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1.
Aging Clin Exp Res ; 31(6): 845-854, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31049877

RESUMO

BACKGROUND: A chronic low-grade inflammatory profile (CLIP) is associated with sarcopenia in older adults. Protein and Vitamin (Vit)D have immune-modulatory potential, but evidence for effects of nutritional supplementation on CLIP is limited. AIM: To investigate whether 13 weeks of nutritional supplementation of VitD and leucine-enriched whey protein affected CLIP in subjects enrolled in the PROVIDE-study, as a secondary analysis. METHODS: Sarcopenic adults (low skeletal muscle mass) aged ≥ 65 years with mobility limitations (Short Physical Performance Battery 4-9) and a body mass index of 20-30 kg/m2 were randomly allocated to two daily servings of active (n = 137, including 20 g of whey protein, 3 g of leucine and 800 IU VitD) or isocaloric control product (n = 151) for a double-blind period of 13 weeks. At baseline and after 13 weeks, circulating interleukin (IL)-8, IL-1 receptor antagonist (RA), soluble tumor-necrosis-factor receptor (sTNFR)1, IL-6, high-sensitivity C-reactive protein, pre-albumin and 25-hydroxyvitamin(OH)D were measured. Data-analysis included repeated measures analysis of covariance (corrected for dietary VitD intake) and linear regression. RESULTS: IL-6 and IL-1Ra serum levels showed overall increases after 13 weeks (p = 0.006 and p < 0.001, respectively). For IL-6 a significant time × treatment interaction (p = 0.046) was observed, with no significant change over time in the active group (p = 0.155) compared to control (significant increase p = 0.012). IL-8 showed an overall significant decrease (p = 0.03). The change in pre-albumin was a significant predictor for changes in IL-6 after 13 weeks. CONCLUSIONS: We conclude that 13 weeks of nutritional supplementation with VitD and leucine-enriched whey protein may attenuate the progression of CLIP in older sarcopenic persons with mobility limitations.


Assuntos
Leucina/uso terapêutico , Sarcopenia/tratamento farmacológico , Vitamina D/uso terapêutico , Proteínas do Soro do Leite/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-6/sangue , Leucina/farmacologia , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Músculo Esquelético/efeitos dos fármacos , Sarcopenia/sangue , Vitamina D/farmacologia , Proteínas do Soro do Leite/farmacologia
2.
Scand J Rheumatol ; 48(3): 235-238, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30668200

RESUMO

OBJECTIVES: Schnitzler syndrome (SchS) is an autoinflammatory disorder characterized by chronic urticaria, fever, and monoclonal gammopathy. The success of interleukin-1 (IL-1) blocking therapies suggests a crucial role for IL-1 in disease induction. The aim of this study is to perform a comprehensive analysis of IL-1 family cytokines and soluble receptors in a group of SchS patients. METHOD: Three patients fulfilling the criteria for the diagnosis of SchS were recruited; 80 blood donors formed the control group. IL-1 family cytokines (IL-1α, IL-1ß, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, sIL-1R4), and antagonists [IL-1Ra, IL-18 binding protein (IL-18BP)] were measured by a multiarray enzyme-linked immunosorbent assay. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Cytokine levels were compared by the Mann-Whitney test. RESULTS: IL-18 and free IL-18 were increased in patients compared with controls (p = 0.005 and p = 0.0082, respectively), while IL-18BP levels were not different. IL-1α, IL-1ß, and IL-33 were undetectable in both patients and controls. The soluble receptors sIL-1R1, sIL-1R2, and ST2/sIL-1R4, and the IL-1 antagonist IL-1Ra were all within normal ranges; sIL-1R3 was significantly lower in patients than in controls (p = 0.039). CONCLUSIONS: The data indicate that SchS is characterized by increased circulating levels of free IL-18, possibly leading to a higher activation of innate/inflammatory effector cells. At variance with other inflammatory diseases, the lack of increase in sIL-1R1 and sIL-1R2 and the decreased levels of sIL-R3 imply a failure in the counterbalancing mechanism aimed at inhibiting excessive IL-1ß in tissues.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-18/sangue , Interleucina-1 , Receptores de Interleucina-1 , Síndrome de Schnitzler , Feminino , Humanos , Inflamação/sangue , Interleucina-1/antagonistas & inibidores , Interleucina-1/sangue , Interleucina-1/classificação , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/sangue , Receptores de Interleucina-1/classificação , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/diagnóstico , Síndrome de Schnitzler/imunologia , Estatísticas não Paramétricas
3.
Crit Care ; 22(1): 348, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30563551

RESUMO

BACKGROUND: Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis. METHODS: In this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs-). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma-induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models. RESULTS: Among 64 CMV+ patients, 45 could be matched to CMVs+ or CMVs- controls or both. The two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. CMV+ patients had increased IP-10 on day 7 after viremia onset (symmetric percentage difference +44% versus -15% when compared with CMVs+ and +37% versus +4% when compared with CMVs-) and decreased IL-1RA (-41% versus 0% and -49% versus +10%, respectively). However, multivariable analyses did not show an independent association between CMV reactivation and time trends of IL-6, IP-10, IL-10, or IL-1RA. CONCLUSION: CMV reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. Therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-CMV therapy.


