Immune-mediated impairment of tonic immobility defensive behavior in an experimental model of colonic inflammation.

Ulcerative colitis has been associated with psychological distress and an aberrant immune response. The immunomodulatory role of systemic cytokines produced during experimental intestinal inflammation in tonic immobility (TI) defensive behavior remains unknown. The present study characterized the TI defensive behavior of guinea pigs subjected to colitis induction at the acute stage and after recovery from intestinal mucosa injury. Moreover, we investigated whether inflammatory mediators (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-8, IL-10, and prostaglandins) act on the mesencephalic nucleus, periaqueductal gray matter (PAG). Colitis was induced in guinea pigs by intrarectal administration of acetic acid. The TI defensive behavior, histology, cytokine production, and expression of c-FOS, IBA-1, and cyclooxygenase (COX)-2 in PAG were evaluated. Colitis reduced the duration of TI episodes from the first day, persisting throughout the 7-day experimental period. Neuronal c-FOS immunoreactivity was augmented in both columns of the PAG (ventrolateral (vlPAG) and dorsal), but there were no changes in IBA-1 expression. Dexamethasone, infliximab, and parecoxib treatments increased the duration of TI episodes, suggesting a modulatory role of peripheral inflammatory mediators in this behavior. Immunoneutralization of TNF-α, IL-1ß, and IL-8 in the vlPAG reversed all effects produced by colitis. In contrast, IL-10 neutralization further reduced the duration of TI episodes. Our results reveal that peripherally produced inflammatory mediators during colitis may modulate neuronal functioning in mesencephalic structures such as vlPAG.

Activity and levels of TNF-α, IL-6 and IL-8 in saliva of children and young adults with dental caries: a systematic review and meta-analysis.

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.

Diagnostic accuracy of interleukin-6, interleukin-10 and tumor necrosis factor alpha cytokine levels in patients with mild cognitive impairment: systematic review and meta-analysis.

There is growing evidence suggesting an association between neurodegeneration and inflammation playing a role in the pathogenesis of age-associated diseases, including Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). Objective: A systematic review and meta-analysis were performed to verify evidence on the diagnostic accuracy parameters of the inflammatory cytokines interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α). Methods: A search of Medical Literature Analysis and Retrieval System Online (Medline), Scientific Electronic Library Online (SciELO), Web of Science and Science Direct databases was performed and nine observational studies associated with peripheral inflammatory biomarkers in MCI were identified. Mean (±standard deviation - SD) concentrations of these biomarkers and values of true positives, true negatives, false positives and false negatives for MCI and healthy controls (HC) were extracted from these studies. Results: Significantly higher levels of IL-10 were observed in subjects in the MCI group and Mini-Mental State Examination (MMSE) scores were lower compared to HC. For the other investigations, no differences were found between the groups. Our meta-analysis for the TNF-α biomarker revealed high heterogeneity between studies in terms of sensitivity and specificity. Conclusion: These findings do not support the involvement of inflammatory biomarkers for detection of MCI, although significant heterogeneity was observed. More studies are needed to evaluate the role of these cytokines in MCI, as well as in other stages of cognitive decline and all-cause dementias.

