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1.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206051

RESUMO

Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches are warranted. Herein, we applied a combined regimen with an α-PD-L1 antibody and gemcitabine in a preclinical tumor model to activate endogenous antitumor immune responses. Mlh1-/- mice with established gastrointestinal tumors received the α-PD-L1 antibody (clone 6E11; 2.5 mg/kg bw, i.v., q2wx3) and gemcitabine (100 mg/kg bw, i.p., q4wx3) in mono- or combination therapy. Survival and tumor growth were recorded. Immunological changes in the blood were routinely examined via multi-color flow cytometry and complemented by ex vivo frameshift mutation analysis to identify alterations in Mlh1-/--tumor-associated target genes. The combined therapy of α-PD-L1 and gemcitabine prolonged median overall survival of Mlh1-/- mice from four weeks in the untreated control group to 12 weeks, accompanied by therapy-induced tumor growth inhibition, as measured by [18F]-FDG PET/CT. Plasma cytokine levels of IL13, TNFα, and MIP1ß were increased and also higher than in mice receiving either monotherapy. Circulating splenic and intratumoral myeloid-derived suppressor cells (MDSCs), as well as M2 macrophages, were markedly reduced. Besides, residual tumor specimens from combi-treated mice had increased numbers of infiltrating cytotoxic T-cells. Frameshift mutations in APC, Tmem60, and Casc3 were no longer detectable upon treatment, likely because of the successful eradication of single mutated cell clones. By contrast, novel mutations appeared. Collectively, we herein confirm the safe application of combined chemo-immunotherapy by long-term tumor growth control to prevent the development of resistance mechanisms.


Assuntos
Antígeno B7-H1/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Proteína 1 Homóloga a MutL/genética , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Quimiocina CCL4/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais Hereditárias sem Polipose/sangue , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/imunologia , Reparo de Erro de Pareamento de DNA/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Interleucina-13/sangue , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Células Supressoras Mieloides , Síndromes Neoplásicas Hereditárias/sangue , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/patologia , Fator de Necrose Tumoral alfa/sangue
2.
Front Immunol ; 12: 693269, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220854

RESUMO

Chronic immune activation has been considered as the driving force for CD4+ T cell depletion in people infected with HIV-1. Interestingly, the normal immune profile of adult HIV-negative individuals living in Africa also exhibit chronic immune activation, reminiscent of that observed in HIV-1 infected individuals. It is characterized by increased levels of soluble immune activation markers, such as the cytokines interleukin (IL)-4, IL-10, TNF-α, and cellular activation markers including HLA-DR, CD-38, CCR5, coupled with reduced naïve and increased memory cells in CD4+ and CD8+ subsets. In addition, it is accompanied by low CD4+ T cell counts when compared to Europeans. There is also evidence that mononuclear cells from African infants secrete less innate cytokines than South and North Americans and Europeans in vitro. Chronic immune activation in Africans is linked to environmental factors such as parasitic infections and could be responsible for previously observed immune hypo-responsiveness to infections and vaccines. It is unclear whether the immunogenicity and effectiveness of anti-SARS-CoV-2 vaccines will also be reduced by similar mechanisms. A review of studies investigating this phenomenon is urgently required as they should inform the design and delivery for vaccines to be used in African populations.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Vacinas contra COVID-19/imunologia , Imunogenicidade da Vacina/imunologia , Ativação Linfocitária/imunologia , SARS-CoV-2/imunologia , ADP-Ribosil Ciclase 1/sangue , África , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , COVID-19/prevenção & controle , Antígenos HLA-DR/sangue , Humanos , Interleucina-10/sangue , Interleucina-4/sangue , Leucócitos Mononucleares/metabolismo , Glicoproteínas de Membrana/sangue , Receptores CCR5/sangue , Fator de Necrose Tumoral alfa/sangue
3.
Eur Rev Med Pharmacol Sci ; 25(12): 4435-4438, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34227081

RESUMO

OBJECTIVE: We aimed at explaining the mechanism of therapeutic effect of Umbilical Cord Mesenchymal Stem Cells (UC-MSC) in subjects with COVID-19 Acute Respiratory Distress Syndrome (ARDS). Patients with COVID-19 ARDS present with a hyperinflammatory response characterized by high levels of circulating pro-inflammatory mediators, including tumor necrosis factor α and ß (TNFα and TNFß). Inflammatory functions of these TNFs can be inhibited by soluble TNF Receptor 2 (sTNFR2). In patients with COVID-19 ARDS, UC-MSC appear to impart a robust anti-inflammatory effect, and treatment is associated with remarkable clinical improvements. We investigated the levels of TNFα, TNFß and sTNFR2 in blood plasma samples collected from subjects with COVID-19 ARDS enrolled in our trial of UC-MSC treatment. PATIENTS AND METHODS: We analyzed plasma samples from subjects with COVID-19 ARDS (n=24) enrolled in a Phase 1/2a randomized controlled trial of UC-MSC treatment. Plasma samples were obtained at Day 0 (baseline, before UC-MSC or control infusion), and Day 6 post infusion. Plasma concentrations of sTNFR2, TNFα, and TNFß were evaluated using a quantitative multiplex protein array. RESULTS: Our data indicate that at Day 6 after infusion, UC-MSC recipients develop significantly increased levels of plasma sTNFR2 and significantly decreased levels of TNFα and TNFß, compared to controls. CONCLUSIONS: These observations suggest that sTNFR2 plays a mechanistic role in mediating UC-MSC effect on TNFα and TNFß plasma levels, determining a decrease in inflammation in COVID-19 ARDS.


