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1.
Cells ; 9(10)2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003471

RESUMO

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host-pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Células Dendríticas/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Pneumonia Viral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Células Cultivadas , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia
2.
Signal Transduct Target Ther ; 5(1): 221, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024073
3.
PLoS Pathog ; 16(9): e1008854, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956405

RESUMO

Aspergillus fumigatus is an opportunistic fungal pathogen of immunocompromised patient populations. Mortality is thought to be context-specific and occurs via both enhanced fungal growth and immunopathogenesis. NLRX1 is a negative regulator of immune signaling and metabolic pathways implicated in host responses to microbes, cancers, and autoimmune diseases. Our study indicates loss of Nlrx1 results in enhanced fungal burden, pulmonary inflammation, immune cell recruitment, and mortality across immuno-suppressed and immuno-competent models of IPA using two clinically derived isolates (AF293, CEA10). We observed that the heightened mortality is due to enhanced recruitment of CD103+ dendritic cells (DCs) that produce elevated amounts of IL-4 resulting in a detrimental Th2-mediated immune response. Adoptive transfer of Nlrx1-/- CD103+ DCs in neutropenic NRG mice results in enhanced mortality that can be ablated using IL-4 neutralizing antibodies. In vitro analysis of CD103+ DCs indicates loss of Nlrx1 results in enhanced IL-4 production via elevated activation of the JNK/JunB pathways. Interestingly, loss of Nlrx1 also results in enhanced recruitment of monocytes and neutrophils. Chimeras of irradiated Nlrx1-/- mice reconstituted with wild type bone marrow have enhanced neutrophil recruitment and survival during models of IPA. This enhanced immune cell recruitment in the absence of Nlrx1 is mediated by excessive production of CXCL8/IL-8 family of chemokines and IL-6 via early and enhanced activation of P38 in response to A. fumigatus conidia as shown in BEAS-2B airway epithelial cells. In summary, our results point strongly towards the cell-specific and contextual function of Nlrx1 during invasive pulmonary aspergillosis and may lead to novel therapeutics to reduce Th2 responses by CD103+ DCs or heightened recruitment of neutrophils.


Assuntos
Aspergillus fumigatus/imunologia , Células Dendríticas/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Proteínas Mitocondriais/imunologia , Aspergilose Pulmonar/imunologia , Células Th2/imunologia , Animais , Linhagem Celular , Citocinas/genética , Citocinas/imunologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/imunologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Neutrófilos/imunologia , Neutrófilos/patologia , Aspergilose Pulmonar/genética , Aspergilose Pulmonar/patologia , Células Th2/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
4.
Eur J Immunol ; 50(9): 1283-1294, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32910469

RESUMO

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM- plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.


Assuntos
Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Isotipos de Imunoglobulinas/sangue , Pulmão/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/classificação , Linfócitos B/virologia , Betacoronavirus/imunologia , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Proliferação de Células , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Estudos Transversais , Citocinas/genética , Citocinas/imunologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/imunologia , Humanos , Imunidade Humoral , Memória Imunológica , Pulmão/patologia , Pulmão/virologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Cultura Primária de Células , Índice de Gravidade de Doença , Análise de Sobrevida
5.
Anticancer Res ; 40(9): 4895-4905, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878777

RESUMO

BACKGROUND/AIM: Nicotinamide phosphoribosyl-transferase (NAMPT) is a rate-limiting enzyme in the pathway synthesizing nicotinamide adenine dinucleotide (NAD (+)) from nicotinamide (NAM). Glioma tissues exhibit up-regulated NAMPT expression associated with a poor prognosis of patients. To determine if NAMPT can be a molecular therapeutic target, we investigated the effects of short hairpin RNA (shRNA)-mediated NAMPT down-regulation. MATERIALS AND METHODS: We designed shRNA to NAMPT and transfected to T98G cells. The characteristics of these cells were analyzed. RESULTS: The NAMPT shRNA-transfected cells exhibited delayed cell growth. However, there was no difference in the increase of sensitivity to temozolomide (TMZ) or X-ray irradiation between the NAMPT and scramble shRNA-transfected cells. The expression of NAMPT in the NAMPT shRNA-transfected cells increased with cell passage. Additionally, the shRNA-mediated transfection was associated with enhanced expression of quinolinic acid phosphoribo-syltransferase (QPRT). CONCLUSION: shRNA-mediated NAMPT down-regulation may not decrease the NADt to a sufficient level to increase TMZ/radiation sensitivity.


