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1.
BMC Infect Dis ; 20(1): 505, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32660552

RESUMO

BACKGROUND: Meningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10-20% of the cases. Recently, we have shown that the matrix metalloproteinase (MMP) inhibitor BB-94 reduced brain injury in a mouse model of MM. The present study aimed to assess whether doxycycline (DOX), a tetracycline that showed a neuroprotective effect as adjuvant therapy in experimental pneumococcal meningitis (PM), would also exert a beneficial effect when given as adjunctive therapy to ceftriaxone (CRO) in experimental MM. METHODS: BALB/c mice were infected by the intracisternal route with a group C Neisseria meningitidis strain. Eighteen h post infection (hpi), animals were randomised for treatment with CRO [100 mg/kg subcutaneously (s.c.)], CRO plus DOX (30 mg/kg s.c.) or saline (control s.c.). Antibiotic treatment was repeated 24 and 40 hpi. Mouse survival and clinical signs, bacterial counts in cerebella, brain damage, MMP-9 and cyto/chemokine levels were assessed 48 hpi. RESULTS: Analysis of bacterial load in cerebella indicated that CRO and CRO + DOX were equally effective at controlling meningococcal replication. No differences in survival were observed between mice treated with CRO (94.4%) or CRO + DOX (95.5%), (p > 0.05). Treatment with CRO + DOX significantly diminished both the number of cerebral hemorrhages (p = 0.029) and the amount of MMP-9 in the brain (p = 0.046) compared to untreated controls, but not to CRO-treated animals (p > 0.05). Levels of inflammatory markers in the brain of mice that received CRO or CRO + DOX were not significantly different (p > 0.05). Overall, there were no significant differences in the parameters assessed between the groups treated with CRO alone or CRO + DOX. CONCLUSIONS: Treatment with CRO + DOX showed similar bactericidal activity to CRO in vivo, suggesting no antagonist effect of DOX on CRO. Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy. In contrast to experimental PM, DOX has no adjunctive activity in experimental MM.


Assuntos
Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Doxiciclina/uso terapêutico , Meningite Meningocócica/tratamento farmacológico , Neisseria meningitidis Sorogrupo C , Animais , Antibacterianos/administração & dosagem , Carga Bacteriana/efeitos dos fármacos , Ceftriaxona/administração & dosagem , Hemorragia Cerebral/tratamento farmacológico , Quimiocinas/análise , Quimiocinas/metabolismo , Modelos Animais de Doenças , Doxiciclina/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/metabolismo , Meningite Meningocócica/mortalidade , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Resultado do Tratamento
2.
Front Immunol ; 11: 1636, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670298

RESUMO

The current pandemic of coronavirus disease 19 (COVID-19) has affected millions of individuals and caused thousands of deaths worldwide. The pathophysiology of the disease is complex and mostly unknown. Therefore, identifying the molecular mechanisms that promote progression of the disease is critical to overcome this pandemic. To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. Here, we provide novel perspectives on the pathophysiology of COVID-19 using robust functional approaches to analyze public transcriptome datasets. In addition, we compared the transcriptional signature of COVID-19 patients with individuals infected with SARS-CoV-1 and Influenza A (IAV) viruses. We identified a core transcriptional signature induced by the respiratory viruses in peripheral leukocytes, whereas the absence of significant type I interferon/antiviral responses characterized SARS-CoV-2 infection. We also identified the higher expression of genes involved in metabolic pathways including heme biosynthesis, oxidative phosphorylation and tryptophan metabolism. A BTM-driven meta-analysis of bronchoalveolar lavage fluid (BALF) from COVID-19 patients showed significant enrichment for neutrophils and chemokines, which were also significant in data from lung tissue of one deceased COVID-19 patient. Importantly, our results indicate higher expression of genes related to oxidative phosphorylation both in peripheral mononuclear leukocytes and BALF, suggesting a critical role for mitochondrial activity during SARS-CoV-2 infection. Collectively, these data point for immunopathological features and targets that can be therapeutically exploited to control COVID-19.