Assuntos
COVID-19/sangue , Linfotoxina-alfa/sangue , Transplante de Células-Tronco Mesenquimais/métodos , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Síndrome do Desconforto Respiratório/sangue , Fator de Necrose Tumoral alfa/sangue , Cordão Umbilical/transplante , Biomarcadores/sangue , COVID-19/terapia , Método Duplo-Cego , Humanos , Síndrome do Desconforto Respiratório/terapia , Cordão Umbilical/citologia
4.
J Med Life ; 14(2): 176-180, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104240

RESUMO

The study of the pathogenetic treatment and prevention of Helicobacter pylori (Hp)-associated gastroduodenopathies (GDP) induced by nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with osteoarthritis (OA) is one of the most serious problems in modern clinical medicine. Sixty patients with OA and concomitant Hp-associated GDP induced by NSAIDs were examined. The levels of epidermal growth factor (EDF), sAPO-1/Fas and tumor necrosis factor-α (TNF-α) were determined. Group I included 30 patients who received triple anti-Helicobacter (AHT) therapy, and group II included 30 patients who received rebamipide. Long-term effects were assessed 6 months and 1 year after treatment. All subjects showed a significant increase in TNF-α (4.7 times), EDF (2.2 times) and a decrease in sAPO-1/Fas (3.6 times) levels compared to healthy individuals. After 1 month of treatment, a significantly more significant decrease in TNF-α and an increase in sAPO-1/Fas and EDF was found in group II. In the long-term treatment, a further decrease in TNF-α and an increase in the content of sAPO-1/Fas levels were observed in all groups. However, these changes were significantly more significant in group I compared to group I. The long-term follow-up showed a declining trend of EDF in all groups. The data obtained indicate the effectiveness of rebamipide in the complex pathogenetic treatment and prevention of Hp-associated GDP induced by NSAIDs in patients with OA.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Duodeno/patologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Osteoartrite/tratamento farmacológico , Gastropatias/induzido quimicamente , Gastropatias/microbiologia , Fator de Crescimento Epidérmico/sangue , Infecções por Helicobacter/sangue , Humanos , Osteoartrite/sangue , Osteoartrite/complicações , Gastropatias/sangue , Fator de Necrose Tumoral alfa/sangue , Receptor fas/sangue
5.
J Immunol Res ; 2021: 6657894, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1269808

RESUMO

Background: The 2019 novel coronavirus SARS-CoV-2 caused large outbreaks of COVID-19 worldwide. COVID-19 resembles community-acquired pneumonia (CAP). Our aim was to identify lymphocyte subpopulations to distinguish between COVID-19 and CAP. Methods: We compared the peripheral blood lymphocytes and their subsets in 296 patients with COVID-19 and 130 patients with CAP. Parameters for independent prediction of COVID-19 were calculated by logistic regression. Results: The main lymphocyte subpopulations (CD3+CD4+, CD16+CD56+, and CD4+/CD8+ ratio) and cytokines (TNF-α and IFN-γ) of COVID-19 patients were significantly different from that of CAP patients. CD16+CD56+%, CD4+/CD8+ratio, CD19+, and CD3+CD4+ were identified as predictors of COVID-19 diagnosis by logistic regression. In addition, the CD3+CD4+counts, CD3+CD8+ counts, andTNF-α are independent predictors of disease severity in patients. Conclusions: Lymphopenia is an important part of SARS-CoV-2 infection, and lymphocyte subsets and cytokines may be useful to predict the severity and clinical outcomes of the disease.


Assuntos
Relação CD4-CD8 , COVID-19/sangue , Interferon gama/sangue , Subpopulações de Linfócitos/citologia , Pneumonia/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , COVID-19/imunologia , COVID-19/patologia , Teste para COVID-19 , Infecções Comunitárias Adquiridas/microbiologia , Feminino , Humanos , Subpopulações de Linfócitos/imunologia , Linfopenia/sangue , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Pneumonia/imunologia , Pneumonia/patologia , Prognóstico , SARS-CoV-2/imunologia , Índice de Gravidade de Doença
6.
Virol J ; 18(1): 117, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: covidwho-1259206

RESUMO

BACKGROUND: To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD. METHODS: The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD. RESULTS: The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time. CONCLUSIONS: The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.


