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1.
Medicine (Baltimore) ; 99(35): e21888, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871918

RESUMO

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with considerable genetic predisposition. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) is crucial for the innate immunity and implicated in SLE pathogenesis. Accordingly, we conducted a case-control study to find the association of NLRP3 variations with SLE susceptibility and disease activity.Three single nucleotide polymorphisms of NLRP3 (rs3806268, rs4612666, and rs10754558) were genotyped in 400 SLE patients and 400 healthy controls; the patients were further divided into mild-to-moderate or high disease activity subgroup. Serum cytokines, complements, and autoantibodies were also detected.We found that rs4612666 TT genotype conferred a higher risk of severe disease activity with adjusted odds ratio = 2.08, P = .02 and adjusted odds ratio  = 2.34, P = .01 in the codominant and recessive model, respectively. Nevertheless, there was no association between the 3 single nucleotide polymorphisms of NLRP3 gene and SLE susceptibility. In addition, C4 decreased significantly in rs3806268 GG (P < .001) and rs4612666 TT genotype carriers (P = .03). A higher trend of interleukin-1ß and interleukin-γ release were identified in rs3806268 AA and rs10754558 CC genotype carriers, respectively.NLRP3 polymorphisms are associated with SLE disease activity and hypocomplementemia. Interleukin-1ß and interleukin-γ levels in SLE patients are correlated with NLRP3 variants as well.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Complemento C4/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Subunidade gama Comum de Receptores de Interleucina/sangue , Interleucina-1beta/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
2.
J Environ Pathol Toxicol Oncol ; 39(3): 235-245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865915

RESUMO

Ulcerative colitis (UC) is an intractable ailment, in which may chronic inflammations/ulcerations may develop in the mucosal lining of the colon with multiple recurrences. Various drugs such as steroids, immunosuppressants, and antibiotics are extensively used to treat UC. The patients suffer from adverse effects of these advanced drugs. So, they need a harmless therapeutic agent from natural sources. The therapeutic D-carvone has an anti-inflammatory action against the investigational colon cancer models. Therefore, we analyzed the effect of D-carvone on dextran sulfate sodium (DSS) provoked colitis model in mice as follows: Group I: noncolitis healthy control mice; Group II: ulcerative colitis mice models; Group III: D-carvone (40 mg/kg) + ulcerative colitis models; Group IV: sulfasalazine (50 mg/kg) + ulcerative colitis models. On the 8th day, the experimental study was terminated and serum samples and colon tissues were processed for further analysis. The effect of D-carvone at different concentration was studied on the LPS challenged RAW 264.7 cell lines. The D-carvone (40 mg/kg) treatment maintained the colon length and decreased disease activity index (DAI) score in UC animals. The increased antioxidant enzymes status and decreased oxidative stress and pro-inflammatory markers were noted in the D-carvone (40 mg/ kg) + UC mice. Histopathological study of colon tissue of D-carvone (40 mg/kg) treated UC mice displayed less mucosal damage and improved crypt integrity and goblet cells compared with DSS only provoked mice. The im-munohistochemical expression of iNOS and COX-2 was drastically diminished in the D-carvone treated UC mice. D-carvone (40 mg/kg) treatment appreciably diminished the LPS provoked NO production and pro-inflammatory modulators in the RAW 264.7 macrophage cell lines. These findings proved that D-carvone has a potential therapeutic effect to prevent LPS induced inflammation in in vitro cells and chemically induced ulcerative colitis in vivo models.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Monoterpenos Cicloexânicos/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue , Animais , Anti-Inflamatórios/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Monoterpenos Cicloexânicos/administração & dosagem , Sulfato de Dextrana , Modelos Animais de Doenças , Lipopolissacarídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7
3.
J Int Med Res ; 48(9): 300060520955037, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32960106