Assuntos
Betacoronavirus/imunologia , Quimiocinas/sangue , Infecções por Coronavirus/imunologia , Interferon Tipo I/sangue , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Infecções por Coronavirus/patologia , Perfilação da Expressão Gênica , Humanos , Inflamação/virologia , Influenza Humana/imunologia , Interferon Tipo I/imunologia , Neutrófilos/citologia , Fosforilação Oxidativa , Pandemias , Pneumonia Viral/patologia , Transcriptoma/genética
3.
Viruses ; 12(6)2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32599823

RESUMO

The respiratory Influenza A Viruses (IAVs) and emerging zoonotic viruses such as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pose a significant threat to human health. To accelerate our understanding of the host-pathogen response to respiratory viruses, the use of more complex in vitro systems such as normal human bronchial epithelial (NHBE) cell culture models has gained prominence as an alternative to animal models. NHBE cells were differentiated under air-liquid interface (ALI) conditions to form an in vitro pseudostratified epithelium. The responses of well-differentiated (wd) NHBE cells were examined following infection with the 2009 pandemic Influenza A/H1N1pdm09 strain or following challenge with the dsRNA mimic, poly(I:C). At 30 h postinfection with H1N1pdm09, the integrity of the airway epithelium was severely impaired and apical junction complex damage was exhibited by the disassembly of zona occludens-1 (ZO-1) from the cell cytoskeleton. wdNHBE cells produced an innate immune response to IAV-infection with increased transcription of pro- and anti-inflammatory cytokines and chemokines and the antiviral viperin but reduced expression of the mucin-encoding MUC5B, which may impair mucociliary clearance. Poly(I:C) produced similar responses to IAV, with the exception of MUC5B expression which was more than 3-fold higher than for control cells. This study demonstrates that wdNHBE cells are an appropriate ex-vivo model system to investigate the pathogenesis of respiratory viruses.


Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/virologia , Mucosa Respiratória/citologia , Mucosa Respiratória/virologia , Animais , Brônquios/citologia , Brônquios/virologia , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Cães , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/epidemiologia , Junções Intercelulares , Células Madin Darby de Rim Canino , Modelos Biológicos , Mucina-5AC/metabolismo , Pandemias , Cultura de Vírus
4.
mSphere ; 5(3)2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581077

RESUMO

COVID-19 is often related to hyperinflammation that drives lung or multiorgan injury. The immunopathological mechanisms that cause excessive inflammation are under investigation and constantly updated. Here, a gene network approach was used on recently published data sets to identify possible COVID-19 inflammatory mechanisms and bioactive genes. First, network analysis of putative SARS-CoV-2 cellular receptors led to the mining of a neutrophil-response signature and relevant inflammatory genes. Second, analysis of RNA-seq data sets of lung cells infected with SARS-CoV-2 revealed that infected cells expressed neutrophil-attracting chemokines. Third, analysis of RNA-seq data sets of bronchoalveolar lavage fluid cells from COVID-19 patients identified upregulation of neutrophil genes and chemokines. Different inflammatory genes mined here, including TNFR, IL-8, CXCR1, CXCR2, ADAM10, GPR84, MME, ANPEP, and LAP3, might be druggable targets in efforts to limit SARS-CoV-2 inflammation in severe clinical cases. The possible role of neutrophils in COVID-19 inflammation needs to be studied further.