Há evidências crescentes que sugerem uma associação entre a neurodegeneração e a inflamação, desempenhando um papel na patogênese de doenças associadas à idade, incluindo a doença de Alzheimer (DA) e o comprometimento cognitivo leve (CCL). Objetivo: Uma revisão sistemática e metanálise foram realizadas para verificar evidências relativas aos parâmetros de acurácia diagnóstica das citocinas inflamatórias interleucina-6 (IL-6), interleucina-10 (IL-10) e fator de necrose tumoral (TNF-α). Métodos: Foi realizada uma busca nas bases de dados Medical Literature Analysis and Retrieval System Online (Medline), Scientific Electronic Library Online (SciELO), Web of Science e Science Direct, e foram identificados nove estudos observacionais associados a biomarcadores inflamatórios periféricos no CCL. As concentrações médias (desvio padrão ­ ±DP) desses biomarcadores e valores de verdadeiros positivos, verdadeiros negativos, falsos positivos e falsos negativos para CCL e controles saudáveis (CS) foram extraídos desses estudos. Resultados: Níveis significativamente mais elevados de IL-10 foram observados em indivíduos do grupo CCL e os escores do Miniexame do Estado Mental foram mais baixos em comparação com o CS. Para as demais investigações não foram encontradas diferenças entre os grupos. Nossa metanálise para o biomarcador TNF-α revelou alta heterogeneidade entre os estudos em termos de sensibilidade e especificidade. Conclusão: Esses achados não apoiam o envolvimento de biomarcadores inflamatórios na detecção do CCL, embora tenha sido observada heterogeneidade significativa. Mais estudos são necessários para avaliar o papel dessas citocinas no CCL, bem como em outros estágios de declínio cognitivo e demências de todas as causas.

The rs11684747 and rs55790676 SNPs of ADAM17 influence tuberculosis susceptibility and plasma levels of TNF, TNFR1, and TNFR2.

Introduction: The proteolytic activity of A Disintegrin and Metalloproteinase 17 (ADAM17) regulates the release of tumor necrosis factor (TNF) and TNF receptors (TNFRs) from cell surfaces. These molecules play important roles in tuberculosis (TB) shaping innate immune reactions and granuloma formation. Methods: Here, we investigated whether single nucleotide polymorphisms (SNPs) of ADAM17 influence TNF and TNFRs levels in 224 patients with active TB (ATB) and 118 healthy close contacts. Also, we looked for significant associations between SNPs of ADAM17 and ATB status. TNF, TNFR1, and TNFR2 levels were measured in plasma samples by ELISA. Four SNPs of ADAM17 (rs12692386, rs1524668, rs11684747, and rs55790676) were analyzed in DNA isolated from peripheral blood leucocytes. The association between ATB status, genotype, and cytokines was analyzed by multiple regression models. Results: Our results showed a higher frequency of rs11684747 and rs55790676 in close contacts than ATB patients. Coincidentally, heterozygous to these SNPs of ADAM17 showed higher plasma levels of TNF compared to homozygous to their respective ancestral alleles. Strikingly, the levels of TNF and TNFRs distinguished participant groups, with ATB patients displaying lower TNF and higher TNFR1/TNFR2 levels compared to their close contacts. Conclusion: These findings suggest a role for SNPs of ADAM17 in genetic susceptibility to ATB.

Soluble levels of 4-1BB (CD137) and OX40 (CD134) are associated with cancer progression in gastric adenocarcinoma.

BACKGROUND AND OBJECTIVES: Previous studies have demonstrated that soluble forms of T-cell costimulatory molecules 4-1BB (s4-1BB) and OX40 (sOX40) interact with immune cells and may constitute a mechanism of immune evasion by tumors in various cancers. The role of the soluble forms of 4-1BB and OX40 in GC remains unclear. We aimed to examine the association between serum levels of s4-1BB and sOX40 and tumor progression in patients with GC. METHODS: Between 2017 and 2018, a cross-sectional study was performed with serum samples of 83 GC patients and 20 healthy controls. RESULTS: Patients with stage IV metastatic gastric cancer had significantly higher levels of soluble OX40 in comparison with stage III patients with lymph nodes metastasis (p = 0.0003) and stages I and II patients (p = 0.005), whereas the opposite was found for soluble 4-1BB levels, with lower levels being found in advanced stage III (p = 0.003) compared with initial stages I/II. CONCLUSIONS: The sOX40 and s4-1BB-mediated T cell interactions may be involved in antitumor immune responses in GC, possibly favoring tumor escape and progression. Serum levels of sOX40 and s4-1BB are associated with staging in GC and may constitute biomarkers for prognosis, as well as potential targets for immunotherapy.