RESUMO

BACKGROUND: The roles of inflammation and hypercoagulation in predicting outcomes of coronavirus disease 2019 (COVID-19) are unclear. METHODS: Adult patients diagnosed with COVID-19 from 28 January 2020 to 4 March 2020 in Tongji Hospital, Wuhan were recruited. Data on related parameters were collected. Univariate analysis and multivariable binary logistic regression were used to explore predictors of critical illness and mortality. RESULTS: In total, 199 and 44 patients were enrolled in the training and testing sets, respectively. Elevated ferritin, tumor necrosis factor-α and D-dimer and decreased albumin concentration were associated with disease severity. Older age, elevated ferritin and elevated interleukin-6 were associated with 28-day mortality. The FAD-85 score, defined as age + 0.01 * ferritin +D-dimer, was used to predict risk of mortality. The sensitivity, specificity and accuracy of FAD-85 were 86.4%, 81.8% and 86.4%, respectively. A nomogram was established using age, ferritin and D-dimer to predict the risk of 28-day mortality. CONCLUSIONS: Thrombo-inflammatory parameters provide key information on the severity and prognosis of COVID-19 and can be used as references for clinical treatment to correct inflammatory and coagulation abnormalities.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/mortalidade , Coagulação Intravascular Disseminada/mortalidade , Pneumonia Viral/mortalidade , Trombose/mortalidade , Adulto , Idoso , Biomarcadores/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/virologia , Feminino , Ferritinas/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Interleucina-6/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Prognóstico , Projetos de Pesquisa , Estudos Retrospectivos , Albumina Sérica/metabolismo , Índice de Gravidade de Doença , Análise de Sobrevida , Trombose/complicações , Trombose/diagnóstico , Trombose/virologia , Fator de Necrose Tumoral alfa/sangue
4.
Cell Mol Immunol ; 17(10): 1092-1094, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32917983
5.
Medicine (Baltimore) ; 99(39): e22012, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991404

RESUMO

BACKGROUND: Traditional Chinese medicine injections (TCMJ) used in the treatment of severe pneumonia have been widely implemented in clinical practice, but their overall efficacy and safety remain unclear. This paper aims to evaluate the efficacy and safety of TCMJ in the treatment of severe pneumonia. METHODS: PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WanFang, and the Chongqing VIP Chinese Science and Technology Periodical Database were all searched for randomized controlled trials focusing on the administration of TCMJ for severe pneumonia. Two researchers independently screened titles, abstracts, full texts, and extracted relevant data. The RevMan 5.3 software (The Cochrane Collaboration, Software Update, Oxford, UK) and Stata 14 software (STATA Corporation, College Station, TX) were used for statistical analysis. RESULTS: This study summarizes the related randomized controlled trials to assess the effect and safety of TCMJ in the treatment of severe pneumonia. CONCLUSION: This article provides theoretical support for the clinical application of TCMJ in the treatment of severe pneumonia. PROSPERO REGISTRATION NUMBER: CRD42020185072.


Assuntos
Medicina Tradicional Chinesa/métodos , Pneumonia/terapia , Proteína C-Reativa/análise , Humanos , Injeções , Interleucina-6/sangue , Tempo de Internação , Contagem de Leucócitos , Medicina Tradicional Chinesa/efeitos adversos , Pneumonia/mortalidade , Pró-Calcitonina/biossíntese , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Respiração Artificial , Fator de Necrose Tumoral alfa/sangue
6.
Medicine (Baltimore) ; 99(35): e21654, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871878

RESUMO

The aim of this study is to investigate the levels of 25(OH)D, inflammation markers and glucose and fat metabolism indexes in pregnant women with Gestational diabetes mellitus (GDM).One hundred and ten cases GDM and 100 cases healthy pregnant women in the First People's Hospital of Lianyungang City from October 2016 to December 2018 were recruited for this observational cross-sectional study. Each participant's anthropometric and demographic data was recorded. Blood samples were collected and analyzed to determine the levels of 25(OH)D, high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), fasting blood glucose, fasting blood insulin, hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol and triglycerides.Inflammatory markers and glucose and fat metabolism indexes were all significantly higher in the GDM group than that in the control group, while Serum 25(OH)D level in the GDM group was significantly lower. Serum 25(OH)D levels were negatively correlated with hs-CRP, while not with TNF-α. Furthermore, Serum 25(OH)D, hs-CRP and TNF-α levels were all associated with increased risk of developing GDM.Nowadays, the reports on the association between 25(OH)D level and GDM were controversial. Our results are consistent with the view that there was association between 25(OH)D level and GDM, and expand the literature by showing the roles of 25(OH)D, inflammation markers as well as glucose and fat metabolism indexes in the risk of developing GDM in the pregnant women with the low overall levels of 25(OH)D before delivery. This broadens our knowledge on the pathophysiology of GDM, which may be helpful in prevention and treatment of GDM.