Assuntos
Betacoronavirus/imunologia , Quimiocinas/imunologia , Infecções por Coronavirus/imunologia , Inflamação/patologia , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Quimiocinas/genética , Infecções por Coronavirus/patologia , Humanos , Inflamação/imunologia , Pneumopatias/imunologia , Pneumopatias/patologia , Infiltração de Neutrófilos/imunologia , Pandemias , Pneumonia Viral/patologia , Receptores Virais/genética
5.
Rev Assoc Med Bras (1992) ; 66(3): 300-306, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32520149

RESUMO

OBJECTIVES: To compare the serum concentrations of adipokines resistin and chemerin in children and adolescents with eutrophic and overweight and to evaluate their relationship with anthropometric, biochemical, and blood pressure variables. METHODS: a cross-sectional epidemiological study was conducted with 234 students enrolled in public elementary schools in the city of Juiz de Fora / MG. Anthropometric evaluation, biochemistry, and blood pressure measurement were performed. Statistical analyzes included the Student-t or Mann-Whitney tests, Pearson or Spearman correlation, used according to the distribution of the variables, and linear regression analysis, by means of the evaluation of the effect of the independent variables on the serum levels of chemerin and resistin, adjusted for age and sex. For the data analysis, SPSS® software version 21.0 and STATA® version 10.1 were used, assuming a significance level of 5%. RESULTS: the concentrations of chemerin were higher in eutrophic individuals than in those with excess weight (p> 0.05). In contrast, levels of resistin were higher in the young with excess weight than in the eutrophic ones (p <0.05). In the multiple linear regression analysis, the levels of chemerin were associated with the values of resistin, systolic, and diastolic blood pressure. Resistance levels maintained association only with BMI and chemerin values. CONCLUSION: the adipokines analyzed presented a distinct profile in the groups of children and adolescents with eutrophic and overweight.


Assuntos
Adiponectina/sangue , Quimiocinas/sangue , Sobrepeso/sangue , Resistina/sangue , Adipocinas , Adolescente , Antropometria , Criança , Estudos Transversais , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Sobrepeso/complicações , Sobrepeso/metabolismo
6.
Braz J Med Biol Res ; 53(6): e9113, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401924

RESUMO

Chemerin is an adipokine that has been associated with components of metabolic syndrome. It has been described to affect adipocyte metabolism and inflammatory responses in adipose tissue, as well as the systemic metabolism of lipids and glucose. Few epidemiological studies have evaluated classical and genetics cardiovascular risk factors (CVRFs) in the mixed adult rural population in Brazil. Therefore, the present study explored possible associations between CVRFs and chemerin. This cross-sectional study included 508 adults from the rural localities of Lavras Novas, Chapada, and Santo Antônio do Salto in Ouro Preto, Minas Gerais, Southeast Brazil. Demographic, behavioral, clinical, biochemical, anthropometric variables, and 12 single nucleotide polymorphisms (SNPs) linked with metabolic syndrome phenotypes were evaluated for associations with chemerin level. There was a significant association of high triglyceride levels [odds ratio (OR)=1.91, 95%CI: 1.23-2.98], insulin resistance (OR=1.82, 95%CI: 1.03-3.22), age (OR=1.64, 95%CI: 1.08-2.49), and sex (OR=1.99, 95%CI: 1.35-2.95) with high levels of chemerin. High chemerin levels were significantly associated with the genetic polymorphisms rs693 in the APOB gene (OR=1.50, 95%CI: 1.03-2.19) and rs1799983 in the NOS3 gene (OR=1.46, 95%CI: 1.01-2.12) for the AA and GT+TT genotypes, respectively. In the concomitant presence of genotypes AA of rs693 and GT+TT of rs1799983, the chance of presenting high levels of chemerin showed a 2.21-fold increase (95%CI: 1.25-3.88) compared to the reference genotype. The development of classical CVRFs in this population may be influenced by chemerin and by two risk genotypes characteristic of variants in well-studied genes for hypertension and dyslipidemia.


