a number of candidate genes, such as IL-6, BDNF, COX2, CYPC19, and GPIIIa could be associated with stroke outcome and recovery. Recent GWAS studies pointed to the variant in genesPATJ and LOC as new genetic markers of long term outcome. Epigenetic regulation of immune response in stroke is also important, with mechanisms of histone modifications, DNA methylation, and activity of non-coding RNAs. These complex processes are changing from acute phase over the repair to establishing homeostasis or to provoke exaggerated reaction and death. Pharmacogenetics and pharmacogenomics of stroke cures might also be evaluated in the context of immuno-inflammation and brain plasticity. Potential novel genetic treatment modalities are challenged but still in the early phase of the investigation.


Assuntos
Isquemia Encefálica/genética , Isquemia Encefálica/imunologia , Imunidade , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/imunologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/imunologia , Animais , Isquemia Encefálica/tratamento farmacológico , Metilação de DNA/genética , Epigênese Genética/imunologia , Predisposição Genética para Doença , Terapia Genética/métodos , Código das Histonas/genética , Humanos , Imunomodulação , Inflamação/genética , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo de Nucleotídeo Único , RNA não Traduzido/genética , Acidente Vascular Cerebral/tratamento farmacológico
20.
Fluids Barriers CNS ; 17(1): 55, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912226

RESUMO

Human coronaviruses are highly pathogenic viruses that pose a serious threat to human health. Examples include the severe acute respiratory syndrome outbreak of 2003 (SARS-CoV-1), the Middle East Respiratory Syndrome (MERS-CoV) outbreak of 2012, and the current SARS-CoV-2 (COVID-19) pandemic. Herein, we review the neurological manifestations of coronaviruses and discuss the potential pathogenic role of blood-brain barrier dysfunction. We present the hypothesis that pre-existing vascular damage (due to aging, cardiovascular disease, diabetes, hypertension or other conditions) facilitates infiltration of the virus into the central nervous system (CNS), increasing neuro-inflammation and the likelihood of neurological symptoms. We also discuss the role of a neuroinflammatory cytokine profile in both blood-brain barrier dysfunction and macrovascular disease (e.g. ischemic stroke and thromboembolism). Future studies are needed to better understand the involvement of the microvasculature in coronavirus neuropathology, and to test the diagnostic potential of minimally-invasive screening tools (e.g. serum biomarkers, fluorescein retinal angiography and dynamic-contrast MRI).


Assuntos
Barreira Hematoencefálica/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Inflamação/fisiopatologia , Microvasos/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Pneumonia Viral/fisiopatologia , Betacoronavirus , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/virologia , COVID-19 , Doenças Cardiovasculares/fisiopatologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Diabetes Mellitus/fisiopatologia , Encefalite/imunologia , Encefalite/fisiopatologia , Humanos , Inflamação/imunologia , Microvasos/imunologia , Doenças do Sistema Nervoso/imunologia , Pandemias , Pneumonia Viral/imunologia , SARS-CoV-2 , Convulsões/imunologia , Convulsões/fisiopatologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/fisiopatologia , Tromboembolia/imunologia , Tromboembolia/fisiopatologia
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