Assuntos
Glicemia/metabolismo , Diabetes Gestacional/sangue , Vitamina D/análogos & derivados , Adulto , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , China , Colesterol/sangue , Estudos Transversais , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/sangue , Resistência à Insulina , Gravidez , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/sangue , Vitamina D/sangue
7.
PLoS One ; 15(9): e0239532, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976531

RESUMO

To investigate the clinical value of changes in the subtypes of peripheral blood lymphocytes and levels of inflammatory cytokines in patients with COVID-19, the total numbers of lymphocytes and CD4+ lymphocytes and the ratio of CD4+/CD8+ lymphocytes were calculated and observed in different groups of patients with COVID-19. The results show that the lymphocytopenia in patients with COVID-19 was mainly manifested by decreases in the CD4+ T lymphocyte number and the CD4+/CD8+ ratio. The decreased number of CD4+ T lymphocytes and the elevated levels of TNF-α and IL-6 were correlated with the severity of COVID-19 disease.


Assuntos
Linfócitos T CD4-Positivos/patologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Citocinas/sangue , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Adolescente , Adulto , Idoso , Betacoronavirus , Contagem de Linfócito CD4 , Relação CD4-CD8 , Criança , Infecções por Coronavirus/diagnóstico , Feminino , Humanos , Interleucina-6/sangue , Linfopenia/sangue , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue
8.
BMC Infect Dis ; 20(1): 553, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736606

RESUMO

BACKGROUND: We examined cytokine immune response profiles among contacts to tuberculosis patients to identify immunologic and epidemiologic correlates of tuberculosis. METHODS: We prospectively enrolled 1272 contacts of culture-confirmed pulmonary tuberculosis patients at 9 United States and Canadian sites. Epidemiologic characteristics were recorded. Blood was collected and stimulated with Mycobacterium tuberculosis culture filtrate protein, and tumor necrosis factor (TNF-α), interferon gamma (IFN-γ), and interleukin 10 (IL-10) concentrations were determined using immunoassays. RESULTS: Of 1272 contacts, 41 (3.2%) were diagnosed with tuberculosis before or < 30 days after blood collection (co-prevalent tuberculosis) and 19 (1.5%) during subsequent four-year follow-up (incident tuberculosis). Compared with contacts without tuberculosis, those with co-prevalent tuberculosis had higher median baseline TNF-α and IFN-γ concentrations (in pg/mL, TNF-α 129 versus 71, P < .01; IFN-γ 231 versus 27, P < .001), and those who subsequently developed incident tuberculosis had higher median baseline TNF-α concentrations (in pg/mL, 257 vs. 71, P < .05). In multivariate analysis, contact age < 15 years, US/Canadian birth, and IFN or TNF concentrations > the median were associated with co-prevalent tuberculosis (P < .01 for each); female sex (P = .03) and smoking (P < .01) were associated with incident tuberculosis. In algorithms combining young age, positive skin test results, and elevated CFPS TNF-α, IFN-γ, and IL-10 responses, the positive predictive values for co-prevalent and incident tuberculosis were 40 and 25%, respectively. CONCLUSIONS: Cytokine concentrations and epidemiologic factors at the time of contact investigation may predict co-prevalent and incident tuberculosis.