Assuntos
Apolipoproteínas B/genética , Doenças Cardiovasculares/genética , Quimiocinas/sangue , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Doenças Cardiovasculares/metabolismo , Quimiocinas/genética , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , População Rural , Adulto Jovem
7.
Medicine (Baltimore) ; 99(19): e20183, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384511

RESUMO

BACKGROUNDS: Lung adenocarcinoma (LUAD) is one of the most common malignancies, and is a serious threat to human health. The aim of the present study was to assess potential biomarkers for the prognosis of LUAD through the analysis of gene expression microarrays. METHODS: The gene expression data for GSE118370 was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between normal lung and LUAD samples were screened using the R language. The DAVID database was used to analyze the functions and pathways of DEGs. The STRING database was used to the map protein-protein interaction (PPI) networks, and these were visualized with the Cytoscape software. Finally, the prognostic analysis of the hub gene in the PPI network was performed using the Kaplan-Meier tool. RESULTS: A total of 406 downregulated and 203 upregulated DEGs were identified. The GO analysis results revealed that downregulated DEGs were significantly enriched in angiogenesis, calcium ion binding and cell adhesion. The upregulated DEGs were significantly enriched in the extracellular matrix disassembly, collagen catabolic process, chemokine-mediated signaling pathway and endopeptidase inhibitor activity. The KEGG pathway analysis revealed that downregulated DEGs were enriched in neuroactive ligand-receptor interaction, hematopoietic cell lineage and vascular smooth muscle contraction, while upregulated DEGs were enriched in phototransduction. In addition, the top 10 hub genes and the most closely interacting modules of the top 3 proteins in the PPI network were screened. Finally, the independent prognostic value of each hub gene in LUAD patients was analyzed through the Kaplan-Meier plotter. Seven hub genes (ADCY4, S1PR1, FPR2, PPBP, NMU, PF4, and GCG) were closely correlated to overall survival time. CONCLUSION: The discovery of these candidate genes and pathways reveals the etiology and molecular mechanisms of LUAD, providing ideas and guidance for the development of new therapeutic approaches to LUAD.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Bases de Dados Genéticas , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Biomarcadores Tumorais , Quimiocinas/metabolismo , Colágeno/metabolismo , Regulação para Baixo/fisiologia , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Estimativa de Kaplan-Meier , Análise em Microsséries , Prognóstico , Inibidores de Proteases/metabolismo , Mapas de Interação de Proteínas , Regulação para Cima/fisiologia
8.
Cell ; 181(5): 1036-1045.e9, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32416070

RESUMO

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Vírus de RNA/imunologia , Animais , Células Cultivadas , Quimiocinas/genética , Quimiocinas/imunologia , Infecções por Coronavirus/genética , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Inflamação/virologia , Interferons/genética , Interferons/imunologia , Pandemias , Pneumonia Viral/genética , Vírus de RNA/classificação , Transcrição Genética
9.
PLoS One ; 15(5): e0233054, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32433651

RESUMO

Smoking, which is highly prevalent in HIV-infected populations, has been shown to exacerbate HIV replication, in part via the cytochrome P450 (CYP)-induced oxidative stress pathway. Recently, we have shown that extracellular vesicles (EVs), derived from tobacco- and/or HIV-exposed macrophages, alter HIV replication in macrophages by cell-cell interactions. We hypothesize that cigarette smoke condensate (CSC) and/or HIV-exposed macrophage-derived EVs carry relatively high levels of pro-oxidant and pro-inflammatory cargos and/or low levels of antioxidant and anti-inflammatory cargos, which are key mediators for HIV pathogenesis. Therefore, in this study, we investigated differential packaging of pro- and anti-inflammatory cytokines/chemokines and pro- and anti-oxidant contents in EVs after CSC exposure to myeloid cells (uninfected U937 and HIV-infected U1 cells). Our results showed that relatively long to short exposures with CSC increased the expression of cytokines in EVs isolated from HIV-infected U1 macrophages. Importantly, pro-inflammatory cytokines, especially IL-6, were highly packaged in EVs isolated from HIV-infected U1 macrophages upon both long and short-term CSC exposures. In general, anti-inflammatory cytokines, particularly IL-10, had a lower packaging in EVs, while packaging of chemokines was mostly increased in EVs upon CSC exposure in both HIV-infected U1 and uninfected U937 macrophages. Moreover, we observed higher expression of CYPs (1A1 and 1B1) and lower expression of antioxidant enzymes (SOD-1 and catalase) in EVs from HIV-infected U1 macrophages than in uninfected U937 macrophages. Together, they are expected to increase oxidative stress factors in EVs derived from HIV-infected U1 cells. Taken together, our results suggest packaging of increased level of oxidative stress and inflammatory elements in the EVs upon exposure to tobacco constituents and/or HIV to myeloid cells, which would ultimately enhance HIV replication in macrophages via cell-cell interactions.