Assuntos
COVID-19/sangue , Síndrome da Liberação de Citocina/sangue , Citocinas/sangue , Síndrome do Desconforto Respiratório/sangue , Injúria Renal Aguda/diagnóstico , Idoso , Nitrogênio da Ureia Sanguínea , COVID-19/patologia , Creatinina/sangue , Síndrome da Liberação de Citocina/diagnóstico , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/patologia , Feminino , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Masculino , Síndrome do Desconforto Respiratório/patologia , Estudos Retrospectivos , SARS-CoV-2 , Fator de Necrose Tumoral alfa/sangue
7.
J Int Soc Sports Nutr ; 18(1): 42, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090451

RESUMO

OBJECTIVE: Systemic elevations in pro-inflammatory cytokines are a marker of non-functional over reaching, and betaine has been shown to reduce the secretion of pro-inflammatory cytokines in vitro. The aim of this study was to investigate the effects of betaine supplementation on tumor necrosis factor alpha (TNF-α), interleukins-1 beta (IL-1ß), - 6 (IL-6) and the complete blood cell (CBC) count in professional youth soccer players during a competitive season. METHODS: Twenty-nine soccer players (age, 15.5 ± 0.3 years) were randomly divided into two groups based on playing position: betaine group (BG, n = 14, 2 g/day) or placebo group (PG, n = 15). During the 14-week period, training load was matched and well-being indicators were monitored daily. The aforementioned cytokines and CBC were assessed at pre- (P1), mid- (P2), and post- (P3) season. RESULTS: Significant (p < 0.05) group x time interactions were found for TNF-α, IL-1ß, and IL-6. These variables were lower in the BG at P2 and P3 compared to P1, while IL-1ß was greater in the PG at P3 compared to P1 (p = 0.033). The CBC count analysis showed there was significant group by time interactions for white blood cells (WBC), red blood cells (RBC), hemoglobin (Hb), and mean corpuscular hemoglobin concentration (MCHC). WBC demonstrated increases at P3 compared to P2 in PG (p = 0.034); RBC was less at P3 compared to P1 in BG (p = 0.020); Hb was greater at P2 compared to P1, whilst it was less at P3 compared to P3 for both groups. MCHC was greater at P3 and P2 compared to P1 in BG, whereas MCHC was significantly lower at P3 compared to P2 in the PG (p = 0.003). CONCLUSION: The results confirmed that 14 weeks of betaine supplementation prevented an increase in pro-inflammatory cytokines and WBC counts. It seems that betaine supplementation may be a useful nutritional strategy to regulate the immune response during a fatiguing soccer season.


Assuntos
Betaína/administração & dosagem , Comportamento Competitivo/fisiologia , Citocinas/sangue , Suplementos Nutricionais , Futebol/fisiologia , Adolescente , Biomarcadores/sangue , Contagem de Células Sanguíneas , Método Duplo-Cego , Índices de Eritrócitos , Hemoglobinometria , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangue
8.
Ecotoxicol Environ Saf ; 221: 112448, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34174739

RESUMO

Atmospheric PM2.5 can induce airway inflammation and mucin secretion. MUC5B is required for airway defense. However, the research on the role of MUC5B in airway inflammation induced by atmospheric PM2.5 remains limited. This study was designed to explore the role of MUC5B in airway inflammation induced by atmospheric PM2.5. In vivo, Wistar rats were exposed to 0, 1.5, 7.5, 37.5 mg/ kg PM2.5 saline suspension via intratracheal instillation. HE staining and AB-PAS staining were used to observe the airway inflammation and goblet cell hyperplasia. In vitro, normal A549 cells and MUC5B-knockdown A549 cells were exposed to 0, 100, 200 and 400 µg/mL PM2.5 for 6 h, 12 h, 24 h and 48 h. ELISA was used to measure the levels of TNF-α and IL-1ß in serum and bronchoalveolar lavage fluid of rats and in cell culture. Real time-PCR and ELISA were used to quantify the mRNA and protein levels of MUC5B in trachea and lung of rats and in A549 cells. PM2.5 could cause the infiltration of inflammatory cells and increase the mucus secretions and goblet cell metaplasia. MUC5B is related to rats' airway inflammation induced by PM2.5. A549 cells exposed to PM2.5 in higher concentration and longer time, the protein level of MUC5B was significantly increased, while the levels of IL-1ß, TNF-α and MUC5B mRNA were significantly decreased. Compared with normal A549 cells, the levels of IL-1ß and TNF-α were significantly higher in Muc5b-knockdown cells. Atmospheric PM2.5 can induce airway inflammation and mucin secretion. MUC5B played a critical role in controlling the inflammatory response induced by PM2.5.