Assuntos
Interferon gama/sangue , Interleucina-10/sangue , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Canadá/epidemiologia , Criança , Pré-Escolar , Busca de Comunicante , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tuberculose/sangue , Estados Unidos/epidemiologia , Adulto Jovem
9.
PLoS One ; 15(8): e0237074, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790694

RESUMO

Androgen dependent tissue factor pathway inhibitor regulating protein (ADTRP) is a novel protein associated with coronary artery disease (CAD) susceptibility, and reduced mRNA expression of ADTRP was shown to be associated with increased CAD risk. This study aimed to determine and compare circulating ADTRP levels between CAD patients and controls, and to test the performance of plasma ADTRP as a biomarker for CAD. We measured plasma ADTRP, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and high sensitivity-C reactive protein (hs-CRP) levels in 362 CAD patients, 150 angiographically negative CAD controls, and 83 healthy adults with no known clinical or medical conditions using commercial ELISA. Statistical analyses were performed using receiver operator characteristic (ROC) curves, quantile regression and logistic regression, with adjustments for age, gender, ethnicity and BMI. CAD patients had significantly lower plasma ADTRP levels 1,545 (1,087-2,408) pg/ml as compared to CAD controls 2,259 (1,533-3,778) pg/ml and healthy adults 3,904 (2,732-5,463) pg/ml. Plasma ADTRP outperformed the other three inflammatory biomarkers (TNF-α, IL-6 and hs-CRP) for CAD (Area under ROC curve: 0.67, Odds ratio (OR): 0.907). Our study has shown for the first time that ADTRP is present in circulation, and that plasma ADTRP may be a novel independent biomarker for CAD.


Assuntos
Doença da Artéria Coronariana/sangue , Proteínas de Membrana/sangue , Adulto , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Mediadores da Inflamação/sangue , Interleucina-6/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Fator de Necrose Tumoral alfa/sangue
10.
PLoS One ; 15(8): e0232302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822373

RESUMO

Sepsis is a life-threatening condition due to a dysregulated immunological response to infection. Apart from source control and broad-spectrum antibiotics, management is based on fluid resuscitation and vasoactive drugs. Fluid resuscitation implicates the risk of volume overload, which in turn is associated with longer stay in intensive care, prolonged use of mechanical ventilation and increased mortality. Antisecretory factor (AF), an endogenous protein, is detectable in most tissues and in plasma. The biologically active site of the protein is located in an 8-peptide sequence, contained in a synthetic 16-peptide fragment, named AF-16. The protein as well as the peptide AF-16 has multiple modulatory effects on abnormal fluid transport and edema formation/resolution as well as in a variety of inflammatory conditions. Apart from its' anti-secretory and anti-inflammatory characteristics, AF is an inhibitor of capillary leakage in intestine. It is not known whether the protein AF or the peptide AF-16 can ameliorate symptoms in sepsis. We hypothesized that AF-16 decreases the degree of hemodynamic instability, the need of fluid resuscitation, vasopressor dose and tissue edema in fecal peritonitis. To test the hypothesis, we induced peritonitis and sepsis by injecting autologous fecal solution into abdominal cavity of anesthetized pigs, and randomized (in a blind manner) the animals to intervention (AF-16, n = 8) or control (saline, n = 8) group. After the onset of hemodynamic instability (defined as mean arterial pressure < 60 mmHg maintained for > 5 minutes), intervention with AF-16 (20 mg/kg (50 mg/ml) in 0.9% saline) intravenously (only the vehicle in the control group) and a protocolized resuscitation was started. We recorded respiratory and hemodynamic parameters hourly for twenty hours or until the animal died and collected post mortem tissue samples at the end of the experiment. No differences between the groups were observed regarding hemodynamics, overall fluid balance, lung mechanics, gas exchange or histology. However, liver wet-to-dry ratio remained lower in AF-16 treated animals as compared to controls, 3.1 ± 0.4, (2.7-3.5, 95% CI, n = 8) vs 4.0 ± 0.6 (3.4-4.5, 95% CI, n = 8), p = 0.006, respectively. Bearing in mind the limited sample size, this experimental pilot study suggests that AF-16 may inhibit sepsis induced liver edema in peritonitis-sepsis.


