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Dengue is a significant health problem due to the high burden of critical infections during outbreaks. In 1997, the World Health Organization (WHO) classified dengue as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). It was revised in 2009 (updated in 2015), and the new guidelines recommended classifying patients as dengue without warning signs (DNS), dengue with warning signs (DWS), and severe dengue (SD). Although the utility of the revised 2009 classification for clinical studies is accepted, for immunological studies it needs to be clarified. We determined the usefulness of the 2009 classification for pediatric studies that analyze the circulating interleukin (IL)-6 and IL-8, two inflammatory cytokines. Plasma levels of IL-6 and IL-8 were evaluated in the acute and convalescent phases by flow cytometry in children with dengue classified using the 1997 and 2009 WHO guidelines. The plasma levels of IL-6 and IL-8 were elevated during the acute and decreased during convalescence, and both cytokines served as a good marker of acute dengue illness compared to convalescence. There were no differences in the plasma level of the evaluated cytokines among children with different clinical severity with any classification, except for the IL-8, which was higher in DWS than DNS. Based on the levels of IL-8, the 2009 classification identified DWS plus SD (hospital-treated children) compared to the DNS group [area under the curve (AUC): 0.7, p = 0.028]. These results support the utility of the revised 2009 (updated in 2015) classification in studies of immune markers in pediatric dengue.
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Dengue , Interleucina-6 , Interleucina-8 , Organização Mundial da Saúde , Humanos , Dengue/imunologia , Dengue/diagnóstico , Criança , Masculino , Feminino , Interleucina-6/sangue , Pré-Escolar , Interleucina-8/sangue , Dengue Grave/diagnóstico , Dengue Grave/imunologia , Dengue Grave/sangue , Adolescente , Índice de Gravidade de Doença , Biomarcadores/sangue , Vírus da Dengue/imunologia , Guias de Prática Clínica como Assunto , Citometria de Fluxo , Lactente , Citocinas/sangueRESUMO
BACKGROUND: Cytokines play an important role in the immunopathogenesis of dental caries. A systematic review and meta-analysis was carried out with the following three objectives: 1)To deepen and discuss through a comprehensive analysis of the literature the effects of dental caries on the activity and levels of TNF-α, IL-6 and IL-8 in saliva of children and young adults, 2)To compare the levels of this cytokines in saliva of the exposure group (moderate-severe dental caries) with the control group (caries-free or mild dental caries), and 3)To determine whether the levels of these cytokines could be used as a complementary clinical diagnostic tool to assess the severity of dental caries. METHODS: The protocol followed PRISMA and Cochrane guidelines and was registered in the Open Science Framework (OSF): https://doi.org/10.17605/OSF.IO/MF74V . A digital search was performed in PubMed/MEDLINE, Cochrane, Scopus, and Google Schoolar databases from February 15th, 2012, to January 13th, 2024. The methodological validity of the selected studies was assessed using Joanna Briggs Institute (JBI) tool. A meta-analysis was performed using a random-effects model to evaluate the association between dental caries/health, and the concentration of TNF-α, IL-6 and IL-8. RESULTS: The search strategy provided a total of 126 articles, of which 15 investigations met the inclusion criteria. The total number of patients studied was 1,148, of which 743 represented the case/exposure group, and 405 represented the control group. The age of the patients ranged from 3 to 25 years. IL-6 was the most prevalent cytokine in the saliva of children and young adults with active dental caries. The meta-analysis revealed that there are significant differences between the levels of IL-6 and TNF-α in saliva of children with active dental caries compared to their control groups. CONCLUSIONS: The findings suggest that IL-6 and TNF-α levels may have potential as complementary biomarkers for assessing dental caries severity. However, further research is needed to validate these findings in larger and more diverse populations before clinical application.
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Cárie Dentária , Interleucina-6 , Interleucina-8 , Saliva , Fator de Necrose Tumoral alfa , Humanos , Cárie Dentária/metabolismo , Saliva/química , Saliva/metabolismo , Interleucina-6/análise , Interleucina-6/metabolismo , Interleucina-8/análise , Interleucina-8/metabolismo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismo , Criança , Adulto Jovem , Adolescente , Biomarcadores/análiseRESUMO
Senescent cells produce a Senescence-Associated Secretory Phenotype (SASP) that involves factors with diverse and sometimes contradictory activities. One key SASP factor, interleukin-6 (IL-6), has the potential to amplify cellular senescence in the SASP-producing cells in an autocrine action, while simultaneously inducing proliferation in the neighboring cells. The underlying mechanisms for the contrasting actions remain unclear. We found that the senescence action does not involve IL-6 secretion nor the interaction with the receptor expressed in the membrane but is amplified through an intracrine mechanism. IL-6 sustains intracrine senescence interacting with the intracellular IL-6 receptor located in anterograde traffic specialized structures, with cytosolic DNA, cGAS-STING, and NFκB activation. This pathway triggered by intracellular IL-6 significantly contributes to cell-autonomous induction of senescence and impacts in tumor growth control. Inactivation of IL-6 in somatotrophic senescent cells transforms them into strongly tumorigenic in NOD/SCID mice, while re-expression of IL-6 restores senescence control of tumor growth. The intracrine senescent IL-6 pathway is further evidenced in three human cellular models of therapy-induced senescence. The compartmentalization of the intracellular signaling, in contrast to the paracrine tumorigenic action, provides a pathway for IL-6 to sustain cell-autonomous senescent cells, driving the SASP, and opens new avenues for clinical consideration to senescence-based therapies.