Assuntos
Inflamação/metabolismo , Mucina-5B/metabolismo , Material Particulado/toxicidade , Células A549 , Animais , Líquido da Lavagem Broncoalveolar/química , Feminino , Humanos , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pulmão/metabolismo , Masculino , Mucina-5B/genética , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
Acta Orthop Traumatol Turc ; 55(3): 235-238, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34100364

RESUMO

OBJECTIVE: Progranulin (PGRN) is a growth factor that has antiinflammatory, immunosuppressive, and chondroprotective effects. It blocks Tumor Necrosis Factor-α (TNF-α) signal pathway by binding its receptor. Recently, it has been claimed that PGRN may be overexpressed in patients with Osteoarthritis (OA). However, these patients tend to be obese and obesity also may be one of the factors that affect PGRN levels. The aim of this study was to compare the PGRN levels of patients with Knee OA (KOA) with that of healthy controls by eliminating the effect of obesity and to evaluate PGRN-to-Tumor Necrosis Factor-α (TNF-α) ratio in KOA, both of which were investigated first in literature by this study. METHODS: A total of 80 individuals (40 patients with KOA and 40 healthy controls) were included in this study. The patients and controls were divided into two groups according to their Body Mass Indexes (BMI): nonobese (BMI between 18.5 and 24.9) and obese (BMI of 30 or higher). Each of the groups included 20 subjects and had an equal number of men and women. Blood samples were obtained from all participants, and the serum PGRN and TNF-α levels were measured using commercial ELISA kits. RESULTS: There was no difference among groups in terms of age (P = 0.416) and gender distribution. There was no statistical difference among study groups with regard to serum PGRN levels. Serum TNF-α levels were significantly higher in obese controls (P < 0.001) and nonobese patients (P = 0.003) compared to that of nonobese healthy controls. Correspondingly, serum PGRN-to-TNF-α ratio was considerably lower in obese controls (P < 0.001) and nonobese patients (P < 0.001) by comparison with that of nonobese healthy controls. CONCLUSION: We determined that both obesity and KOA increased serum TNF-α levels and concordantly decreased serum PGRNto- TNF-α ratio. The results of the study suggest that the activation of the PGRN pathway and/or the inhibition of the TNFα pathway may be essential in terms of the reestablishment of the disrupted inflammatory balance in patients with KOA. LEVEL OF EVIDENCE: Level III, Diagnostic study.


Assuntos
Obesidade , Osteoartrite do Joelho , Progranulinas/sangue , Fator de Necrose Tumoral alfa/sangue , Índice de Massa Corporal , Comorbidade , Correlação de Dados , Feminino , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/metabolismo , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/epidemiologia , Osteoartrite do Joelho/imunologia , Transdução de Sinais/imunologia
10.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067023

RESUMO

Classical inflammation in response to bacterial, parasitic, or viral infections such as HIV includes local recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines. Proposed biomarkers of organ integrity in Alcohol Use Disorders (AUD) include elevations in peripheral plasma levels of proinflammatory proteins. In testing this proposal, previous work included a group of human immunodeficiency virus (HIV)-infected individuals as positive controls and identified elevations in the soluble proteins TNFα and IP10; these cytokines were only elevated in AUD individuals seropositive for hepatitis C infection (HCV). The current observational, cross-sectional study evaluated whether higher levels of these proinflammatory cytokines would be associated with compromised brain integrity. Soluble protein levels were quantified in 86 healthy controls, 132 individuals with AUD, 54 individuals seropositive for HIV, and 49 individuals with AUD and HIV. Among the patient groups, HCV was present in 24 of the individuals with AUD, 13 individuals with HIV, and 20 of the individuals in the comorbid AUD and HIV group. Soluble protein levels were correlated to regional brain volumes as quantified with structural magnetic resonance imaging (MRI). In addition to higher levels of TNFα and IP10 in the 2 HIV groups and the HCV-seropositive AUD group, this study identified lower levels of IL1ß in the 3 patient groups relative to the control group. Only TNFα, however, showed a relationship with brain integrity: in HCV or HIV infection, higher peripheral levels of TNFα correlated with smaller subcortical white matter volume. These preliminary results highlight the privileged status of TNFα on brain integrity in the context of infection.


Assuntos
Alcoolismo/sangue , Infecções por HIV/sangue , Hepatite C/sangue , Fator de Necrose Tumoral alfa/sangue , Substância Branca/patologia , Alcoolismo/complicações , Comorbidade , Feminino , Infecções por HIV/complicações , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Análise de Componente Principal , Solubilidade
11.
Virol J ; 18(1): 117, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34088317

RESUMO

BACKGROUND: To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD. METHODS: The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD. RESULTS: The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time. CONCLUSIONS: The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.