Assuntos
Biomarcadores/sangue , Infecções por Citomegalovirus/diagnóstico , Imunidade Humoral/fisiologia , Sepse/imunologia , Idoso , Biomarcadores/análise , Quimiocina CXCL10/análise , Quimiocina CXCL10/sangue , Distribuição de Qui-Quadrado , Estudos de Coortes , Estado Terminal , Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/imunologia , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Proteína Antagonista do Receptor de Interleucina 1/análise , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-10/análise , Interleucina-10/sangue , Interleucina-6/análise , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Ativação Viral/fisiologia
4.
Int J Cardiol ; 257: 24-29, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29395365

RESUMO

BACKGROUND: IL-1ß-mediated inflammation contributes to development and progression of coronary artery disease (CAD). We aimed to assess the prognostic impact of the inflammatory marker Interleukin-1 receptor antagonist (IL1-Ra), reflecting high IL-1ß activity, in patients with documented CAD. METHODS: IL-1Ra levels were determined in 1337 subjects of the AtheroGene study, a prospective cardiovascular registry comprising patients with CAD as detected by coronary angiography presenting with acute coronary syndrome (ACS) or stable angina. Median follow-up was 6.4 years. RESULTS: Patients with IL1-Ra levels in the highest tertile presented more often with ACS (55% vs. 40% vs. 34%, p < 0.001), were more commonly treated with PCI (47% vs. 39% vs. 34%, p < 0.001), had lower left ventricular ejection fraction (LVEF) (61 ±â€¯15% vs. 62 ±â€¯15% vs. 65 ±â€¯14%, p = 0.001) and higher hs-CRP levels (10.0 vs. 4.2 vs. 2.5 mg/L, p < 0.001). IL1-Ra levels at baseline were predictive for all-cause mortality in the total study cohort after adjustment for conventional cardiovascular risk factors, LVEF, hs-CRP and Troponin T (adjusted HR 1.45 (95% CI 1.16-1.82), p < 0.001). In a subgroup of patients with ACS, but not in those with stable angina, IL1-Ra was an independent predictor for cardiovascular mortality (ACS: adjusted HR 1.93 (95% CI 1.33-2.80), p < 0.001; stable angina: adjusted HR: 1.26 (95% CI 0.92-1.73), p = 0.16). CONCLUSION: IL1-Ra is an independent predictor for adverse outcome in patients with documented CAD, beyond the prognostic value of hs-CRP and Troponin T in particular in the setting of ACS. For CAD patients our finding might improve both, risk assessment in secondary prevention and patient selection for anti-inflammatory treatment.


Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Proteína Antagonista do Receptor de Interleucina 1/sangue , Idoso , Biomarcadores/sangue , Doença da Artéria Coronariana/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Prognóstico , Estudos Prospectivos , Sistema de Registros , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia
5.
Gene ; 652: 1-6, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29425823

RESUMO

It has been reported that an increased function of the P2X7 purinergic receptor is associated with an increase in both insulin sensitivity and secretion. Accordingly, we explored the possible effect of the 1068 G>A polymorphism of the gene P2RX7 on glucose homeostasis and the levels of the anti-inflammatory cytokine IL-1Ra in T2D patients. The presence of the 1068 G>A polymorphism in T2D patients (n = 100) and healthy subjects (n = 100) was determined by DNA sequencing, and serum levels of IL-1Ra were measured by ELISA. Pancreatic ß-cell function, insulin resistance, blood glucose levels and glycated hemoglobin (HbA1c) were also analyzed. We detected a significant negative association between T2D and the 1068 G>A SNP (Odds ratio 0.3916, p = 0.0045). In addition, we observed that T2D patients bearing the 1068 G>A variant showed higher serum levels of IL-1Ra compared to both, patients with the GG genotype or healthy individuals (GG or G>A). Moreover, T2D patients bearing the 1068 G>A SNP showed increased insulin levels and a better pancreatic ß-cell function (p < 0.05 in both cases) compared to patients with the wild type genotype. However, the HbA1c levels, fasting glucose levels and the degree of insulin resistance were similar in T2D patients carrying or not the G>A SNP. Our results suggest that although the 1068 G>A polymorphism of the P2RX7 gene is associated with an increased ß-cell function and IL-1Ra release in T2D patients, the glycemic control is not significantly affected by the presence of this SNP.