Exploring novel protein biomarkers for early-stage diagnosis and prognosis of T-acute lymphoblastic leukemia (T-ALL).

BACKGROUND: Efficient classification of T-acute lymphoblastic leukemia (T-ALL) involves considering various factors, such as age, white blood cell count, and chromosomal alterations. However, studying protein markers are crucial to improving T-ALL patients' diagnosis and treatment. A study analyzing the expression of proteomes was conducted to identify promising early-stage biomarkers for T-ALL patients METHODS: Label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the blood proteins of both patients and healthy individuals to identify new biomarkers for T-ALL. The findings were validated by RT-PCR, ELISA and computational analysis RESULTS: The study identified 1467 proteins in the blood, of which nine were upregulated and 35 were downregulated by more than 2-fold. T-ALL patients showed a significant increase in specific disease-related proteins, such as eleven-nineteen lysine-rich leukemia protein, triggering receptor expressed on myeloid cells 1, cisplatin resistance-associated-overexpressed protein, X-ray radiation resistance-associated protein 1, tumor necrosis factor receptor superfamily member 10D, protein S100-A8, and copine-4, by more than 3-fold CONCLUSION: The findings of this study provide a valuable protein map of leukemic cells and identify potential biomarkers for leukemic aggressiveness. However, further studies using larger T-ALL patient samples must confirm these preliminary results.

Association of COX-2, TNF-α, TLR4, and IKKα With Survival of Patients With Oral Squamous Cell Carcinomas: A Systematic Review.

BACKGROUND: This review investigated the association of COX-2, TNF-α, TLR4, and IKKα with the survival of patients with oral squamous cell carcinoma (SCC). METHODS: A systematic search was conducted in the databases PUBMED, Web of Science, LILACS, EMBASE, Scopus, and Cochrane Library. The studies should assess the expression of those proteins in the tumor and survival outcomes. RESULTS: Twenty-one articles were included. The meta-analysis results leaned towards an association of COX-2 overexpression with a lower overall survival. The estimated hazard ratio was 1.51 (95% CI 0.97, 2.33), but not statistically significant (p=0.07). A low heterogeneity was observed (I2=0%). Regarding TNF-α, TLR4, and IKKα, statistically significant results for the association with survival were presented, but there was not enough data to a meta-analysis. CONCLUSION: COX-2 overexpression may be associated with a poorer prognosis in oral SCC. The insufficiency of studies about TNF-α, TLR4, and IKKα restrained their validation as predictors of prognosis.

Effects of intra-articular injection of platelet-rich plasma on the inflammatory process and histopathological characteristics of cartilage and synovium in animals with osteoarthritis: a systematic review with meta-analysis.

BACKGROUND: Osteoarthritis (OA) affects the entire joint, causing structural changes in articular cartilage, subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles that afflicts millions of people globally, leading to persistent pain and diminished quality of life. The intra-articular use of platelet-rich plasma (PRP) is gaining recognition as a secure therapeutic approach due to its potential regenerative capabilities. However, there is controversial clinical data regarding efficacy of PRP for OA treatment. In this context, gathering scientific evidence on the effects of PRP in treating OA in animal models could provide valuable insights into understanding its impact on aspects like cartilage health, synovial tissue integrity, and the inflammatory process in affected joints. Thus, the objective of this study was to assess the effects of PRP injections on inflammation and histopathological aspects of cartilage and synovium in animal models of OA through a comprehensive systematic review with meta-analysis. METHODS: A electronic search was conducted on Medline, Embase, Web of Science, The Cochrane Library, LILACS, and SciELO databases for relevant articles published until June 2022. A random-effects meta-analysis was employed to synthesize evidence on the histological characteristics of cartilage and synovium, as well as the inflammatory process. The GRADE approach was utilized to categorize the quality of evidence, and methodological quality was assessed using SYRCLE's RoB tool. RESULTS: Twenty-one studies were included in the review, with twelve of them incorporated into the meta-analysis. PRP treatment demonstrated superior outcomes compared to the control group in terms of cartilage histology (very low quality; p = 0.0002), synovium histology (very low quality; p < 0.0001), and reductions in proinflammatory markers, including IL-1 (low quality; p = 0.002), IL-6 (very low quality; p < 0.00001), and TNF-α (very low; p < 0.00001). However, PRP treatment did not yield a significant impact on PDGF-A levels (very low quality; p = 0.81). CONCLUSION: PRP appears capable of reducing proinflammatory markers (IL-1, IL-6, TNF-α) and mitigating cartilage and synovium damage in animals with OA. However, the levels of evidence of these findings are low to very low. Therefore, more rigorous studies with larger samples are needed to improve the quality of evidence. PROSPERO REGISTRATION: CRD42022250314.