Assuntos
COVID-19/sangue , Síndrome da Liberação de Citocina/sangue , Citocinas/sangue , Síndrome do Desconforto Respiratório/sangue , Injúria Renal Aguda/diagnóstico , Idoso , Nitrogênio da Ureia Sanguínea , COVID-19/patologia , Creatinina/sangue , Síndrome da Liberação de Citocina/diagnóstico , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/patologia , Feminino , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Masculino , Síndrome do Desconforto Respiratório/patologia , Estudos Retrospectivos , SARS-CoV-2 , Fator de Necrose Tumoral alfa/sangue
12.
J Immunol Res ; 2021: 6657894, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34150910

RESUMO

Background: The 2019 novel coronavirus SARS-CoV-2 caused large outbreaks of COVID-19 worldwide. COVID-19 resembles community-acquired pneumonia (CAP). Our aim was to identify lymphocyte subpopulations to distinguish between COVID-19 and CAP. Methods: We compared the peripheral blood lymphocytes and their subsets in 296 patients with COVID-19 and 130 patients with CAP. Parameters for independent prediction of COVID-19 were calculated by logistic regression. Results: The main lymphocyte subpopulations (CD3+CD4+, CD16+CD56+, and CD4+/CD8+ ratio) and cytokines (TNF-α and IFN-γ) of COVID-19 patients were significantly different from that of CAP patients. CD16+CD56+%, CD4+/CD8+ratio, CD19+, and CD3+CD4+ were identified as predictors of COVID-19 diagnosis by logistic regression. In addition, the CD3+CD4+counts, CD3+CD8+ counts, andTNF-α are independent predictors of disease severity in patients. Conclusions: Lymphopenia is an important part of SARS-CoV-2 infection, and lymphocyte subsets and cytokines may be useful to predict the severity and clinical outcomes of the disease.


Assuntos
Relação CD4-CD8 , COVID-19/sangue , Interferon gama/sangue , Subpopulações de Linfócitos/citologia , Pneumonia/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , COVID-19/imunologia , COVID-19/patologia , Teste para COVID-19 , Infecções Comunitárias Adquiridas/microbiologia , Feminino , Humanos , Subpopulações de Linfócitos/imunologia , Linfopenia/sangue , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Pneumonia/imunologia , Pneumonia/patologia , Prognóstico , SARS-CoV-2/imunologia , Índice de Gravidade de Doença
13.
J Int Soc Sports Nutr ; 18(1): 50, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34154603

RESUMO

BACKGROUND: Acute capsaicinoid and capsinoid supplementation has endurance and resistance exercise benefits; however, if these short-term performance benefits translate into chronic benefits when combined with resistance training is currently unknown. This study investigated changes of chronic Capsiate supplementation on muscular adaptations, inflammatory response and performance in untrained men. METHODS: Twenty untrained men were randomized to ingest 12 mg Capsiate (CAP) or placebo in a parallel, double-blind design. Body composition and performance were measured at pre-training and after 6 weeks of resistance training. An acute resistance exercise session test was performed pre and post-intervention. Blood samples were collected at rest and post-resistance exercise to analyze Tumor necrosis factor- (TNF-), Soluble TNF- receptor (sTNF-r), Interleukin-6 (IL-6) and Interleukin-10 (IL-10). RESULTS: Exercise and CAP supplementation increased fat-free mass in comparison to baseline by 1.5 kg (P < 0.001), however, the majority of the increase (1.0 kg) resulted from an increase in total body water. The CAP change scores for fat-free mass were significantly greater in comparison to the placebo (CAP ∆%= 2.1 ± 1.8 %, PLA ∆%= 0.7 ± 1.3 %, P = 0.043) and there was a significant difference between groups in the bench press exercise (P = 0.034) with greater upper body strength change score for CAP (∆%= 13.4 ± 9.1 %) compared to placebo (∆%= 5.8 ± 5.2 %), P = 0.041. CAP had no effect on lower body strength and no supplementation interactions were observed for all cytokines in response to acute resistance exercise (P > 0.05). CONCLUSION: Chronic Capsiate supplementation combined with resistance training during short period (6 weeks) increased fat-free mass and upper body strength but not inflammatory response and performance in young untrained men.