Assuntos
Citocinas/metabolismo , Regulação para Baixo , Glioma/enzimologia , Nicotinamida Fosforribosiltransferase/metabolismo , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/genética , Glioma/metabolismo , Glioma/patologia , Humanos , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Pentosiltransferases/genética , Pentosiltransferases/metabolismo , RNA Interferente Pequeno/genética , Temozolomida/farmacologia
8.
In Vivo ; 34(5): 3027-3028, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32871847
9.
Medicine (Baltimore) ; 99(38): e22362, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957410

RESUMO

Cytokines are extensively involved in the process of hepatitis C virus (HCV) infection and take a crucial part in host immune regulation. We aimed to explore the potential correlation of cytokine single nucleotide polymorphisms (SNPs) with HCV susceptibility and response rate of interferon (IFN)-based antiviral therapy in Chinese Han population.A case-control genetic association study was conducted between 198 patients with chronic HCV genotype 1b infection and 142 healthy controls. Genetic polymorphisms of TNF-α (rs1800629), TGF-ß (rs1800469), IL-10 (rs1800896, rs1800871, and rs1800872), IL-6 (rs1800795, rs1800796), IFN-γ (rs2430561), and IL-28B (rs12979860, rs12980275, and rs8099917) were analyzed by MassARRAY SNP technology. Patients were treated with IFNα-2b or pegylated-IFNα-2a plus ribavirin for 48 weeks. Sustained virological response (SVR) was assessed 6 months after the completion of the treatment.The IL-28B rs12979860-CC (odds ratio [OR] = 4.35, 95% confidence interval [CI]: 1.69-11.21, P = .001), rs12980275-AA (OR = 3.41, 95% CI: 1.08-10.76, P = .028), and rs8099917-TT (OR = 3.86, 95% CI: 1.49-10.12, P = .004) were significantly associated with SVR, and IL-10 rs1800871-TT (OR = .50, 95% CI: 0.25-1.00, P = .049) and rs1800872-AA (OR = .50, 95% CI: 0.25-1.00, P = .049) were also significant for SVR. No association was found between the cytokine SNPs and HCV susceptibility. Additionally, multivariate analysis showed that low baseline viral load (OR = 3.63, 95% CI: 1.01-13.02, P = .048), pegylated-IFN (OR = 9.68, 95% CI: 1.14-82.13, P = .037) and rs12979860-CC (OR = 6.08, 95% CI: 2.00-18.46, P = .001) were independent factors for SVR.IL-28 and IL-10 gene polymorphisms played an important role in predicting host response to IFN-based antiviral therapy in HCV genotype 1b infection.


Assuntos
Citocinas/genética , Hepatite C Crônica/tratamento farmacológico , Resposta Viral Sustentada , Adulto , Idoso , Antivirais/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Carga Viral/genética
10.
Am J Hum Genet ; 107(3): 527-538, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758447

RESUMO

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.


Assuntos
Inflamação/genética , Interleucinas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Adulto , Animais , Citocinas/genética , Armadilhas Extracelulares/genética , Feminino , Humanos , Inflamação/patologia , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Camundongos , Mutação/genética , Neutrófilos/metabolismo , Psoríase/patologia , Doenças Raras/enzimologia , Doenças Raras/genética , Doenças Raras/patologia , Pele/enzimologia , Pele/patologia , Dermatopatias/patologia
12.
Int J Mol Sci ; 21(16)2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32806722

RESUMO

The coronavirus disease 2019 COVID-19 pandemic is rapidly spreading worldwide and is becoming a major public health crisis. Increasing evidence demonstrates a strong correlation between obesity and the COVID-19 disease. We have summarized recent studies and addressed the impact of obesity on COVID-19 in terms of hospitalization, severity, mortality, and patient outcome. We discuss the potential molecular mechanisms whereby obesity contributes to the pathogenesis of COVID-19. In addition to obesity-related deregulated immune response, chronic inflammation, endothelium imbalance, metabolic dysfunction, and its associated comorbidities, dysfunctional mesenchymal stem cells/adipose-derived mesenchymal stem cells may also play crucial roles in fueling systemic inflammation contributing to the cytokine storm and promoting pulmonary fibrosis causing lung functional failure, characteristic of severe COVID-19. Moreover, obesity may also compromise motile cilia on airway epithelial cells and impair functioning of the mucociliary escalators, reducing the clearance of severe acute respiratory syndrome coronavirus (SARS-CoV-2). Obese diseased adipose tissues overexpress the receptors and proteases for the SARS-CoV-2 entry, implicating its possible roles as virus reservoir and accelerator reinforcing violent systemic inflammation and immune response. Finally, anti-inflammatory cytokines like anti-interleukin 6 and administration of mesenchymal stromal/stem cells may serve as potential immune modulatory therapies for supportively combating COVID-19. Obesity is conversely related to the development of COVID-19 through numerous molecular mechanisms and individuals with obesity belong to the COVID-19-susceptible population requiring more protective measures.