Assuntos
Diabetes Mellitus Tipo 2/genética , Células Secretoras de Insulina/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/genética , Polimorfismo de Nucleotídeo Único , Receptores Purinérgicos P2X7/genética , Adulto , Glicemia/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Feminino , Expressão Gênica , Genótipo , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/patologia , Proteína Antagonista do Receptor de Interleucina 1/sangue , Masculino , Pessoa de Meia-Idade , Receptores Purinérgicos P2X7/sangue
6.
J Clin Endocrinol Metab ; 103(3): 1180-1187, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29346597

RESUMO

Purpose: We previously demonstrated the anti-inflammatory and antioxidant effects of exenatide. We now hypothesized that exenatide also increases the plasma concentration of interleukin-1 receptor antagonist (IL-1RA), an endogenous anti-inflammatory protein, and modulates the nuclear factor erythroid 2‒related factor‒Kelchlike ECH-associated protein 1‒antioxidant response element (Nrf-2‒Keap-1‒ARE) system to induce key antioxidant enzymes to suppress inflammatory and oxidative stress. Methods: Twenty-four patients with obesity and type 2 diabetes receiving combined oral and insulin therapy were randomly assigned to receive either exenatide 10 µg or placebo twice a day for 12 weeks. Results: Exenatide increased IL-1RA concentration by 61% (from 318 ± 53 to 456 ± 88 pg/mL; P < 0.05). Exenatide treatment also suppressed Keap-1 protein (P < 0.05) and increased messenger RNA expression of NQO-1, glutathione S-transferase PI, heme oxygenase-1, and p21 and increased NAD(P)H dehydrogenase [quinone] 1 protein (P < 0.05) in mononuclear cells. Conclusions: Because IL-1RA protects, maintains, and stimulates ß-cell function in humans and Nrf-2‒Keap-1‒ARE protects ß cells in animals with experimental diabetes, these actions of exenatide may contribute to a potential protective effect on ß cells in diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/sangue , Obesidade/tratamento farmacológico , Peptídeos/farmacologia , Peçonhas/farmacologia , Elementos de Resposta Antioxidante/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Quimioterapia Combinada , Indução Enzimática/efeitos dos fármacos , Exenatida , Feminino , Glutationa S-Transferase pi/biossíntese , Heme Oxigenase-1/biossíntese , Humanos , Insulina/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/biossíntese , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Obesidade/sangue , Obesidade/complicações
7.
Gynecol Endocrinol ; 34(7): 574-578, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29345164

RESUMO

OBJECTIVE: The purpose of this study was to determine whether higher circulating interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory cytokine, was associated with insulin resistance in postmenopausal women. METHODS: We measured IL-1Ra concentrations in 160 naturally postmenopausal women without a history of diabetes mellitus. A Pearson coefficient was computed to assess the relationship between plasma IL-1Ra and homeostasis model assessment of insulin resistance (HOMA-IR). The association between HOMA-IR and IL-1Ra plasma level above the median was assessed by logistic regression. Linear regression was used to explore the determinants of IL-1Ra plasma levels. RESULTS: A significant positive correlation existed between IL-1Ra and HOMA-IR (r = 0.42, p < .0001). The upper-tertile group of HOMA-IR was associated with approximately 4.5-fold increased risk of plasma IL-1Ra level above the median compared with the low-tertile group after adjustments. When multiple correlates were entered into the regression model simultaneously, only Log HOMA-IR remained significantly related to Log IL-1Ra (p = .007). CONCLUSIONS: Our results demonstrated a positive association between plasma IL-1Ra and insulin resistance in postmenopausal women. This analysis suggested that insulin resistance was an important determinant of circulating IL-1Ra for these women.


Assuntos
Resistência à Insulina/fisiologia , Proteína Antagonista do Receptor de Interleucina 1/sangue , Pós-Menopausa/sangue , Idoso , Glicemia/metabolismo , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/metabolismo , Sistema de Registros , Estudos Retrospectivos
8.
Surgery ; 163(2): 409-414, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29129362