Assuntos
Edema/tratamento farmacológico , Peptídeos/farmacologia , Peritonite/complicações , Sepse/complicações , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Edema/complicações , Edema/patologia , Edema/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hemoglobinas/metabolismo , Interleucina-6/sangue , Lactatos/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Peptídeos/uso terapêutico , Projetos Piloto , Troca Gasosa Pulmonar/efeitos dos fármacos , Suínos , Fator de Necrose Tumoral alfa/sangue , Resistência Vascular/efeitos dos fármacos
11.
Cytokine ; 134: 155190, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32673995

RESUMO

Coronavirus disease 2019 (COVID19) is a life-threatening infection with uncertain progression and outcome. Assessing the severity of the disease for worsening patients is of importance in making decisions related to supportive mechanical ventilation and aggressive treatments. This was a prospective, non-randomized study that included hospitalized patients diagnosed with COVID19. Pro-inflammatory cytokines were assessed during hospitalization, and we calculated a prediction paradigm for 30-day mortality based on the serum levels of interleukin1ß (IL1ß), interleukin6 (IL6), interleukin8 (IL8), and tumor necrosis factor alpha (TNFα) measured by next-generation ELISA. Data of 71 COVID19 patients, mean age 62 years, SD13.8, 50 males, 21 females, were analyzed. Twelve (16.9%) patients died within 7-39 days of their first COVID19 positive nasopharyngeal test. Levels of IL6 and TNFα were significantly higher in patients that did not survive. IL6 predicted mortality at the cut-off value of 163.4 pg/ml, with a sensitivity of 91.7% and specificity of 57.6%. Our findings demonstrate that IL6 expression is significant for the prediction of 30-day mortality in hospitalized COVID19 patients and, therefore, may assist in treatment decisions.


Assuntos
Infecções por Coronavirus/mortalidade , Interleucina-1beta/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Pneumonia Viral/mortalidade , Fator de Necrose Tumoral alfa/sangue , Betacoronavirus/imunologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/mortalidade , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Prognóstico , Estudos Prospectivos
12.
Pharmacol Res Perspect ; 8(4): e00631, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32715661

RESUMO

We propose a new hypothesis that the established drug pentoxifylline deserves attention as a potential repurposed therapeutic for COVID-19. Pentoxifylline is an immunomodulator with anti-inflammatory properties. It is a nonselective phosphodiesterase inhibitor and through Adenosine A2A Receptor-mediated pathways reduces tumor necrosis factor alpha, interleukin 1, interleukin 6, and interferon gamma and may act to reduce tissue damage during the cytokine storm host response to SARS-CoV-2 infection. This agent has been used clinically for many years and has a favorable profile of safety and tolerability. Pre-clinical data support pentoxifylline as effective in cytokine-driven lung damage. Clinical studies of pentoxifylline in radiation and cytokine-induced lung damage in humans are positive and consistent with anti-inflammatory efficacy. Pentoxifylline is a readily available, off-patent and inexpensive drug, suitable for large-scale use including in resource-limited countries. Current trials of therapeutics are largely focused on the inhibition of viral processes. We advocate urgent randomized trials of pentoxifylline for COVID-19 as a complementary approach to target the host responses.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pentoxifilina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Humanos , Pandemias , Pentoxifilina/farmacologia , Projetos de Pesquisa , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/fisiologia
13.
JCI Insight ; 5(17)2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32706339

RESUMO

BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Pneumonia Viral/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Sepse/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Síndrome da Liberação de Citocina/sangue , Citocinas/sangue , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-18/sangue , Interleucina-18/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Síndrome do Desconforto Respiratório do Adulto/sangue , Sepse/sangue , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
14.
Am J Physiol Regul Integr Comp Physiol ; 319(2): R195-R202, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32640833