Relación entre el polimorfismo g-238a del factor de necrosis tumoral alfa y la pérdida gestacional recurrente / Relation of polymorphism g-238a of tumor necrosis factor alpha with recurrent pregnancy loss

Resumen OBJETIVO: Determinar si existe asociación entre los polimorfismos G-308A (rs1800629) y G-238A (rs361525) del promotor del factor de necrosis tumoral alfa y la pérdida gestacional recurrente. MATERIALES Y MÉTODOS: Estudio observacional, transversal, descriptivo de casos y controles llevado a cabo entre enero de 2020 y diciembre de 2021 en el Hospital de la Mujer de Aguascalientes y en el Laboratorio de Virología e Ingeniería Genética de la Universidad Autónoma de Aguascalientes. Se estudiaron pacientes con pérdidas gestacionales recurrentes y sin éstas, con embarazo normal (controles). RESULTADOS: Se estudiaron 300 pacientes: 150 con pérdida gestacional recurrente y 150 con embarazo normal (controles). Se encontraron 19 pacientes (12.6%) con pérdida gestacional recurrente primaria y 131 (87.4%) con pérdida gestacional recurrente secundaria. Las pacientes con pérdida gestacional recurrente tuvieron, significativamente, mayor edad (28 ± 6.43 en comparación con 26 ± 6.07 años; p = 0.006), más abortos (mediana de 2 en comparación con 0; p = 0.049) y menos semanas de gestación (13.18 ± 12.51 en compoaración con 34.55 ± 10.99; p = 0.0001) que las pacientes del grupo control. De los diferentes modelos genéticos, ninguno demostró un incremento significativo de riesgo para G-308A (rs1800629); sin embargo, para G-238A (rs361525) los modelos heterocigoto (RM 4.36, IC95%: 1.2-15.78; p = 0.012) y dominante (RM 4.36, IC95%: 1.42-13.36; p = 0.005) sí mostraron un aumento de probabilidad. En el análisis multivariado ninguna variable clínica demostró significación estadística. CONCLUSIÓN: En el grupo estudiado, el polimorfismo G-238 A (rs361525) del gen TNF-α mostró asociación con la pérdida gestacional recurrente, no así el polimorfismo G-308A (rs1800629).