Assuntos
Infecções por Coronavirus/epidemiologia , Citocinas/metabolismo , Obesidade/epidemiologia , Pneumonia Viral/epidemiologia , Adipócitos/metabolismo , Animais , Infecções por Coronavirus/imunologia , Citocinas/genética , Humanos , Obesidade/imunologia , Pandemias , Pneumonia Viral/imunologia
13.
Proc Natl Acad Sci U S A ; 117(33): 20159-20170, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747553

RESUMO

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N6 -methylation of adenosine (m6A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m6A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m6A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m6A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Vacinas Anticâncer/imunologia , Lactatos/metabolismo , Melanoma/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/fisiologia , Homólogo AlkB 5 da RNA Desmetilase/genética , Anticorpos , Citocinas/genética , Citocinas/metabolismo , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/terapia , Metiltransferases/genética , Metiltransferases/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Células Supressoras Mieloides/fisiologia , Sítios de Splice de RNA , Processamento de RNA , Simportadores/genética , Simportadores/metabolismo , Transcriptoma , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Protein Cell ; 11(10): 740-770, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32780218

RESUMO

Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.


Assuntos
Envelhecimento/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Sistema Imunitário/imunologia , Pandemias , Pneumonia Viral/imunologia , Análise de Célula Única , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Linfócitos T CD4-Positivos/metabolismo , Linhagem da Célula , Montagem e Desmontagem da Cromatina , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/biossíntese , Citocinas/genética , Suscetibilidade a Doenças , Citometria de Fluxo/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Rearranjo Gênico , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/crescimento & desenvolvimento , Imunocompetência/genética , Inflamação/genética , Inflamação/imunologia , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Análise de Sequência de RNA , Transcriptoma , Adulto Jovem
15.
Arch Virol ; 165(10): 2165-2176, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740830

RESUMO

The PI3K/Akt signalling pathway is a crucial signalling cascade that regulates transcription, protein translation, cell growth, proliferation, cell survival, and metabolism. During viral infection, viruses exploit a variety of cellular pathways, including the well-known PI3K/Akt signalling pathway. Conversely, cells rely on this pathway to stimulate an antiviral response. The PI3K/Akt pathway is manipulated by a number of viruses, including DNA and RNA viruses and retroviruses. The aim of this review is to provide up-to-date information about the role of the PI3K-Akt pathway in infection with members of five different families of negative-sense ssRNA viruses. This pathway is hijacked for viral entry, regulation of endocytosis, suppression of premature apoptosis, viral protein expression, and replication. Although less common, the PI3K/Akt pathway can be downregulated as an immunomodulatory strategy or as a mechanism for inducing autophagy. Moreover, the cell activates this pathway as an antiviral strategy for interferon and cytokine production, among other strategies. Here, we present new data concerning the role of this pathway in infection with the paramyxovirus Newcastle disease virus (NDV). Our data seem to indicate that NDV uses the PI3K/Akt pathway to delay cell death and increase cell survival as a means of improving its replication. The interference of negative-sense ssRNA viruses with this essential pathway might have implications for the development of antiviral therapies.


Assuntos
Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Infecções por Vírus de RNA/genética , Apoptose/genética , Autofagia/genética , Autofagia/imunologia , Citocinas/genética , Citocinas/imunologia , Endocitose/genética , Endocitose/imunologia , Filoviridae/genética , Filoviridae/metabolismo , Filoviridae/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Interferons/genética , Interferons/imunologia , Orthomyxoviridae/genética , Orthomyxoviridae/metabolismo , Orthomyxoviridae/patogenicidade , Paramyxoviridae/genética , Paramyxoviridae/metabolismo , Paramyxoviridae/patogenicidade , Fosfatidilinositol 3-Quinase/imunologia , Pneumovirinae/genética , Pneumovirinae/metabolismo , Pneumovirinae/patogenicidade , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-akt/imunologia , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/virologia , Rhabdoviridae/genética , Rhabdoviridae/metabolismo , Rhabdoviridae/patogenicidade , Transdução de Sinais , Proteínas Virais/genética , Proteínas Virais/imunologia , Internalização do Vírus , Replicação Viral
16.
Cardiovasc Ther ; 2020: 9397109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821285