RESUMO

BACKGROUND: During the past decades' sepsis has become the major cause of death in severely burned patients. Despite the importance of burn sepsis, its diagnosis, let alone its prediction, is difficult if not impossible. Recently, we have demonstrated burn patients have increased NLRP3 inflammasome activation in white adipose tissue. We aimed to delineate a unique immune profile that can be used to identify septic outcomes in severely burned patients. METHODS: Adult burn patients (n = 37) admitted to our burn center between June 2013-2015 were enrolled in this study. White adipose tissue from the site of injury and plasma were collected from severely burned patients (>20% total body surface area) within 96 hours after thermal injury, indiscriminate of sex or age. RESULTS: We found that patients exhibiting aberrantly high levels of proinflammatory interleukin-1ß and decreased macrophages at the site of injury are highly susceptible to development of sepsis. Septic patients also had increased anti-inflammatory (interleukin-10, interleukin-1RA) cytokines in plasma. The Septic Predictor Index was generated as a quotient for the site of injury macrophage proportion and interleukin-1ß production. All patients who eventually develop sepsis had septic predictor index values >0.5. Septic patients with Septic Predictor Index values >1 all had sepsis onset within 12 days post-injury, whereas patients with Septic Predictor Index values between 0.5-1 all had later onset (>12 days). CONCLUSION: The Septic Predictor Index can determine sepsis onset accurately in thermally injured patients a priori and further enables surgeons to develop clinical studies and focused therapies specifically designed for septic cohorts.


Assuntos
Queimaduras/complicações , Sepse/etiologia , Adulto , Idoso , Queimaduras/imunologia , Feminino , Citometria de Fluxo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , Medição de Risco
9.
Biomarkers ; 23(2): 161-166, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28972805

RESUMO

BACKGROUND AND AIM: Altered gene expression in intestinal mucosa is thought to contribute to inflammatory process in Crohn's disease (CD). The present study investigated changes in the expression of genes associated with gut inflammation in CD patients by RNA microarray to identify disease biomarkers. METHODS: Microarray analysis was carried out in formalin-fixed, paraffin-embedded intestinal tissue specimens from six CD patients who underwent surgery without prior treatment and from two healthy control subjects. Transcripts overexpressed in CD patients were validated by enzyme-linked immunosorbent assay (ELISA) using specimens from 46 CD patients and 60 healthy controls. RESULTS: Among the genes over-expressed with statistical significance, five genes including decay-accelerating factor, interleukin-1 receptor (IL1R) A, tumour necrosis factor receptor 2, (C-X-C motif) ligand (CXCL) 1, and granzyme (GZM) B proposed to have functional association with CD were selected to validate the expressed transcripts in serum. Serum concentration of IL1RA, CXCL1, and GZMB measured by ELISA were significantly higher in CD patients. CONCLUSIONS: We identified that IL1RA, CXCL1, and GZMB are overexpressed in CD patients. Serum IL1RA and GZMB levels were markedly increased in CD patients, suggesting that these markers can serve as biomarkers to identify gut inflammation. Further studies will be required to evaluate this possibility.


Assuntos
Biomarcadores/metabolismo , Doença de Crohn/genética , Perfilação da Expressão Gênica , Granzimas/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Adulto , Biomarcadores/sangue , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Ensaio de Imunoadsorção Enzimática , Feminino , Granzimas/sangue , Humanos , Inflamação/genética , Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/sangue , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Curva ROC , Adulto Jovem
10.
Gynecol Endocrinol ; 34(1): 40-44, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28678568

RESUMO

OBJECTIVE: To study the associations between androgens, glucose homeostasis, inflammation and statin treatment in women with polycystic ovary syndrome (PCOS). DESIGN AND METHODS: Oral glucose tolerance tests, androgens, hs-CRP and interleukin-1 receptor antagonist (IL-1Ra) were analyzed at baseline and after 6 months of atorvastatin (20 mg/d) or placebo treatment in 27 women with PCOS. RESULTS: Testosterone associated with insulin resistance measured with ISIMatsuda independently of BMI, age and SHBG concentrations and the full model, including IL-1Ra, hs-CRP and HDL-C, also showed independency of BMI and waist circumference (p ≤ .042). Free androgen index (FAI) associated with ISIMatsuda independently of adiposity (p ≤ .025) but in the full model with waist circumference the association was insignificant. ISIMatsuda decreased with testosterone >1.2 nmol/l compared with lower levels at baseline (p = .043) and at six months (p = .003). Accordingly, 30-minute insulin levels were increased with moderately elevated testosterone independently of adiposity (p ≤ .046). Increased fasting glucose and AUC insulin associated with statin treatment independently of adiposity and the associations attenuated after adjusting for testosterone. CONCLUSIONS: Moderately elevated testosterone concentrations together with obesity-related inflammatory factors modify glucose homeostasis by increasing insulin resistance and early insulin secretion.