Assuntos
Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Macrófagos/citologia , Fumaça/efeitos adversos , Linhagem Celular , Quimiocinas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/imunologia , Macrófagos/virologia , Estresse Oxidativo/efeitos dos fármacos , Tabaco
11.
Cytokine Growth Factor Rev ; 53: 25-32, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32446778

RESUMO

In 2019-2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called "cytokine storm" an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.


Assuntos
Betacoronavirus/imunologia , Quimiocinas/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Pneumonia Viral/patologia , Receptores de Quimiocinas/metabolismo , Quimiocinas/sangue , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Humanos , Pandemias , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/patologia
12.
PLoS One ; 15(4): e0231131, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32282838

RESUMO

In reproductive hens, a feed restriction is an usual practice to improve metabolic and reproductive disorders. However, it acts a stressor on the animal. In mammals, grape seed extracts (GSE) reduces oxidative stress. However, their effect on endocrine and tissue response need to be deepened in reproductive hens. Here, we evaluated the effects of time and level of GSE dietary supplementation on growth performance, viability, oxidative stress and metabolic parameters in plasma and metabolic tissues in reproductive hens and their offsprings. We designed an in vivo trial using 4 groups of feed restricted hens: A (control), B and C (supplemented with 0.5% and 1% of the total diet composition in GSE since week 4, respectively) and D (supplemented with 1% of GSE since the hatch). In hens from hatch to week 40, GSE supplementation did not affect food intake and fattening whatever the time and dose of supplementation. Body weight was significantly reduced in D group as compared to control. In all hen groups, GSE supplementation decreased plasma oxidative stress index associated to a decrease in the mRNA expression of the NOX4 and 5 oxidant genes in liver and muscle and an increase in SOD mRNA expression. This was also associated to decreased plasma chemerin and increased plasma adiponectin and visfatin levels. Interestingly, maternal GSE supplementation increased the live body weight and viability of chicks at hatching and 10 days of age. This was associated to a decrease in plasma and liver oxidative stress parameters. Taken together, GSE maternal dietary supplementation reduces plasma and tissue oxidative stress associated to modulation of adipokines without affecting fattening in reproductive hens. A 1% GSE maternal dietary supplementation increased offspring viability and reduced oxidative stress suggesting a beneficial transgenerational effect and a potential use to improve the quality of the progeny in reproductive hens.


Assuntos
Criação de Animais Domésticos/métodos , Antioxidantes/administração & dosagem , Galinhas/crescimento & desenvolvimento , Suplementos Nutricionais , Extrato de Sementes de Uva/administração & dosagem , Adiponectina/sangue , Adiponectina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Cruzamento/métodos , Quimiocinas/sangue , Quimiocinas/metabolismo , Galinhas/sangue , Dieta/efeitos adversos , Dieta/veterinária , Feminino , Troca Materno-Fetal/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Gravidez , Reprodução/fisiologia
13.
PLoS One ; 15(4): e0226444, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240177