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Interleukin-6 (IL-6) is a versatile cytokine crucial for immune response modulation, inflammation regulation, and various physiological processes in the body. Its wide-ranging functions underscore its importance in maintaining health. Dysregulated IL-6 is closely associated with many diseases, making it a key research and therapeutic target. Elevated IL-6 levels in the central nervous system worsen neuroinflammation in neurodegenerative diseases by activating microglia and astrocytes and releasing pro-inflammatory cytokines and neurotoxic molecules. Moreover, dysregulated IL-6 weakens the blood-brain barrier, exacerbating neuroinflammation and neuronal damage by allowing peripheral immune cells and inflammatory mediators to enter the brain. Mesenchymal stem cells (MSCs) show promise in modulating neuroinflammation by regulating IL-6 levels. They effectively suppress pro-inflammatory cytokines, including IL-6, while promoting anti-inflammatory factors. This therapeutic approach highlights the importance of targeting IL-6 and other inflammatory mediators to alleviate neuroinflammation and its adverse effects on neurological disorders. This review provides a comprehensive overview of IL-6's involvement in neurological disorders, examining endogenous IL-6 and IL-6 derived from MSCs. We explore IL-6's mechanisms affecting neuronal function, survival, and immune modulation in the central nervous system. Additionally, we discuss the potential of MSC-derived IL-6 in neuroregeneration and neuroprotection. By elucidating IL-6's interplay with neurological pathologies, this review offers insights into novel therapeutic strategies targeting IL-6 signaling pathways for neurological disorders.
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Interleucina-6 , Células-Tronco Mesenquimais , Animais , Humanos , Interleucina-6/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Doenças do Sistema Nervoso/terapia , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/metabolismo , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/terapia , Transdução de SinaisRESUMO
Background: Resistance to thyroid hormone beta (RTHß) is a rare disease resulting from mutations in the THRB gene, characterized by reduced T3 action in tissues with high thyroid hormone receptor ß expression. Thyroid hormones regulate body composition and metabolism in general, and increased or decreased hormone levels are associated with insulin resistance. This study evaluated the presence of cardiometabolic risk factors and insulin sensitivity in patients with RTHß. Methods: In all, 16 patients, 8 adults (52.3 ± 16.3 years of age) and 8 children (10.9 ± 3.9 years of age), were compared to 28 control individuals matched for age, sex, and body mass index (BMI). Anthropometry evaluation and blood samples were collected for glycemia, lipids, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, adiponectin, ultrasensitive C-reactive protein (CRPus), free thyroxine, total triiodothyronine, thyrotropin, and anti-thyroid peroxidase measurements. Body composition was assessed using dual-emission X-ray absorptiometry and bioimpedance. Insulin sensitivity was evaluated in adult patients and controls using the hyperinsulinemic-euglycemic clamp (HEC), whereas homeostasis model assessment of insulin resistance (HOMA-IR) was calculated in all individuals studied. Results: Patients and controls presented similar weight, BMI, abdominal perimeter, and total fat body mass. Patients with RTHß demonstrated higher total cholesterol (TC), p = 0.04, and low-density lipoprotein cholesterol (LDL-C), p = 0.03, but no alteration was observed in other parameters associated with metabolic risk, such as leptin, TNF-α, and CRPus. Two adult patients met the criteria for metabolic syndrome. There was no evidence of insulin resistance assessed by HEC or HOMA-IR. Elevated IL-6 levels were observed in patients with RTHß. Conclusion: Using HEC as the gold standard method, no evidence of reduced insulin sensitivity in skeletal muscle was documented in RTHß adult patients; however, higher levels of TC and LDL-C were observed in these patients, which suggest the need for active monitoring of this abnormality to minimize cardiometabolic risk. In addition, we demonstrated, for the first time, that the increase in IL-6 levels in patients with RTHß is probably secondary to metabolic causes as they have normal levels of TNF-α and CRPus, which may contribute to an increase in cardiovascular risk. A larger number of patients must be studied to confirm these results.