Assuntos
Capsaicina/análogos & derivados , Mediadores da Inflamação/sangue , Força Muscular/efeitos dos fármacos , Treinamento de Força/métodos , Adulto , Desempenho Atlético , Composição Corporal/efeitos dos fármacos , Água Corporal/efeitos dos fármacos , Água Corporal/metabolismo , Capsaicina/administração & dosagem , Capsaicina/farmacologia , Método Duplo-Cego , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Receptores do Fator de Necrose Tumoral/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
14.
EBioMedicine ; 67: 103369, 2021 May.
Artigo em Inglês | MEDLINE | ID: covidwho-1220821

RESUMO

BACKGROUND: Coronavirus-2 (SARS-CoV-2) infection causes an acute respiratory syndrome accompanied by multi-organ damage that implicates a prothrombotic state leading to widespread microvascular clots. The causes of such coagulation abnormalities are unknown. The receptor tissue factor, also known as CD142, is often associated with cell-released extracellular vesicles (EV). In this study, we aimed to characterize surface antigens profile of circulating EV in COVID-19 patients and their potential implication as procoagulant agents. METHODS: We analyzed serum-derived EV from 67 participants who underwent nasopharyngeal swabs molecular test for suspected SARS-CoV-2 infection (34 positives and 33 negatives) and from 16 healthy controls (HC), as referral. A sub-analysis was performed on subjects who developed pneumonia (n = 28). Serum-derived EV were characterized for their surface antigen profile and tested for their procoagulant activity. A validation experiment was performed pre-treating EV with anti-CD142 antibody or with recombinant FVIIa. Serum TNF-α levels were measured by ELISA. FINDINGS: Profiling of EV antigens revealed a surface marker signature that defines circulating EV in COVID-19. A combination of seven surface molecules (CD49e, CD209, CD86, CD133/1, CD69, CD142, and CD20) clustered COVID (+) versus COVID (-) patients and HC. CD142 showed the highest discriminating performance at both multivariate models and ROC curve analysis. Noteworthy, we found that CD142 exposed onto surface of EV was biologically active. CD142 activity was higher in COVID (+) patients and correlated with TNF-α serum levels. INTERPRETATION: In SARS-CoV-2 infection the systemic inflammatory response results in cell-release of substantial amounts of procoagulant EV that may act as clotting initiation agents, contributing to disease severity. FUNDING: Cardiocentro Ticino Institute, Ente ospedaliero Cantonale, Lugano-Switzerland.


Assuntos
COVID-19/complicações , Vesículas Extracelulares/imunologia , Tromboplastina/metabolismo , Trombose/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície/análise , Biomarcadores/análise , COVID-19/sangue , COVID-19/imunologia , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , SARS-CoV-2/isolamento & purificação , Suíça , Trombose/etiologia , Trombose/imunologia , Fator de Necrose Tumoral alfa/sangue
15.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1228897

RESUMO

COVID-19, the syndrome caused by the infection with SARS-CoV-2 coronavirus, is characterized, in its severe form, by interstitial diffuse pneumonitis and acute respiratory distress syndrome (ARDS). ARDS and systemic manifestations of COVID-19 are mainly due to an exaggerated immune response triggered by the viral infection. Cytokine release syndrome (CRS), an inflammatory syndrome characterized by elevated levels of circulating cytokines, and endothelial dysfunction are systemic manifestations of COVID-19. CRS is also an adverse event of immunotherapy (IMTX), the treatment of diseases using drugs, cells, and antibodies to stimulate or suppress the immune system. Graft-versus-host disease complications after an allogeneic stem cell transplant, toxicity after the infusion of chimeric antigen receptor-T cell therapy and monoclonal antibodies can all lead to CRS. It is hypothesized that anti-inflammatory drugs used for treatment of CRS in IMTX may be useful in reducing the mortality in COVID-19, whereas IMTX itself may help in ameliorating effects of SARS-CoV-2 infection. In this paper, we focused on the potential shared mechanisms and differences between COVID-19 and IMTX-related toxicities. We performed a systematic review of the clinical trials testing anti-inflammatory therapies and of the data published from prospective trials. Preliminary evidence suggests there might be a benefit in targeting the cytokines involved in the pathogenesis of COVID-19, especially by inhibiting the interleukin-6 pathway. Many other approaches based on novel drugs and cell therapies are currently under investigation and may lead to a reduction in hospitalization and mortality due to COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/terapia , Síndrome da Liberação de Citocina/tratamento farmacológico , Imunoterapia/métodos , Interleucina-6/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/patologia , Síndrome da Liberação de Citocina/patologia , Humanos , Imunização Passiva/métodos , Imunoterapia/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/sangue , Interleucina-6/sangue , Pirazóis/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Fator de Necrose Tumoral alfa/sangue
16.
Front Immunol ; 12: 592727, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1225860