Assuntos
Adiposidade/fisiologia , Resistência à Insulina , Síndrome do Ovário Policístico/fisiopatologia , Testosterona/sangue , Adulto , Androgênios/sangue , Índice de Massa Corporal , Proteína C-Reativa/análise , HDL-Colesterol/sangue , Método Duplo-Cego , Feminino , Teste de Tolerância a Glucose , Homeostase , Humanos , Inflamação/sangue , Insulina/sangue , Proteína Antagonista do Receptor de Interleucina 1/sangue , Pessoa de Meia-Idade , Obesidade/complicações , Placebos , Globulina de Ligação a Hormônio Sexual/análise
11.
Cardiovasc Diabetol ; 16(1): 153, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29195493

RESUMO

BACKGROUND: Biomarkers of inflammation and adiponectin are associated with cardiovascular autonomic neuropathy (CAN) in cross-sectional studies, but prospective data are scarce. This study aimed to assess the associations of biomarkers of subclinical inflammation and adiponectin with subsequent changes in heart rate (HR) and heart rate variability (HRV) in non-diabetic and diabetic individuals. METHODS: Data are based on up to 25,050 person-examinations for 8469 study participants of the Whitehall II cohort study. Measures of CAN included HR and several HRV indices. Associations between baseline serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra) and adiponectin and 5-year changes in HR and six HRV indices were estimated using mixed-effects models adjusting for age, sex, ethnicity, body mass index (BMI), metabolic covariates and medication. A modifying effect of diabetes was tested. RESULTS: Higher levels of IL-1Ra were associated with higher increases in HR. Additional associations with measures of HRV were observed for hsCRP, IL-6 and IL-1Ra, but these associations were explained by BMI and other confounders. Associations between adiponectin, HR and HRV differed depending on diabetes status. Higher adiponectin levels were associated with more pronounced decreases in HR and increases in three measures of HRV reflecting both sympathetic and vagal activity, but these findings were limited to individuals with type 2 diabetes. CONCLUSIONS: Higher IL-1Ra levels appeared as novel risk marker for increases in HR. Higher adiponectin levels were associated with a more favourable development of cardiovascular autonomic function in individuals with type 2 diabetes independently of multiple confounders.


Assuntos
Adiponectina/sangue , Doenças do Sistema Nervoso Autônomo/sangue , Sistema Nervoso Autônomo/fisiopatologia , Neuropatias Diabéticas/sangue , Cardiopatias/sangue , Frequência Cardíaca , Coração/inervação , Mediadores da Inflamação/sangue , Inflamação/sangue , Adulto , Idoso , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Biomarcadores/sangue , Proteína C-Reativa/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/fisiopatologia , Feminino , Cardiopatias/diagnóstico , Cardiopatias/fisiopatologia , Humanos , Inflamação/diagnóstico , Inflamação/fisiopatologia , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-6/sangue , Londres , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
12.
Autoimmunity ; 50(8): 468-475, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29226727

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and pro-inflammatory cytokines production. IL-1Ra is an anti-inflammatory cytokine codified by IL1RN gene that blocks IL-1 signalling. A VNTR polymorphism of 86 bp in IL1RN gene has been associated with RA risk and regulation of IL-1Ra expression. In this study, we determined mRNA and protein expression of IL-1Ra in RA patients and control subjects (CS). This study included 85 RA patients classified according to the ACR/EULAR 2010 criteria and 67 CS. Polymerase chain reaction was used to identify IL1RN VNTR polymorphism, the expression of sIL-1Ra (secreted isoform) mRNA was determined by SYBR Green-based real time quantitave-PCR assay, and IL-1Ra soluble levels quantification was evaluated by ELISA test. RA patients had higher soluble levels of IL-1Ra than CS (p < .01), sIL-1Ra mRNA expression was higher in RA patients compared to CS (p < .01). Carriers of IL1RN*2/2 homozygous genotype show increased IL-1Ra soluble levels compared to IL1RN*long/long and IL1RN*2/long genotypes (p < .05) in the CS group, whereas mRNA expression in carriers of IL1RN*2/2 genotype was 1.2 times higher compared to IL1RN*long/long genotypes in the same group. Regarding RA patients, high expression of sIL-1Ra mRNA on carriers of IL1RN*long/long genotype was observed. Nevertheless, in RA patients IL-1Ra soluble levels among genotypes did not show significant differences. High expression of IL-1Ra in RA patients under treatment or not with antirheumatic drugs was detected. Additionally, carriers of IL1RN*2/2 genotype had higher IL-1Ra expression than carriers of other genotypes.