RESUMO

Glioblastoma, the most aggressive form of glioma, has a 5-year survival rate of <5%. While radiation and immunotherapies are routinely studied in the murine Gl261 glioma model, little is known about its inherent immune response. This study quantifies the temporal and spatial localization of immune cell populations and mediators during glioma development. Eight-week old male C57Bl/6 mice were orthotopically inoculated with 1x106 Gl261 cells and tumor morphology, local and systemic immune cell populations, and plasma cytokines/chemokines assessed at day 0, 1, 3, 7, 14, and 21 post-inoculation by magnetic resonance imaging, chromogenic immunohistochemistry, multiplex immunofluorescent immunohistochemistry, flow cytometry and multiplex immunoassay respectively. From day 3 tumors were distinguishable with >30% Ki67 and increased tissue vascularization (p<0.05). Increasing tumor proliferation/malignancy and vascularization were associated with significant temporal changes in immune cell populations within the tumor (p<0.05) and systemic compartments (p = 0.02 to p<0.0001). Of note, at day 14 16/24 plasma cytokine/chemokines levels decreased coinciding with an increase in tumor cytotoxic T cells, natural killer and natural killer/T cells. Data derived provide baseline characterization of the local and systemic immune response during glioma development. They reveal that type II macrophages and myeloid-derived suppressor cells are more prevalent in tumors than regulatory T cells, highlighting these cell types for further therapeutic exploration.


Assuntos
Glioma/imunologia , Imunidade Inata , Células Matadoras Naturais/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Linhagem da Célula/imunologia , Proliferação de Células/genética , Quimiocinas/sangue , Quimiocinas/imunologia , Citocinas/sangue , Citocinas/imunologia , Progressão da Doença , Citometria de Fluxo , Glioma/sangue , Glioma/patologia , Humanos , Células Matadoras Naturais/metabolismo , Camundongos , Linfócitos T Citotóxicos/metabolismo
14.
Emerg Microbes Infect ; 9(1): 761-770, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32228226

RESUMO

Circulating in China and 158 other countries and areas, the ongoing COVID-19 outbreak has caused devastating mortality and posed a great threat to public health. However, efforts to identify effectively supportive therapeutic drugs and treatments has been hampered by our limited understanding of host immune response for this fatal disease. To characterize the transcriptional signatures of host inflammatory response to SARS-CoV-2 (HCoV-19) infection, we carried out transcriptome sequencing of the RNAs isolated from the bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMC) specimens of COVID-19 patients. Our results reveal distinct host inflammatory cytokine profiles to SARS-CoV-2 infection in patients, and highlight the association between COVID-19 pathogenesis and excessive cytokine release such as CCL2/MCP-1, CXCL10/IP-10, CCL3/MIP-1A, and CCL4/MIP1B. Furthermore, SARS-CoV-2 induced activation of apoptosis and P53 signalling pathway in lymphocytes may be the cause of patients' lymphopenia. The transcriptome dataset of COVID-19 patients would be a valuable resource for clinical guidance on anti-inflammatory medication and understanding the molecular mechansims of host response.


Assuntos
Líquido da Lavagem Broncoalveolar , Quimiocinas/análise , Infecções por Coronavirus/genética , Citocinas/análise , Leucócitos Mononucleares , Pneumonia Viral/genética , Transcriptoma , Apoptose , Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Humanos , Linfopenia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , RNA-Seq , Transdução de Sinais , Proteína Supressora de Tumor p53
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(2): 682-685, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32319416

RESUMO

Abstract  Chemokines and their receptors play an important role in development and migration of normal immune cells. In recent years, relevant studies have shown that the expression of chemokine receptor on the surface of non-Hodgkin's lymphoma cells is up-regulated, which regulates the disease's occurrence and metastasis, and influences prognosis of patients. Agents targeting chemokine receptors are under research and applied in hematopoietic stem cell mobilization and anti-lymphoma therapy. A new family of atypical chemokines has been gradually discovered and shown the anti-lymphoma effect, which is potential to become a new theraputic method. In this review, the research advance of chemokines and their receptors in non-Hodgkin's lymphoma is summarized.