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Fatores de Risco Cardiometabólico , Técnica Clamp de Glucose , Resistência à Insulina , Síndrome da Resistência aos Hormônios Tireóideos , Humanos , Masculino , Feminino , Adulto , Síndrome da Resistência aos Hormônios Tireóideos/sangue , Síndrome da Resistência aos Hormônios Tireóideos/complicações , Pessoa de Meia-Idade , Criança , Idoso , Adolescente , Composição Corporal , Estudos de Casos e Controles , Insulina/sangue , Glicemia/metabolismo , Glicemia/análise , Fatores de RiscoRESUMO
OBJECTIVE: This study evaluated the methodological quality of published systematic reviews on randomized and non-randomized clinical trials to synthesize evidence on the association between IL-6, immunosenescence, and aerobic and/or resistance exercise. METHOD: The Preferred Reporting Items for Overviews of Systematic Reviews (PRIO-harms) guideline was used, with registration number CRD42022346142-PROSPERO. Relevant databases such as Cochrane Library, PubMed, Web of Science, Scopus, and Google Scholar were searched using English Medical Subject Headings terms. Inclusion criteria were systematic reviews analyzing aerobic exercise, resistance exercise, or a combination of both and assessing IL-6 as a biomarker of cellular immunosenescence in humans. The Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) was employed. RESULTS: Out of 742 identified articles, 18 were eligible, and 13 were selected for analysis. Sample sizes ranged from 249 to 1421 participants, mostly female, with ages ranging from 17 to 95 years. Aerobic exercise was the most studied type (46.15%), followed by combined exercise (38.46%) and resistance exercise (15.38%). Aerobic exercise showed a statistically significant reduction in IL-6, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) levels. Among the 13 reviews analyzed using AMSTAR-2, 8 were rated as critically low quality, and 5 were classified as low quality. CONCLUSION: Aerobic exercise has anti-inflammatory properties and the potential to modulate IL-6, CRP, and TNF-α levels in immunosenescence. However, the limited methodological quality of the analyzed systematic reviews highlights the urgent need for robust, high-quality studies to improve access to information and facilitate evidence-based decision-making in healthcare.
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Severe acute respiratory syndrome coronavirus 2 has caused a global pandemic, leading to health, economic, and political crisis. The virus triggers the activation of inflammatory reactants including interleukin-6 (IL-6), ferritin, and C-reactive protein (CRP), causing multiorgan damage, particularly affecting the lungs. Tocilizumab, an IL-6 receptor blocker, has the potential to diminish the progression of the disease and reduce organ damage and long-term complications. The aim of this observational retrospective cohort study was to evaluate the efficacy of tocilizumab in decreasing CRP levels in hospitalized coronavirus disease 2019 (COVID-19) patients compared to standard care without the drug. The study included 141 patients during their Hospital Stay (HS), with 100 in the Tocilizumab group and 41 in the non-Tocilizumab group. Clinical information was collected from the electronic clinical record, analyzed using statistical software, and homogenized the CRP levels from the severe group to the levels of the less complicated group at 48 h of hospitalization. The results showed a statistically significant greater decrease in CRP levels in the Tocilizumab group at 48 h after the use of the treatment, with no differences in mortality or length of stay between the groups. In conclusion, tocilizumab accelerates the diminishing of CRP levels compared to standard treatment alone, and its use may have potential benefits in the management of severe COVID-19 patients when used alongside with follow-up quantification of CRP levels reduction.IMPORTANCESevere acute respiratory syndrome coronavirus 2 has caused a global pandemic, leading to health, economic, and political crises. International guidelines for managing coronavirus disease 2019 (COVID-19) give recommendations according to the severity of the disease and the level of oxygen therapy needed. Tocilizumab is an option for the therapeutic management of hospitalized patients with any level of oxygen therapy; IL-6 serum level is the parameter for the follow-up on the efficacy, but it is not available at many hospitals. In this study, we demonstrate that C-reactive protein determination can predict the response to tocilizumab in severe COVID-19, the target patients for treatment with this drug. The use of this affordable and extensively available biomarker supports clinical decisions for the early escalation of the therapy and for the rational use of this drug on those prone to improve with the use of it.