Abstract OBJECTIVE: To determine if there is an association between polymorphisms G-308A (rs1800629) and G-238A (rs361525) of the tumor necrosis factor alpha (TNF-α) with the presence of recurrent pregnancy loss in patients treated at the Women's Hospital of the City of Aguascalientes. MATERIALS AND METHODS: An observational, case-control study was conducted in 150 patients with recurrent pregnancy loss and 150 patients with normal pregnancies. Different clinical variables were studied and the polymorphisms of the TNF-α tumor gene, G-308A (rs1800629) and G-238A (rs361525). Were genotyped by restriction fragment length polymorphism (RFLP) reaction and the prevalences of the genotypes between both groups was compared, as well as the Odds ratios (OR) of the genotypes and mutated alleles using various genetic models. Multivariate analysis was performed to determine the effect of clinical variables and the presence of these polymorphisms. RESULTS: Patients with recurrent pregnancy loss were significantly older, had more miscarriages and a lower gestational age than those in the control group. For the G-308A (rs1800629) polymorphism, no significant difference was observed in the prevalences between both groups. For G-238A (rs361525) the prevalence was 6.7% for patients and 1.7% for women with normal pregnancies, with a statistically significant difference (p = 0.004). None of the different genetic models showed a significant increase for G-308A (rs1800629), however, for G-238A (rs361525) the heterozygous (OR 4.36, 95%IC: 1.2-15.78; p=0.012) and dominant (OR 4.36, 95%IC: 1.42-13.36, p=0.005) models did show an increase in said probability. In the multivariate analysis, no clinical variable showed statistical significance. CONCLUSION: The G-238A (rs361525) polymorphism of the tumor necrosis factor alpha gene shows an association, and a higher risk of recurrent pregnancy loss in our population.

TNF-α promoter hypomethylation is frequent in oncopediatric patients who recovered from mucositis

Abstract The aim of this study was to investigate the DNA methylation profile in genes encoding catalase (CAT) and superoxide dismutase (SOD3) enzymes, which are involved in oxidative stress mechanisms, and in genes encoding pro-inflammatory cytokines interleukin-6 (IL6) and tumor necrosis factor-alpha (TNF-α) in the oral mucosa of oncopediatric patients treated with methotrexate (MTX®). This was a cross-sectional observational study and the population comprised healthy dental patients (n = 21) and those with hematological malignancies (n = 64) aged between 5 and 19 years. Oral conditions were evaluated using the Oral Assessment Guide and participants were divided into 4 groups: 1- healthy individuals; 2- oncopediatric patients without mucositis; 3- oncopediatric patients with mucositis; 4- oncopediatric patients who had recovered from mucositis. Methylation of DNA from oral mucosal cells was evaluated using the Methylation-Specific PCR technique (MSP). For CAT, the partially methylated profile was the most frequent and for SOD3 and IL6, the hypermethylated profile was the most frequent, with no differences between groups. For TNF-α, the hypomethylated profile was more frequent in the group of patients who had recovered from mucositis. It was concluded that the methylation profiles of CAT, SOD3, and IL6 are common profiles for oral cells of children and adolescents and have no association with oral mucositis or exposure to chemotherapy with MTX®. Hypomethylation of TNF-α is associated with oral mucosal recovery in oncopediatric patients who developed oral mucositis during chemotherapy.

Diagnostic accuracy of interleukin-6, interleukin-10 and tumor necrosis factor alpha cytokine levels in patients with mild cognitive impairment: systematic review and meta-analysis / Precisão diagnóstica dos níveis das citocinas IL-6, IL-10 e TNF-α em pacientes com comprometimento cognitivo leve: revisão sistemática e metanálise

ABSTRACT There is growing evidence suggesting an association between neurodegeneration and inflammation playing a role in the pathogenesis of age-associated diseases, including Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). Objective: A systematic review and meta-analysis were performed to verify evidence on the diagnostic accuracy parameters of the inflammatory cytokines interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α). Methods: A search of Medical Literature Analysis and Retrieval System Online (Medline), Scientific Electronic Library Online (SciELO), Web of Science and Science Direct databases was performed and nine observational studies associated with peripheral inflammatory biomarkers in MCI were identified. Mean (±standard deviation — SD) concentrations of these biomarkers and values of true positives, true negatives, false positives and false negatives for MCI and healthy controls (HC) were extracted from these studies. Results: Significantly higher levels of IL-10 were observed in subjects in the MCI group and Mini-Mental State Examination (MMSE) scores were lower compared to HC. For the other investigations, no differences were found between the groups. Our meta-analysis for the TNF-α biomarker revealed high heterogeneity between studies in terms of sensitivity and specificity. Conclusion: These findings do not support the involvement of inflammatory biomarkers for detection of MCI, although significant heterogeneity was observed. More studies are needed to evaluate the role of these cytokines in MCI, as well as in other stages of cognitive decline and all-cause dementias.