RESUMO

Chronic systemic inflammation contributes to cardiovascular disease (CVD) and correlates with the abundance of acute phase response (APR) proteins in the liver and plasma. Bromodomain and extraterminal (BET) proteins are epigenetic readers that regulate inflammatory gene transcription. We show that BET inhibition by the small molecule apabetalone reduces APR gene and protein expression in human hepatocytes, mouse models, and plasma from CVD patients. Steady-state expression of serum amyloid P, plasminogen activator inhibitor 1, and ceruloplasmin, APR proteins linked to CVD risk, is reduced by apabetalone in cultured hepatocytes and in humanized mouse liver. In cytokine-stimulated hepatocytes, apabetalone reduces the expression of C-reactive protein (CRP), alpha-2-macroglobulin, and serum amyloid P. The latter two are also reduced by apabetalone in the liver of endotoxemic mice. BET knockdown in vitro also counters cytokine-mediated induction of the CRP gene. Mechanistically, apabetalone reduces the cytokine-driven increase in BRD4 BET occupancy at the CRP promoter, confirming that transcription of CRP is BET-dependent. In patients with stable coronary disease, plasma APR proteins CRP, IL-1 receptor antagonist, and fibrinogen γ decrease after apabetalone treatment versus placebo, resulting in a predicted downregulation of the APR pathway and cytokine targets. We conclude that CRP and components of the APR pathway are regulated by BET proteins and that apabetalone counters chronic cytokine signaling in patients.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Citocinas/metabolismo , Endotoxemia/tratamento farmacológico , Epigênese Genética/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Quinazolinonas/farmacologia , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Proteína C-Reativa/genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Células Cultivadas , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Citocinas/genética , Modelos Animais de Doenças , Endotoxemia/genética , Endotoxemia/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Regiões Promotoras Genéticas , Componente Amiloide P Sérico/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , alfa-Macroglobulinas/genética , alfa-Macroglobulinas/metabolismo
17.
PLoS One ; 15(8): e0238202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32846428

RESUMO

The immune system of ectotherms, particularly non-avian reptiles, remains poorly characterized regarding the genes involved in immune function, and their function in wild populations. We used RNA-Seq to explore the systemic response of Mojave desert tortoise (Gopherus agassizii) gene expression to three levels of Mycoplasma infection to better understand the host response to this bacterial pathogen. We found over an order of magnitude more genes differentially expressed between male and female tortoises (1,037 genes) than differentially expressed among immune groups (40 genes). There were 8 genes differentially expressed among both variables that can be considered sex-biased immune genes in this tortoise. Among experimental immune groups we find enriched GO biological processes for cysteine catabolism, regulation of type 1 interferon production, and regulation of cytokine production involved in immune response. Sex-biased transcription involves iron ion transport, iron ion homeostasis, and regulation of interferon-beta production to be enriched. More detailed work is needed to assess the seasonal response of the candidate genes found here. How seasonal fluctuation of testosterone and corticosterone modulate the immunosuppression of males and their susceptibility to Mycoplasma infection also warrants further investigation, as well as the importance of iron in the immune function and sex-biased differences of this species. Finally, future transcriptional studies should avoid drawing blood from tortoises via subcarapacial venipuncture as the variable aspiration of lymphatic fluid will confound the differential expression of genes.


Assuntos
Infecções por Mycoplasma/imunologia , Infecções por Mycoplasma/veterinária , Mycoplasma/imunologia , Tartarugas/genética , Tartarugas/imunologia , Animais , Anticorpos Antibacterianos/sangue , California , Citocinas/genética , Citocinas/imunologia , Clima Desértico , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Transporte de Íons/genética , Ferro/metabolismo , Masculino , Infecções por Mycoplasma/microbiologia , Nevada , Fatores Sexuais
18.
Life Sci ; 258: 118197, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781059