RESUMO

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected over 112M patients and resulted in almost 2.5M deaths worldwide. The major clinical feature of severe COVID-19 patients requiring ventilation is acute respiratory distress syndrome (ARDS) possibly associated with a cytokine storm. Objectives: To elucidate serum levels of TNF-α and soluble TNF-Receptor 1 (sTNFR1) in patients with severe and mild COVID-19 disease as determinants of disease severity. Methods: We determined serum TNF-α and sTNFR1 concentrations in 46 patients with laboratory-confirmed COVID-19 (17 patients with severe disease within the intensive care unit [ICU] and 29 non-severe, non-ICU patients) and 15 healthy controls upon admission using ELISA. Subjects were recruited between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran. Results: Serum levels of sTNFRI were significantly higher in ICU patients (P<0.0001) and non-ICU patients (P=0.0342) compared with healthy subjects. Serum sTNFR1 were significantly higher in ICU patients than in non-ICU patients (P<0.0001). Serum TNF-α levels were greater in ICU and non-ICU patients than in the healthy subjects group (p<0.0001). The sTNFRI concentration in ICU (r=0.79, p=0.0002) and non-ICU (r=0.42, p=0.02) patients positively correlated with age although serum sTNFRI levels in ICU patients were significantly higher than in older healthy subjects. The sTNFRI concentration in ICU patients negatively correlated with ESR. Conclusions: The study demonstrates higher sTNFRI in ICU patients with severe COVID-19 disease and this be a biomarker of disease severity and mortality. Future studies should examine whether lower levels of systemic sTNFR1 at admission may indicate a better disease outcome.


Assuntos
COVID-19/sangue , COVID-19/mortalidade , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/patologia , Cuidados Críticos , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/mortalidade , Feminino , Humanos , Unidades de Terapia Intensiva , Interleucina-6/sangue , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Projetos Piloto , SARS-CoV-2 , Índice de Gravidade de Doença
17.
Int Heart J ; 62(3): 607-615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054001

RESUMO

The aim was to investigate the role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation (AF).18 beagles (standard dogs for testing) were used in this study, and the effective refractory period (ERP) of atrium and pulmonary veins and AF inducibility were measured hourly during rapid atrial pacing at 800 beats/minute for 6 hours in all beagles. After cessation of 3 hours of RAP, the low-level vagal nerve stimulation (LL-VNS) group (n = 6) was given LL-VNS and injection of salinne (0.5 mL/GP) into four GPs, the methyllycaconitine (MLA, the antagonist of α7nAChR) group (n = 6) was given LL-VNS and injection of MLA into four GPs, and the Control group (n = 6) was given saline into four GPs and the right cervical vagal nerve was exposed without stimulation. Then, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), acetylcholine (ACh), STAT3, and NF-κB proteins were measured. During the first 3 hours of RAP, the ERPs gradually decreased while the dispersion of ERPs (dERPs) and AF inducibility gradually increased in all three groups. During the last 3 hours of 6 hours' RAP in this study, the ERPs in the LL-VNS group were higher, while the dERPs and AF inducibility were significantly lower when compared with the Control and MLA groups at the same time points. The levels of ACh in the serum and atrium in the LL-VNS and MLA groups were higher than in the Control group, and the levels of TNF-α and IL-6 were higher in the Control and MLA groups than in the LL-VNS group. The concentrations of STAT3 in RA and LA tissues were higher in the LL-VNS group while those of NF-κB were lower.In conclusion, the cholinergic anti-inflammatory pathway mediated by α7nACh plays an important role in low-level vagal nerve-regulated AF.


Assuntos
Aconitina/análogos & derivados , Fibrilação Atrial/fisiopatologia , Neuroimunomodulação/efeitos dos fármacos , Nervo Vago/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Acetilcolina/sangue , Aconitina/administração & dosagem , Aconitina/farmacologia , Animais , Estimulação Cardíaca Artificial/efeitos adversos , Estimulação Cardíaca Artificial/métodos , Estudos de Casos e Controles , Modelos Animais de Doenças , Cães , Átrios do Coração/inervação , Átrios do Coração/fisiopatologia , Interleucina-6/sangue , NF-kappa B/sangue , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Veias Pulmonares/inervação , Veias Pulmonares/fisiopatologia , Período Refratário Eletrofisiológico/efeitos dos fármacos , Fator de Transcrição STAT3/sangue , Fator de Necrose Tumoral alfa/sangue , Estimulação do Nervo Vago/efeitos adversos , Estimulação do Nervo Vago/métodos
18.
Front Immunol ; 12: 592727, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968010