RESUMO

Neutralization of FasL is linked to suppression of hypertension, placental inflammation, and endothelin system activation in an animal model of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. During HELLP syndrome the placenta has been reported to serve as the primary source of Fas ligand (FasL), which has an impact on inflammation and hypertension during pregnancy and is dysregulated in women with severe preeclampsia and HELLP syndrome. We hypothesize that neutralization of FasL during pregnancy in an animal model of HELLP syndrome decreases inflammation and placental apoptosis, improves endothelial damage, and improves hypertension. On gestational day (GD) 12, rats were chronically infused with placental antiangiogenic factors sFlt-1 and sEng to induce HELLP syndrome. To neutralize FasL, MFL4 or FasL antibody was infused into a subset of HELLP or normal pregnant rats on GD13. IgG infusion into another group of NP and HELLP rats on GD13 was used as a control for FasL antibody, and all rats were euthanized on GD19 after blood pressure measurement. Plasma and placentas were collected to assess inflammation, apoptosis, and the degree of placental debris activation of endothelial cells. Administration of MFL4 to HELLP rats significantly decreased blood pressure compared with untreated HELLP rats and HELLP rats infused with IgG and improved the biochemistry of HELLP syndrome. Both circulating and placental FasL were significantly attenuated in response to MFL4 infusion, as were levels of placental and circulating TNFα when compared with untreated HELLP rats and HELLP rats infused with IgG. Endothelial cells exposed to placental debris and media from HP + MFL4 rats secreted significantly less endothelin-1 compared with stimulated endothelial cells from HELLP placentas. Neutralization of FasL is associated with decreased MAP and improvement in placental inflammation and endothelial damage in an animal model of HELLP syndrome.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Endotelina-1/sangue , Proteína Ligante Fas/imunologia , Síndrome HELLP/tratamento farmacológico , Placenta/fisiopatologia , Animais , Modelos Animais de Doenças , Proteína Ligante Fas/sangue , Feminino , Síndrome HELLP/sangue , Síndrome HELLP/imunologia , Síndrome HELLP/fisiopatologia , Imunoglobulina G , Placenta/imunologia , Gravidez , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
15.
Life Sci ; 258: 118139, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32721463

RESUMO

AIMS: Atopic dermatitis is a chronic inflammatory disease characterized by eczematous lesions and has become a serious health problem worldwide. Pseudoephedrine (PSE) is a nasal decongestant to treat the common cold. PSE has been reported that is beneficial to allergic diseases. However, whether PSE has the potential in atopic dermatitis remains to be elucidated. MAIN METHODS: Male BALB/c mice were challenged with 2,4-dinitrochlorobenzene (DNCB) to induce atopic dermatitis-like lesion and orally administrated with PSE for two weeks. The skin hydration and the scratching behavior were detected. The skin lesions and histopathological changes were evaluated and inflammatory factors levels were detected. Human Keratinocytes (HaCaT cells) were stimulated by TNF-α/IFN-γ after PSE-pretreatment. The transcriptions of inflammatory factors were detected. KEY FINDINGS: PSE decreased skin lesion area and skin thickness in atopic dermatitis mice. PSE improved skin hydration and scratching. Histologically, PSE reduced mast cell and CD4+ cell infiltration. PSE suppressed serum TNF-α and IgE levels, reducing cytokines (IL-1ß, IL-4, IL-6, IL-13, IL-33, TSLP, and IL-23) and neutrophil migration factors (CCL2 and MMP-9) in skin tissues. In addition, PSE inhibited TNF-α/IFN-γ-induced release of inflammatory factors (TNF-α, IL-1ß, and IL-23) in HaCaT cells. Furthermore, PSE suppressed the activation of MAPKs and NF-κB signaling pathways in vivo and in vitro. SIGNIFICANCE: These results demonstrate that PSE could inhibit inflammatory responses in atopic dermatitis models. PSE may serve as a viable alternatives drug for the treatment of atopic dermatitis.