RESUMO Há evidências crescentes que sugerem uma associação entre a neurodegeneração e a inflamação, desempenhando um papel na patogênese de doenças associadas à idade, incluindo a doença de Alzheimer (DA) e o comprometimento cognitivo leve (CCL). Objetivo: Uma revisão sistemática e metanálise foram realizadas para verificar evidências relativas aos parâmetros de acurácia diagnóstica das citocinas inflamatórias interleucina-6 (IL-6), interleucina-10 (IL-10) e fator de necrose tumoral (TNF-α). Métodos: Foi realizada uma busca nas bases de dados Medical Literature Analysis and Retrieval System Online (Medline), Scientific Electronic Library Online (SciELO), Web of Science e Science Direct, e foram identificados nove estudos observacionais associados a biomarcadores inflamatórios periféricos no CCL. As concentrações médias (desvio padrão — ±DP) desses biomarcadores e valores de verdadeiros positivos, verdadeiros negativos, falsos positivos e falsos negativos para CCL e controles saudáveis (CS) foram extraídos desses estudos. Resultados: Níveis significativamente mais elevados de IL-10 foram observados em indivíduos do grupo CCL e os escores do Miniexame do Estado Mental foram mais baixos em comparação com o CS. Para as demais investigações não foram encontradas diferenças entre os grupos. Nossa metanálise para o biomarcador TNF-α revelou alta heterogeneidade entre os estudos em termos de sensibilidade e especificidade. Conclusão: Esses achados não apoiam o envolvimento de biomarcadores inflamatórios na detecção do CCL, embora tenha sido observada heterogeneidade significativa. Mais estudos são necessários para avaliar o papel dessas citocinas no CCL, bem como em outros estágios de declínio cognitivo e demências de todas as causas.

Hepatitis B reactivation risk and physician awareness in rheumatological patients receiving anti-tumor necrosis factor-α treatment

SUMMARY OBJECTIVE: We aimed to evaluate the risk of hepatitis B virus reactivation in rheumatic patients using anti-tumor necrosis factor-alpha drugs and the awareness of physicians about hepatitis B virus reactivation. METHODS: Demographic characteristics, pre- and post-treatment hepatitis markers, and laboratory parameters of patients receiving anti-tumor necrosis factor-alpha therapy in our rheumatology clinic were retrospectively examined. RESULTS: A total of 448 patients, 240 (53.6%) female and 208 (46.4%) male, were evaluated. Their mean age was 48.02±14.64 years. While HBsAg was examined in 443 (98.9%) patients before treatment, 7 (1.6%) patients were found to be HBsAg positive. While anti-HBc IgG was examined in 405 (90.4%) patients, it was positive in 69 (17%) patients. HBs Ag (total 446-99.6%) test was performed in three patients who were not tested for HBsAg before the treatment, and anti-HBc total (431-96.2% total) test was performed in 26 patients who were not tested for anti-HBc total. All HBsAg positive patients and 17 (24.6%) of those with previous hepatitis B received antiviral treatment. While the median follow-up period of the patients was 24 (6-60) months, no patient developed hepatitis B virus reactivation. CONCLUSION: The screening rates and awareness of physicians providing anti-tumor necrosis factor-alpha therapy for hepatitis B virus infection were found to be higher compared to similar studies. Hepatitis B virus reactivation did not develop in any patient. Since the risk of hepatitis B virus reactivation is low, especially in patients with previous hepatitis B, it would be more appropriate to follow up the patients without giving antiviral prophylaxis.