Assuntos
Linfoma não Hodgkin , Quimiocinas , Mobilização de Células-Tronco Hematopoéticas , Humanos , Receptores de Quimiocinas
16.
Geroscience ; 42(2): 505-514, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32274617

RESUMO

SARS-CoV-2 virus, the causative agent of the coronavirus infectious disease-19 (COVID-19), is taking the globe by storm, approaching 500,000 confirmed cases and over 21,000 deaths as of March 25, 2020. While under control in some affected Asian countries (Taiwan, Singapore, Vietnam), the virus demonstrated an exponential phase of infectivity in several large countries (China in late January and February and many European countries and the USA in March), with cases exploding by 30-50,000/day in the third and fourth weeks of March, 2020. SARS-CoV-2 has proven to be particularly deadly to older adults and those with certain underlying medical conditions, many of whom are of advanced age. Here, we briefly review the virus, its structure and evolution, epidemiology and pathogenesis, immunogenicity and immune, and clinical response in older adults, using available knowledge on SARS-CoV-2 and its highly pathogenic relatives MERS-CoV and SARS-CoV-1. We conclude by discussing clinical and basic science approaches to protect older adults against this disease.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Idoso , Animais , Anticorpos Antivirais/imunologia , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Quimiocinas/imunologia , Citocinas/imunologia , Febre/diagnóstico , Febre/virologia , Geriatria , Humanos , Imunossenescência , Coronavírus da Síndrome Respiratória do Oriente Médio , Pandemias , Peptidil Dipeptidase A/genética , Vírus da SARS , Glicoproteína da Espícula de Coronavírus/genética
17.
Nat Commun ; 11(1): 1143, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123168

RESUMO

By offering the possibility to manipulate cellular functions with spatiotemporal control, optogenetics represents an attractive tool for dissecting immune responses. However, applying these approaches to single cells in vivo remains particularly challenging for immune cells that are typically located in scattering tissues. Here, we introduce an improved calcium actuator with sensitivity allowing for two-photon photoactivation. Furthermore, we identify an actuator/reporter combination that permits the simultaneous manipulation and visualization of calcium signals in individual T cells in vivo. With this strategy, we document the consequences of defined patterns of calcium signals on T cell migration, adhesion, and chemokine release. Manipulation of individual immune cells in vivo should open new avenues for establishing the functional contribution of single immune cells engaged in complex reactions.


Assuntos
Sinalização do Cálcio/fisiologia , Optogenética/métodos , Linfócitos T/metabolismo , Animais , Proteínas de Arabidopsis/genética , Linfócitos T CD8-Positivos/metabolismo , Adesão Celular , Movimento Celular , Quimiocinas/metabolismo , Criptocromos/genética , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fótons , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Análise de Célula Única/métodos , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo , Linfócitos T/citologia
18.
PLoS One ; 15(3): e0229765, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130282

RESUMO

AIM: To evaluate the serum concentrations of inflammatory mediators in patients with type 2 diabetes mellitus (T2DM) with or without renal alteration (RA) function. METHODS: Serum samples from 76 patients with T2DM and 24 healthy individuals were selected. Patients with T2DM were divided into two groups according to eGFR (> or < 60mL/min/1.73m2). Cytokines, chemokines and adipokines levels were evaluated using the Multiplex immunoassay and ELISA. RESULTS: TNFR1 and leptin were higher in the T2DM group with RA than in the T2DM group without RA and control group. All patients with T2DM showed increased resistin, IL-8, and MIP-1α compared to the control group. Adiponectin were higher and IL-4 decreased in the T2DM group with RA compared to the control group. eGFR positively correlated with IL-4 and negatively with TNFR1, TNFR2, and leptin in patients with T2DM. In the T2DM group with RA, eGFR was negatively correlated with TNFR1 and resistin. TNFR1 was positively correlated with resistin and leptin, as well as resistin with IL-8 and leptin. CONCLUSION: Increased levels of TNFR1, adipokines, chemokines and decrease of IL-4 play important role in the inflammatory process developed in T2DM and decreased renal function. We also suggest that TNFR1 is a strong predictor of renal dysfunction in patients with T2DM.