Assuntos
Dermatite Atópica/tratamento farmacológico , Inflamação/tratamento farmacológico , Pseudoefedrina/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Dermatite Atópica/sangue , Dermatite Atópica/enzimologia , Dermatite Atópica/patologia , Humanos , Imunoglobulina E/sangue , Inflamação/sangue , Inflamação/patologia , Interferon gama/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Pseudoefedrina/química , Pseudoefedrina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/farmacologia
16.
DNA Cell Biol ; 39(9): 1723-1729, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32700971

RESUMO

Sepsis-related mortality and morbidity are major health care problems worldwide. More effort is required to identify factors associated with adverse outcome. Evaluate the prognostic capacity of tumor necrosis factor (TNF), kidney injury molecule (KIM), and lactate and TNF-α-308 G > A gene polymorphism for prediction of 28 days-intensive care unit (ICU) mortality. TNF-α-308 G > A single nucleotide polymorphisms was detected by real-time-PCR on 112 had septic shock and 88 were septic. Serum TNF-α and urinary KIM were assessed by enzyme-linked immunosorbent assay. This study included 200 critically ill patients, 125 (62.5%) of them died within 28 days in ICU (nonsurvivors). Frequencies of TNF-308 G > A was (70.7) GG, (28) GA and (1.3) AA in survivors versus (85.6) GG, (12) GA and (2.4) AA for nonsurvivors, revealed significant association with ICU mortality but not sepsis severity (p = 0.15) or sepsis-induced acute kidney injury (AKI). In contrast, urinary KIM-1 revealed significant association with sepsis severity (p = 0.036) and AKI (p = 0.0001), but not 28-days ICU mortality. The relative risk of death in patients with GG genotype was 2.5 mainly in ICU younger male patients (odds ratios 24 and 4.9, p = 0.001). The genotype GG and GA were significantly associated with [increased urinary KIM-1 (0.29 ± 0.1) (p = 0.0001), terminal creatinine (1.67 ± 0.8) (p = 0.0001)] and [increased terminal urea (109 ± 0.001) (p = 0.001) and basal serum TNF (60 ± 0.001) (p = 0.0001)], respectively. In linear regression analysis, AKI 0.0001 (0.4-0.67), basal serum TNF 0.04 (0.0001-0.04), and TNF-308 GG 0.007 (0.05-0.33) were associated with 28 days ICU mortality [p value (95% confidence interval)]. The same results were observed for initial urea 0.024 (0.0001-0.003) and lack of diuretic usage 0.0001 (0.35-0.7) mainly in septic patients. Major frequency of TNF-308 G > A polymorphism (mainly in young age male patients), AKI and serum TNF were associated with increased risk for 28 days-ICU mortality. Furthermore, sepsis severity was influenced by TNF and urinary KIM-1, which reflects in AKI.


Assuntos
Lesão Renal Aguda/genética , Polimorfismo de Nucleotídeo Único , Choque Séptico/genética , Fator de Necrose Tumoral alfa/genética , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/patologia , Adulto , Fatores Etários , Idoso , Estado Terminal , Feminino , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Choque Séptico/complicações , Choque Séptico/patologia , Fator de Necrose Tumoral alfa/sangue
17.
DNA Cell Biol ; 39(9): 1678-1684, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32716219

RESUMO

Coronary artery disease (CAD) is the main cause of death worldwide. Atherosclerosis, the leading underlying cause of CAD, is a progressive inflammatory disease. miRNAs play a substantial role in inflammation. The aim of this study was to investigate the associations of peripheral blood mononuclear cells (PBMCs) gene expression of IP10 and miRNA 296-a and serum levels of IP10 and serum inflammatory cytokines interleukin-6 (IL-6) in CAD patients and controls. This is a case-control study conducted on 82 angiography confirmed CAD patients and 82 controls. PBMC expressions of miR-296a and IP10 were evaluated by real-time method, and serum concentrations of IL-6 and TNF-α were evaluated by enzyme-linked immunosorbent assay in the study population. A significant increase was found for serum IP10, IL-6, and TNF-α levels, and PBMC expression of IP10 and miRNA 296-a genes expression of CAD as comparison with controls. No significant correlation was found between IP10 gene expression and miRNA 296-a. A significant positive correlation was found between PBMC gene expression level of IP10 and serum concentrations of IP10 and cytokines IL-6 and TNF-α levels. Taking together, in PBMC of CAD patients, the IP10 and 296-a miRNA genes expression levels were increased significantly than controls. IP10, IL-6, and TNF-α levels in CAD patients were more than those in controls significantly. Concerning positive relationship between miRNA 296-a gene expression level and serum concentrations of IL-6 and TNF-α in CAD patients, it is proposed that IL-6 and TNF-α inhibitor could be the main targets of miRNA 296a and, thereby the IL-6 and TNF-α levels were increased; however, further study is needed.