Hepatic and skeletal muscle tissue immunometabolism in trained rats / Inmunometabolismo del tejido hepático y muscular esquelético de ratas entrenadas / Imunometabolismo tecidual hepático e muscular esquelético de ratos treinados

ABSTRACT Introduction: Physical exercise can be an alternative for preventing and treating the harmful effects of obesity, mainly inflammatory effects on skeletal muscle and liver tissues. However, no consensus exists regarding this purpose's best physical training model. Objective: Evaluate morphological, metabolic, and inflammatory alterations in rats' skeletal and hepatic muscle tissues caused by aerobic and resistance training. Methods: 24 Wistar rats were divided into sedentary (S), aerobic (AE), and resistance training (R) groups. Blood glucose, total cholesterol, and serum triglycerides were measured periodically. After euthanasia, body mass was measured to calculate the total mass gain during the experiment. High-density lipoprotein (HDL) was measured. Adipose tissue was extracted to calculate its percentage relative to body mass and the liver, soleus, and gastrocnemius muscles for morphological analyses and concentrations of glycogen, lipids, and Tumor Necrosis Factor α (TNF-α). The Kruskall-Wallis test and Dunn's post-test were performed for statistical analysis, adopting p<0.05. Results: Both training models reduced the percentage of adipose tissue, body mass gain, and hepatic TNF-α concentration (p<0.05). AE increased serum HDL, gastrocnemius fiber diameter and reduced the fractal dimension in the soleus (p<0.05). R reduced blood glucose and serum and liver lipids, increased liver and soleus glycogen concentrations, increased gastrocnemius fiber diameter, and decreased TNF-α (p<0.05). Conclusion: Both training models reduced body mass, relative visceral adipose tissue, serum total cholesterol concentration, and liver inflammation. However, resistance training was more effective in promoting metabolic effects in the liver and skeletal muscle and reducing muscle inflammation in rats. Level of Evidence V; Expert Opinion.

RESUMEN Introducción: El ejercicio físico puede ser una alternativa para prevenir y tratar los efectos nocivos de la obesidad, principalmente los efectos inflamatorios sobre los tejidos del músculo esquelético y del hígado. Sin embargo, no existe consenso sobre cuál es el mejor modelo de entrenamiento físico para este fin. Objetivo: Evaluar las alteraciones morfológicas, metabólicas e inflamatorias del entrenamiento aeróbico y de resistencia en sobre los tejidos músculo esqueléticos y hepáticos de ratas. Métodos: 24 ratas Wistar se dividieron en grupos sedentarios (S), aeróbicos (AE) y de entrenamiento de resistencia (R). Se midieron periódicamente glucosa en sangre, colesterol total y triglicéridos. Después de la eutanasia, se midió la masa corporal para calcular la ganancia de masa total durante el experimento. Se midió la lipoproteína de alta densidad (HDL). Se extrajo tejido adiposo para calcular su porcentaje relativo a la masa corporal, así como hígado, músculos sóleo y gastrocnemio para análisis morfológicos y concentraciones de glucógeno, lípidos y Factor de Necrosis Tumoral α (TNF-α). Para el análisis estadístico fueron utilizados Kruskall-Wallis y el post-test de Dunn, adoptando p<0,05. Resultados: Ambos entrenamientos redujeron el porcentaje de tejido adiposo, masa corporal y la concentración de TNF-α hepático (p<0,05). AE aumentó el HDL sérico, el diámetro de la fibra del gastrocnemio y redujo la dimensión fractal en el sóleo (p<0,05). R redujo la glucosa en sangre y los lípidos séricos y hepáticos, aumentó las concentraciones de glucógeno hepático y sóleo, aumentó el diámetro de la fibra del gastrocnemio y disminuyó el TNF-α (p<0,05). Conclusión: Ambos modelos de entrenamiento redujeron la masa corporal, el tejido adiposo visceral relativo, la concentración sérica de colesterol total y la inflamación hepática. El entrenamiento de resistencia demostró ser más eficaz para promover los efectos metabólicos en el hígado y el músculo esquelético, además de reducir la inflamación muscular en ratas. Nivel de Evidencia V; Opinión del Especialista.