Assuntos
Adipocinas/sangue , Quimiocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Interleucinas/sangue , Rim/fisiopatologia , Adulto , Biomarcadores/sangue , Antígenos CD40/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
PLoS Pathog ; 16(3): e1008374, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32168364

RESUMO

Antimicrobial resistance is increasing in pathogenic bacteria. Yet, the effect of antibiotic exposure on resistant bacteria has been underexplored and may affect pathogenesis. Here we describe the discovery that propagation of the human pathogen Acinetobacter baumannii in an aminoglycoside antibiotic results in alterations to the bacterium that interact with lung innate immunity resulting in enhanced bacterial clearance. Co-inoculation of mice with A. baumannii grown in the presence and absence of the aminoglycoside, kanamycin, induces enhanced clearance of a non-kanamycin-propagated strain. This finding can be replicated when kanamycin-propagated A. baumannii is killed prior to co-inoculation of mice, indicating the enhanced bacterial clearance results from interactions with innate host defenses in the lung. Infection with kanamycin-propagated A. baumannii alters the kinetics of phagocyte recruitment to the lung and reduces pro- and anti-inflammatory cytokine and chemokine production in the lung and blood. This culminates in reduced histopathologic evidence of lung injury during infection despite enhanced bacterial clearance. Further, the antibacterial response induced by killed aminoglycoside-propagated A. baumannii enhances the clearance of multiple clinically relevant Gram-negative pathogens from the lungs of infected mice. Together, these findings exemplify cooperation between antibiotics and the host immune system that affords protection against multiple antibiotic-resistant bacterial pathogens. Further, these findings highlight the potential for the development of a broad-spectrum therapeutic that exploits a similar mechanism to that described here and acts as an innate immunity modulator.


Assuntos
Infecções por Acinetobacter/imunologia , Acinetobacter baumannii/imunologia , Imunidade Inata/efeitos dos fármacos , Canamicina/farmacologia , Pulmão/imunologia , Pneumonia Bacteriana/imunologia , Infecções por Acinetobacter/patologia , Acinetobacter baumannii/patogenicidade , Animais , Quimiocinas/imunologia , Feminino , Pulmão/patologia , Camundongos , Camundongos Knockout , Fagócitos/patologia , Pneumonia Bacteriana/microbiologia
20.
Nat Commun ; 11(1): 1114, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111837

RESUMO

Little is known regarding lymph node (LN)-homing of immune cells via afferent lymphatics. Here, we show, using a photo-convertible Dendra-2 reporter, that recently activated CD4 T cells enter downstream LNs via afferent lymphatics at high frequencies. Intra-lymphatic immune cell transfer and live imaging data further show that activated T cells come to an instantaneous arrest mediated passively by the mechanical 3D-sieve barrier of the LN subcapsular sinus (SCS). Arrested T cells subsequently migrate randomly on the sinus floor independent of both chemokines and integrins. However, chemokine receptors are imperative for guiding cells out of the SCS, and for their subsequent directional translocation towards the T cell zone. By contrast, integrins are dispensable for LN homing, yet still contribute by increasing the dwell time within the SCS and by potentially enhancing T cell sensing of chemokine gradients. Together, these findings provide fundamental insights into mechanisms that control homing of lymph-derived immune cells.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Movimento Celular/imunologia , Quimiocinas/metabolismo , Integrinas/metabolismo , Linfonodos/fisiologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Endotélio Linfático/fisiologia , Integrinas/genética , Linfa/citologia , Linfonodos/citologia , Ativação Linfocitária , Camundongos , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores de Retorno de Linfócitos/metabolismo
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