RESUMO

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected over 112M patients and resulted in almost 2.5M deaths worldwide. The major clinical feature of severe COVID-19 patients requiring ventilation is acute respiratory distress syndrome (ARDS) possibly associated with a cytokine storm. Objectives: To elucidate serum levels of TNF-α and soluble TNF-Receptor 1 (sTNFR1) in patients with severe and mild COVID-19 disease as determinants of disease severity. Methods: We determined serum TNF-α and sTNFR1 concentrations in 46 patients with laboratory-confirmed COVID-19 (17 patients with severe disease within the intensive care unit [ICU] and 29 non-severe, non-ICU patients) and 15 healthy controls upon admission using ELISA. Subjects were recruited between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran. Results: Serum levels of sTNFRI were significantly higher in ICU patients (P<0.0001) and non-ICU patients (P=0.0342) compared with healthy subjects. Serum sTNFR1 were significantly higher in ICU patients than in non-ICU patients (P<0.0001). Serum TNF-α levels were greater in ICU and non-ICU patients than in the healthy subjects group (p<0.0001). The sTNFRI concentration in ICU (r=0.79, p=0.0002) and non-ICU (r=0.42, p=0.02) patients positively correlated with age although serum sTNFRI levels in ICU patients were significantly higher than in older healthy subjects. The sTNFRI concentration in ICU patients negatively correlated with ESR. Conclusions: The study demonstrates higher sTNFRI in ICU patients with severe COVID-19 disease and this be a biomarker of disease severity and mortality. Future studies should examine whether lower levels of systemic sTNFR1 at admission may indicate a better disease outcome.


Assuntos
COVID-19/sangue , COVID-19/mortalidade , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/patologia , Cuidados Críticos , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/mortalidade , Feminino , Humanos , Unidades de Terapia Intensiva , Interleucina-6/sangue , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Projetos Piloto , SARS-CoV-2 , Índice de Gravidade de Doença
19.
Biomed Res Int ; 2021: 5567046, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959658

RESUMO

Stroke is the main cause of acquired epilepsy in elderly people. Poststroke epilepsy (PSE) not only affects functional recovery after stroke but also brings considerable social consequences. While some factors such as cortical involvement, hemorrhagic transformation, and stroke severity are associated with increased seizure risk, so far that remains controversial. In recent years, there are an increasing number of studies on potential biomarkers of PSE as tools for diagnosing and predicting epileptic seizures. Biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glutamate, and S100 calcium-binding protein B (S100B) in blood are associated with the occurrence of PSE. This review is aimed at summarizing the progress on potential biomarkers of PSE.


Assuntos
Biomarcadores/sangue , Epilepsia , Acidente Vascular Cerebral/complicações , Epilepsia/sangue , Epilepsia/diagnóstico , Epilepsia/etiologia , Ácido Glutâmico/sangue , Humanos , Interleucina-6/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Fator de Necrose Tumoral alfa/sangue
20.
Biomed Res Int ; 2021: 2043415, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33969115

RESUMO

The protective effect of aspirin against myocardial hypertrophy (MH) was studied. Model rats of pressure overload MH were prepared by abdominal aortic coarctation. Rats were randomly divided into the sham group (n = 9), MH model group (n = 9), and MH+aspirin group (n = 9), which was, respectively, divided into the 4-week group and 8-week group according to the time of intragastric administration. Arterial blood pressure and left ventricular mass index (LVMI) were measured. Changes in myocardial tissue structure were observed by HE staining, Masson staining, and reticular fiber staining. Cardiomyocyte apoptosis was detected by TUNEL assay. The levels of TNF-α, IL-10, TXA2, and PGI2 in myocardium and plasma were detected by ELISA. The arterial blood pressure in the MH model group was significantly higher than that in the 4- and 8-week sham groups, but that in the MH+aspirin group was significantly lower than that in the MH model group. At 4 and 8 weeks, the LVWI in the MH model group was significantly higher than that in the sham group, but it was significantly reduced after aspirin treatment. The myocardial cell hypertrophy was obvious, collagen fibers were proliferated, and reticular fibers were reduced in the 4- and 8-week MH model groups. Compared with the MH model groups, myocardial cells in the MH+aspirin groups were significantly reduced, the collagen fiber content was significantly reduced, and the reticular fiber content was increased. The apoptotic cardiomyocytes in the 4- and 8-week MH model groups were obviously increased. The apoptosis of myocardial cells in the MH+aspirin groups was obviously decreased. The TNF-α levels in the myocardial tissue of the 4- and 8-week MH model groups were significantly increased, while those of the MH+aspirin groups were significantly decreased. There was no significant change in the IL-10 level or PGI2 level at 4 weeks. At 8 weeks, the PGI2 level was significantly decreased in the MH model group while significantly increased in the MH+aspirin group. The TXA2 levels were significantly increased in the 4- and 8-week MH model groups and those in the 4- and 8-week MH+aspirin groups were significantly lower. Aspirin has an anti-inflammatory effect, can effectively reduce the expression of inflammatory factors, inhibit myocardial apoptosis, and has a certain protective effect against MH.


Assuntos
Aspirina/farmacologia , Cardiotônicos/farmacologia , Miocárdio/patologia , Animais , Apoptose/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Colágenos Fibrilares/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Hipertrofia , Mediadores da Inflamação/metabolismo , Interleucina-10/sangue , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Tamanho do Órgão/efeitos dos fármacos , Prostaglandinas/sangue , Ratos Wistar , Tromboxano A2/sangue , Fator de Necrose Tumoral alfa/sangue
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