Assuntos
Artrite Reumatoide/genética , Expressão Gênica , Genótipo , Proteína Antagonista do Receptor de Interleucina 1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Polimorfismo Genético , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
13.
Int J Rheum Dis ; 20(11): 1704-1713, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29105312

RESUMO

AIM: To assess the acute effect of resistance exercise (RE) on circulating biomarkers of cartilage breakdown and inflammation in women with rheumatoid arthritis (RA). METHODS: Thirty-four volunteers (17 with and 17 without RA), participated in a 25 min RE session (knee extension, knee flexion, hip abduction and hip adduction) with one set of 12 repetitions at 50% of one repetition maximum (1RM) and one set of eight repetitions at 75% of 1RM. Blood samples were collected 30 and 5 min before, immediately after and 1, 2 and 24 h after the session. We used analysis of variance for repeated-measures with Bonferroni adjustments to assess differences between groups over time. RESULTS: In both groups we found significant changes in interleukin (IL)-1 beta (P = 0.045), IL-1 receptor antagonist (IL-1ra) (P < 0.001), IL-10 (P = 0.004), IL-6 (P < 0.001) and cartilage oligomeric matrix protein (COMP) P < 0.001) in response to exercise, but no changes in tumor necrosis factor-alpha and C-reactive protein levels. We found no differences in the responses of the two groups to the session, except for COMP levels, which are more sensitive to exercise and rest effects in RA patients. CONCLUSION: Women with and without RA have similar changes in response to a RE session in levels of inflammation biomarkers, but not of cartilage breakdown. IL-10 and IL-1ra increased after the RE session, indicating that RE may have an acute anti-inflammatory effect. Additional studies are necessary to clarify if repeated RE sessions can have long-term anti-inflammatory effects and the possible clinical repercussions of this cartilage breakdown characteristic in response to exercise in RA patients.


Assuntos
Artrite Reumatoide/sangue , Proteína de Matriz Oligomérica de Cartilagem/sangue , Cartilagem Articular/metabolismo , Mediadores da Inflamação/sangue , Treinamento de Resistência , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Biomarcadores/sangue , Cartilagem Articular/patologia , Estudos de Casos e Controles , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Pessoa de Meia-Idade , Fatores de Tempo
14.
Mult Scler Relat Disord ; 18: 1-7, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29141788

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a multi-factorial disease of the Central Nervous System (CNS) affecting young adults leading to significant disabilities over time. MS is now believed to be prevalent in Arabian Gulf area with high incidence due to environmental factors and unknown genetic variations. The objectives of this study was to detect up-regulated potential genes that might be involved in neuroinflammatory process in MS patients in Bahrain and to measure the protein levels of the expressed genes. METHODS: A microarray was used to investigate mRNA expression from 12 MS patients and 12 control subjects in Bahrain where the mRNA came from peripheral blood leukocytes. Also, 80 MS patients and 80 control subjects were analyzed to measure serum protein levels of the expressed genes by ELISA. RESULTS: The data showed 15,480 genes expressed from over 47,000 transcripts and variants. Only 5 genes were significantly up-regulated in MS patients vs control subjects; namely TNF-AIP6, IL-1RA, OASL, CLC and DOCK4 (p < 0.05). Conversely, KIAA0125 gene was significantly down-regulated (p < 0.0003). Analysis of the effector molecules of the up-regulated genes revealed that 83 MS patients had positive serum level of OASL, 87 MS patients had positive serum levels of IL-1RA, and none of the 88 MS patients showed detectable serum levels of TNF-AIP6, CLC or DOCK4. CONCLUSIONS: OASL and IL-1RA genes were strongly expressed in MS patients and that their effector molecules may be considered as biomarkers associated with the inflammatory process of the disease and possibly treatment response.


Assuntos
2',5'-Oligoadenilato Sintetase/sangue , Proteína Antagonista do Receptor de Interleucina 1/sangue , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Adolescente , Adulto , Barein , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação da Expressão Gênica , Humanos , Leucócitos/metabolismo , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , RNA Mensageiro/sangue , Adulto Jovem
15.
J Neuroinflammation ; 14(1): 200, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-29017522

RESUMO

BACKGROUND: Febrile seizures are the most common form of childhood seizures. Fever generation involves many cytokines, including both pro- and anti-inflammatory cytokines. Some of these cytokines also induce febrile seizures. We compared cytokine production in children with a fever alone (healthy control group) and febrile seizure children group. Also, we evaluated the cytokine level of children with a fever alone and febrile seizure history. METHODS: Fifty febrile seizure patients and 39 normal control patients who visited the emergency department of Konkuk University Hospital from December 2015 to December 2016 were included in this study. Blood was taken from the peripheral vessels of children in all groups within 1 h of the seizure, and serum was obtained immediately. Serum samples from patients with only a fever and a febrile seizure history (N = 13) and afebrile seizure controls (N = 12) were also analyzed. RESULTS: The serum IL-10 and IL-1Ra levels were significantly higher in the febrile seizure patients than in the fever-only control, fever only with a febrile seizure history, and afebrile seizure groups (p < 0.05). The serum IFN-γ and IL-6 levels were significantly higher in the febrile seizure patients than in the afebrile seizure group (p < 0.05). The serum IL-8 levels were higher in the febrile seizure patients than in the fever only controls (p < 0.05). CONCLUSIONS: The serum levels of the IFN-γ, IL-6, and IL-8 pro-inflammatory cytokines and the serum levels of the IL-10 and IL-1Ra anti-inflammatory cytokines were significantly higher in the febrile seizure children. Furthermore, the serum level of IL-1Ra was more increased in the febrile seizure group than in the same patients with only a fever. Our data suggest that increased serum IL-10 and IL-1Ra may play potential roles as anti-inflammatory cytokines in a compensation mechanism that shortens the seizure duration or prevents a febrile seizure attack. Therefore, anti-inflammatory cytokines, including IL-10 and IL-1Ra, have potential as therapeutic targets for the prevention of seizures and nervous system development of children.