RESUMO

AIMS: Patients with neurodevelopmental disorders, usually suffer from bone diseases. Many studies have revealed a higher risk of fracture after atypical antipsychotic drug Risperidone (RIS) treatment, which is usually used to treat such disorders. It remains debatable whether neurodevelopmental disorders by itself are the cause of bone diseases or pharmacotherapy may be the reason. MATERIALS AND METHODS: This study attempts to evaluate the biomechanical, histological, stereological, and molecular properties of bones in the offspring of Lipopolysaccharide (LPS) and saline-treated mothers that received saline, drug vehicle or the atypical antipsychotic drug risperidone (RIS) at different days of postnatal development. After postnatal drug treatment, animals were assessed for autistic-like behaviors. Then their bones were taken for evaluations. RESULTS: Maternal LPS exposure resulted in deficits in all behavioral tests and RIS ameliorated these behaviors (p < 0.01& p < 0.05). The administration of LPS and RIS individually led to a significant decrease in the biomechanical parameters such as bone stiffness, strength and the energy used to fracture of bone. The numerical density of osteocalcin-positive cells were significantly decreased in these groups. These rats also had decreased RUNX2 and osteocalcin gene expression. When LPS rats were treated with RIS, these conditions were accelerated (p < 0.001). DISCUSSIONS: The results of our preclinical study, consistent with previous studies in animals, explore that autistic-like deficits induced by prenatal exposure to LPS, can reduce bone stability and bone mass similar to those observed in neurodevelopmental disorders, and, for the first time, reveal that this condition worsened when these animals were treated with RIS.


Assuntos
Transtorno Autístico/induzido quimicamente , Reabsorção Óssea/induzido quimicamente , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal/patologia , Risperidona/efeitos adversos , Animais , Animais Recém-Nascidos , Transtorno Autístico/sangue , Transtorno Autístico/complicações , Comportamento Animal , Fenômenos Biomecânicos , Reabsorção Óssea/sangue , Reabsorção Óssea/fisiopatologia , Citocinas/sangue , Citocinas/genética , Feminino , Lipopolissacarídeos/administração & dosagem , Masculino , Atividade Motora , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Risperidona/administração & dosagem , Comportamento Estereotipado
19.
Cardiovasc Pathol ; 49: 107261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32771878

RESUMO

Cardiac inflammation in Coxsackievirus B3 (CVB3)-induced myocarditis is a consequence of viral-related cardiac injury and immune response. Caspase-associated recruitment domain 9 (CARD9) is a critical adaptor protein involved in transduction of signals from various innate pattern recognition receptors. In this study, the role of CARD9 in acute viral myocarditis was evaluated. CARD9-/- and C57BL/6 mice were infected with CVB3. On day 7 postinfection, myocardial tissue and blood samples were collected and examined. After CARD9 knockout, mRNA and protein levels of transforming growth factor-ß(TGF-ß), interleukin-17A(IL-17A), and CARD domain of B-cell CLL/lymphoma 10(BCL-10) in the myocardium were markedly lower in CARD9-/- mice than in C57BL/6 mice with CVB3-induced viral myocarditis. This trend was similar for the pathological scores for inflammation and serum levels of cytokines interleukin-6(IL-6), interleukin-10(IL-10), interferon -γ(IFN-γ), TGF-ß, and IL-17A. These results suggest that the CARD9-mediated secretion of pro-inflammatory cytokines plays an important role in the immune response to acute viral myocarditis.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Infecções por Coxsackievirus/metabolismo , Enterovirus Humano B/imunologia , Miocardite/metabolismo , Miocárdio/metabolismo , Linfócitos T/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/genética , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/genética , Miocardite/imunologia , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/patologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/virologia
20.
Adv Biol Regul ; 77: 100741, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773102

RESUMO

Pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses an unprecedented challenge to healthcare systems due to the lack of a vaccine and specific treatment options. Accordingly, there is an urgent need to understand precisely the pathogenic mechanisms underlying this multifaceted disease. There is increasing evidence that the immune system reacts insufficiently to SARS-CoV-2 and thus contributes to organ damage and to lethality. In this review, we suggest that the overwhelming production of reactive oxygen species (ROS) resulting in oxidative stress is a major cause of local or systemic tissue damage that leads to severe COVID-19. It increases the formation of neutrophil extracellular traps (NETs) and suppresses the adaptive arm of the immune system, i.e. T cells that are necessary to kill virus-infected cells. This creates a vicious cycle that prevents a specific immune response against SARS-CoV-2. The key role of oxidative stress in the pathogenesis of severe COVID-19 implies that therapeutic counterbalancing of ROS by antioxidants such as vitamin C or NAC and/or by antagonizing ROS production by cells of the mononuclear phagocyte system (MPS) and neutrophil granulocytes and/or by blocking of TNF-α can prevent COVID-19 from becoming severe. Controlled clinical trials and preclinical models of COVID-19 are needed to evaluate this hypothesis.


Assuntos
Antioxidantes/uso terapêutico , Infecções por Coronavirus/epidemiologia , Armadilhas Extracelulares/imunologia , Linfopenia/epidemiologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Acetilcisteína/uso terapêutico , Ácido Ascórbico/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
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