Assuntos
Doença da Artéria Coronariana/sangue , MicroRNAs/sangue , Receptores de Citocinas/sangue , Idoso , Biomarcadores/sangue , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Interleucina-6/sangue , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Monócitos/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Fator de Necrose Tumoral alfa/sangue
18.
Signal Transduct Target Ther ; 5(1): 121, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641705
19.
Exp Parasitol ; 217: 107934, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698075

RESUMO

The inadequacy of available treatments for leishmaniasis has presented up to 40% therapeutic failure. This fact suggests an urgency in the discovery of new drugs or alternative approaches for treating this disease. The objective of this study was to evaluate the antileishmanial activity of combined therapy between crotamine (CTA) from Crotalus durissus terrificus and the pentavalent antimonial Glucantime® (GLU). The assays were in vitro performed measuring the inhibition of Leishmania amazonensis amastigotes, followed by the evaluation of cellular production of cytokines and nitrites. After that, analytical methods were performed in order to characterize the molecules involved in the study by Mass Spectrometry, molecular affinity through an in silico assay and Surface Plasmon Resonance. In vivo experiments with BALB/c mice were performed by analyzing parasitemia, lesion size and immunological mediators. In the in vitro experiments, the pharmacological association improved the inhibition of the amastigotes, modulated the production of cytokines and nitric oxide. The therapy improved the effectiveness of the GLU, demonstrating a decreased parasitemia in the infected tissues. Altogether, the results suggest that the combined approach with CTA and GLU may be a promising alternative for the treatment of cutaneous leishmaniasis.


Assuntos
Antiprotozoários/uso terapêutico , Venenos de Crotalídeos/uso terapêutico , Crotalus , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/uso terapêutico , Animais , Antiprotozoários/farmacologia , Venenos de Crotalídeos/farmacologia , Combinação de Medicamentos , Interleucina-12/sangue , Interleucina-12/metabolismo , Leishmania mexicana/isolamento & purificação , Linfonodos/parasitologia , Macrófagos Peritoneais , Espectrometria de Massas , Antimoniato de Meglumina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Nitritos/análise , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
20.
PLoS One ; 15(6): e0229806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555600

RESUMO

The A2 adenosine receptors play an important role, among others, in the regulation of inflammatory process and glucose homeostasis in diabetes and obesity. Thus, the presented project evaluated of influence of the selective antagonist of A2A adenosine receptor-KD-64 as compared to the known non-selective antagonist-caffeine on these two particular processes. Two different inflammation models were induced namely local and systemic inflammation. Obesity was induced in mice by high-fat diet and the tested compounds (KD-64 and caffeine) were administrated for 21 days. KD-64 showed anti-inflammatory effect in both tested inflammation models and administered at the same dose as ketoprofen exerted stronger effect than this reference compound. Elevated levels of IL-6 and TNF-α observed in obese control mice were significantly lowered by the administration of KD-64 and were similar to the values observed in control non-obese mice. Interestingly, caffeine increased the levels of these parameters. In contrast to caffeine which had no influence on AlaT activity, KD-64 administration significantly lowered AlaT activity in the obese mice. Although, contrary to caffeine, KD-64 did not reduce diet-induced obesity in mice, it improved glucose tolerance. Thus, the activity of the selective adenosine A2A receptor antagonist was quite different from that of the non-selective.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Anti-Inflamatórios/farmacologia , Dieta/efeitos adversos , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Peso Corporal/efeitos dos fármacos , Cafeína/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Interleucina-6/sangue , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Peritônio/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue
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