Assuntos
Citocinas/sangue , Convulsões Febris/sangue , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-10/sangue , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas
16.
Acta Psychiatr Scand ; 136(4): 400-408, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28815548

RESUMO

OBJECTIVE: We evaluated if plasma levels of inflammatory markers are persistently altered in severe mental disorders with psychotic symptoms or associated with state characteristics in a longitudinal study. METHODS: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), von Willebrand factor (VWF), and osteoprotegerin (OPG) were measured in schizophrenia (n = 69) and affective (n = 55) spectrum patients at baseline and at one-year follow-up, and compared to healthy controls (HC) (n = 92) with analysis of covariance. Association between change in symptoms and inflammatory markers was analyzed with mixed-effects models. RESULTS: sTNF-R1 was higher in the schizophrenia (P < 0.0001) and affective disorders (P = 0.02) compared to HC, while IL-1Ra was higher in schizophrenia (P = 0.01) compared to HC at one year follow-up. There were no significant differences between schizophrenia and affective groups; however, levels in the affective group were in between schizophrenia and HC for sTNF-R1 and IL-1Ra. There were no significant associations between change in symptoms and inflammatory markers. CONCLUSION: Persistently increased sTNF-R1 and IL-1Ra after one year in patients with severe mental disorders primarily reflecting data from the schizophrenia group may suggest that inflammation is a trait phenomenon, and not only the result of stress-related mechanisms associated with acute episodes.


Assuntos
Transtorno Bipolar/sangue , Transtorno Depressivo Maior/sangue , Inflamação/sangue , Proteína Antagonista do Receptor de Interleucina 1/sangue , Osteoprotegerina/sangue , Transtornos Psicóticos/sangue , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Esquizofrenia/sangue , Fator de von Willebrand/análise , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Clin Immunol ; 181: 43-50, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28578025

RESUMO

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP-MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.


Assuntos
Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Quimiocina CCL11 , Quimiocina CCL2 , Quimiocina CCL4 , Quimiocina CCL5 , Quimiocina CXCL10/sangue , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocina CXCL9/sangue , Quimiocina CXCL9/líquido cefalorraquidiano , Árvores de Decisões , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/líquido cefalorraquidiano , Diagnóstico Precoce , Fator de Crescimento Epidérmico , Fator 2 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/líquido cefalorraquidiano , Fator de Crescimento de Hepatócito , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-7/sangue , Interleucina-7/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Análise Multivariada , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/diagnóstico , Prognóstico , Medição de Risco
18.
Cytokine ; 97: 73-79, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28582647

RESUMO

OBJECTIVE: Langerhans cell histiocytosis (LCH) is characterized by immature dendritic cell proliferation, infiltration of LCH lesions by various inflammatory cells, and a lesional cytokine storm. It is classified into three groups on the basis of disease extent, namely, multisystem with risk-organ involvement (MS+), multisystem without risk-organ involvement (MS-), and single-system (SS) disease. We comprehensively analyzed whether serum levels of cytokines/chemokines reflect the disease extent. METHODS: Serum samples from 52 children with LCH (eight, 25, and 19 with MS+, MS-, and SS, respectively) and 34 control children were analyzed quantitatively for 48 humoral factors. DNA samples extracted from biopsied LCH lesions from 12 patients were tested for BRAF V600E status. RESULTS: The LCH patients had significantly higher serum levels of IL-1Ra, IL-3, IL-6, IL-8, IL-9, IL-10, IL12, IL-13, IL-15, IL-17, IL-18, TNF-α, G-CSF, M-CSF, MIF, HGF, VEGF, CCL2, CCL3, CCL7, CXCL1, and CXCL9 than the controls by univariate analysis. Of these IL-9, IL-15 and MIF were significant by multivariate analysis; but not differed between MS and SS diseases. MS disease associated with significantly higher IL-2R, IL-3, IL-8, IL-18, M-CSF, HGF, CCL2, CXCL1, and CXCL9 levels than SS disease by univariate analysis. Of these, CCL2 and M-CSF were significant by multivariate analysis. IL-18 levels were significantly higher in MS+ disease than MS- disease. The LCH patients with BRAF V600E mutation had higher serum levels of CCL7. CONCLUSION: Numerous inflammatory cytokines and chemokines play a role in LCH. Of those, more specific ones reflect the disease extent (MS vs. SS and MS+ vs. MS-) or the BRAF V600E mutation status. It is thought that the most responsible cytokines and chemokines involved in the poor outcome may become future candidate therapeutic targets in LCH.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Histiocitose de Células de Langerhans/imunologia , Adolescente , Quimiocinas/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Histiocitose de Células de Langerhans/sangue , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-10/sangue , Interleucina-15/sangue , Interleucina-17/sangue , Interleucina-18 , Interleucina-6/sangue , Masculino , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Fator de Necrose Tumoral alfa/sangue
19.
Environ Int ; 105: 1-11, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28478232