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Anticorpos Monoclonais Humanizados , Proteína C-Reativa , Tratamento Farmacológico da COVID-19 , COVID-19 , Hospitalização , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , COVID-19/mortalidade , COVID-19/sangue , Interleucina-6/sangue , Estudos Retrospectivos , SARS-CoV-2/efeitos dos fármacosRESUMO
Abstract Objectives: This paper aims to review data on the association of obesity and iron deficiency in children and adolescents, exposing the possible involvement of hepcidin and interleukin-6 (IL-6), obesity's inflammation biomarkers. Data source: Articles from PUBMED and WEB OF SCIENCE database with no chronological limit were reviewed to write this systematic review. Keywords such as children, obesity, iron deficiency, and hepcidin were used. After deleting duplicated and review articles, 91 were screened, and 39 were selected as eligible. Sixteen articles were included because they involved serum hepcidin levels in obese children and adolescents as outcomes. Summary of findings: Finally, those 16 articles were organized in two tables: one includes therapeutic interventions, and the other does not. As hepcidin was discovered in 2000, the first articles that presented serum hepcidin's quantification in obese children and adolescents, homeostasis iron markers, and their possible association with obesity's inflammatory environment began to be published in 2008. Conclusions: Obesity's chronic inflammation state leads to the production of IL-6, which acts as a signaling molecule for hepcidin synthesis, resulting in iron deficiency, which is common in obese children and adolescents who respond inadequately to iron supplementation. On the other hand, that population responds adequately to therapeutic intervention programs that lead to weight loss, guaranteeing iron homeostasis improvement. Therefore, perhaps it is time to discuss serum hepcidin level quantification as part of evaluating children and adolescents with iron deficiency, which could guide clinical choices that might lead to better therapeutic outcomes.
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Introduction: Studies in cholesterol-fed rabbits showed that anti-proliferative chemotherapeutic agents such as paclitaxel associated with solid lipid nanoparticles (LDE) have marked anti-atherosclerotic effects. In addition, association with LDE nearly abolishes paclitaxel toxicity. We investigated whether treatment with LDE-paclitaxel changes plaque progression by coronary CT angiography and is safe in patients with chronic coronary artery disease. Methods: We conducted a prospective, randomized, double-blind, placebo-controlled pilot study in patients with multi-vessel chronic coronary artery disease. Patients were randomized to receive IV infusions of LDE-paclitaxel (paclitaxel dose: 175â mg/m2 body surface) or LDE alone (placebo group), administered every 3 weeks for 18 weeks. All participants received guideline-directed medical therapy. Clinical and laboratory safety evaluations were made at baseline and every 3 weeks until the end of the study. Analysis of inflammatory biomarkers and coronary CTA was also performed at baseline and 4 weeks after treatment. Results: Forty patients aged 65.6 ± 8 years, 20 in LDE-paclitaxel and 20 in placebo group were enrolled. Among those, 58% had diabetes, 50% had myocardial infarction, and 91% were in use of statin and aspirin. Baseline demographics, risk factors, and laboratory results were not different between groups. In all patients, no clinical or laboratory toxicities were observed. From the baseline to the end of follow-up, there was a non-significant trend toward a decrease in IL-6 levels and hsCRP in the LDE-paclitaxel group (-16% and -28%, respectively), not observed in placebo. Regarding plaque progression analysis, variation in plaque parameter values was wide, and no difference between groups was observed. Conclusion: In patients with multivessel chronic coronary artery disease and optimized medical therapy, LDE-paclitaxel was safe and showed clues of potential benefits in reducing inflammatory biomarkers. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT04148833, identifier (NCT04148833).
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Although perianal Crohn's disease (PCD) is highly associated with the exacerbated inflammation, the molecular basis and immunological signature that distinguish patients who present a history of perianal lesions are still unclear. This paper aims to define immunological characteristics related to PCD. In this cross-sectional observational study, we enrolled 20 healthy controls and 39 CD patients. Blood samples were obtained for the detection of plasma cytokines and lipopolysaccharides (LPS). Peripheral blood mononuclear cells (PBMCs) were phenotyped by flow cytometry. Leukocytes were stimulated with LPS or anti-CD3/anti-CD28 antibodies. Our results show that CD patients had augmented plasma interleukin (IL)-6 and LPS. However, their PBMC was characterized by decreased IL-6 production, while patients with a history of PCD produced higher IL-6, IL-8, and interferon-γ, along with decreased tumor necrosis factor alpha (TNF). CD patients had augmented FoxP3 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulatory markers, though the PCD subjects presented a significant reduction in CTLA-4 expression. CTLA-4 as well as IL-6 and TNF responses were able to distinguish the PCD patients from those who did not present perianal complications. In conclusion, IL-6, TNF, and CTLA-4 exhibit a distinct expression pattern in CD patients with a history of PCD, regardless of disease activity. These findings clarify some mechanisms involved in the development of the perianal manifestations and may have a great impact on the disease management.