RESUMO

BACKGROUND: Exposure to disinfectants and disinfection byproducts (DBPs) due to swimming in chlorinated water has been associated with allergic and respiratory health effects, including asthma. OBJECTIVES: Biological mechanisms contributing to these associations are largely unknown. We hypothesized a potential pathway involving modulation of the immune system. METHODS: We assessed levels of immune markers (CCL11, CCL22, CXCL10, CRP, EGF, GCSF, IL-8, IL-17, IL-1RA, MPO, VEGF, Periostin) in serum collected from 30 women and 29 men before and after 40min of swimming in a chlorinated pool. Exposure to DBPs was assessed by measuring bromodichloromethane, bromoform, chloroform, and dibromochloromethane in exhaled breath before and after swimming. Covariate data including information on physical activity was available through questionnaires and measurements. We assessed the association between indicators of swimming in a chlorinated pool and changes in serum immune marker concentrations using linear regression with bivariate normal distributions and adjusted for multiple comparisons by applying the Benjamini-Hochberg procedure. RESULTS: We observed a significant decrease in serum concentrations of IL-8 (-12.53%; q=2.00e-03), CCL22 (-7.28%; q=4.00e-04), CCL11 (-7.15%; q=9.48e-02), CRP (-7.06%; q=4.68e-05), and CXCL10 (-13.03%; q=6.34e-14) and a significant increase in IL-1RA (20.16%; q=4.18e-06) from before to after swimming. Associations with quantitative measurements of DBPs or physical activity were similar in direction and strength. Most of the observed associations became non-significant when we adjusted the effects of exposure to DBPs for physical activity or vice-versa. CONCLUSIONS: Our study indicates that swimming in a chlorinated pool induces perturbations of the immune response through acute alterations of patterns of cytokine and chemokine secretion. The observed effects could not be uniquely attributed to either exposure to DBPs or physical activity. Evidence in the literature suggests that observed decreases in immune markers are possibly due to an immunosuppressive effect of DBPs, while the increase in IL-1RA might be due to physical activity.


Assuntos
Biomarcadores/sangue , Desinfetantes/toxicidade , Halogenação , Hidrocarbonetos Clorados/toxicidade , Piscinas , Adolescente , Adulto , Testes Respiratórios , Clorofórmio/análise , Desinfecção/métodos , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-17/sangue , Masculino , Natação , Trialometanos/análise , Adulto Jovem
20.
Sci Rep ; 7: 46165, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28383060

RESUMO

Activation of TLR4 by lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Type 4 phosphodiesterases (PDE4) are key cAMP-hydrolyzing enzymes, and PDE4 inhibitors are considered as immunosuppressors to various inflammatory responses. We demonstrate here that PDE4 inhibitors enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-activated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability. Studies with PDE4-deficient macrophages revealed that the IL-1Ra upregulation elicited by LPS alone is PKA-independent, whereas the rolipram-enhanced response was mediated by inhibition of only PDE4B, one of the three PDE4 isoforms expressed in macrophages, and it requires PKA but not Epac activity. However, both pathways activate CREB to induce IL-1Ra expression. PDE4B ablation also promoted STAT3 phosphorylation (Tyr705) to LPS stimulation, but this STAT3 activation is not entirely responsible for the IL-1Ra upregulation in PDE4B-deficient macrophages. In a model of LPS-induced sepsis, only PDE4B-deficient mice displayed an increased circulating IL-1Ra, suggesting a protective role of PDE4B inactivation in vivo. These findings demonstrate that PDE4B negatively modulates anti-inflammatory cytokine expression in innate immune cells, and selectively targeting PDE4B should retain the therapeutic benefits of nonselective PDE4 inhibitors.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/deficiência , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/sangue , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Fosfodiesterase 4/farmacologia , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Rolipram/farmacologia , Fator de Transcrição STAT3/metabolismo , Sepse/sangue , Sepse/patologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
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