RESUMO Introdução: O exercício físico pode se apresentar como uma alternativa para prevenção e tratamento de efeitos deletérios da obesidade, principalmente efeitos inflamatórios sobre os tecidos muscular esquelético e hepático. No entanto, não há consenso quanto ao melhor modelo de treinamento físico para tal finalidade. Objetivos: Avaliar alterações morfológicas, metabólicas e inflamatórias dos treinamentos aeróbico e resistido sobre os tecidos muscular esquelético e hepático de ratos. Métodos: 24 ratos Wistar foram divididos nos grupos sedentário (S), treinamento aeróbico (AE) e resistido (R). Glicemia, colesterol total e triglicerídeos séricos foram mensurados periodicamente. Após a eutanásia, a massa corporal foi mensurada para calcular o ganho total de massa durante o experimento. A lipoproteína de alta densidade (HDL) foi dosada. O tecido adiposo foi extraído para cálculo de sua porcentagem relativa à massa corporal assim como o fígado e os músculos sóleo e gastrocnêmio para as análises morfológicas e das concentrações de glicogênio, lipídios e Fator de Necrose Tumoral α (TNF-α). Para análise estatística, foram utilizados o teste de Kruskall-Wallis e o pós-teste de Dunn, adotando-se p<0,05. Resultados: Ambos os modelos de treinamento reduziram o percentual de tecido adiposo, ganho de massa corporal e concentração hepática de TNF-α (p<0,05). AE aumentou o HDL sérico, o diâmetro das fibras do gastrocnêmio e reduziu a dimensão fractal no sóleo (p<0,05). R reduziu a glicemia e os lipídios séricos e hepáticos, aumentou a concentração de glicogênio hepático e sóleo, aumentou o diâmetro das fibras gastrocnêmicas e diminuiu o TNF-α (p<0,05). Conclusão: Ambos os modelos de treinamento reduziram a massa corporal, o tecido adiposo visceral relativo, a concentração sérica de colesterol total e a inflamação hepática. No entanto, o treinamento resistido mostrou-se mais eficaz em promover efeitos metabólicos no fígado e no músculo esquelético, além de reduzir a inflamação muscular em ratos. Nível de Evidência V; Opinião do Especialista.

New immunological aspects of peri-implantitis

ABSTRACT Objective: This study aimed to compare the levels of HIF1-α, VEGF, TNF-α, and IL-10 in the peri-implant crevicular fluid of patients with and without peri-implantitis. Methods: Forty patients, comprising 16 with and 24 without peri-implantitis were selected. Results: Patients with peri-implantitis exhibited significantly higher HIF-1α levels than those without peri-implantitis (p=0.0005). TNF-α revealed significant positive correlations with IL-10 (p=0.0008) and VEGF (p=0.0246), whereas HIF-1α and IL-10 levels (p=0.0041) demonstrated a negative and significative correlation in the peri-implantitis group. Conclusion: This study, for the first time demonstrates the balance of HIF-1α, TNFα, IL-10, and VEGF in peri-implantitis. It shows an elevated HIF-1α levels in patients with peri-implantitis, which could have stemmed from persistent inflammation- triggered hypoxia. Furthermore, the positive correlation between TNF-α and VEGF suggests intensified proinflammatory activity in peri-implantitis. Nevertheless, further studies are essential to understand these immune dynamics in peri-implantitis.

TRAIL-Sensitizing Effects of Flavonoids in Cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies.

Adenoviral Vector Codifying for TNF as a Co-Adjuvant Therapy against Multi-Drug-Resistant Tuberculosis.

Mycobacterium tuberculosis is the main causal agent of pulmonary tuberculosis (TB); the treatment of this disease is long and involves a mix of at least four different antibiotics that frequently lead to abandonment, favoring the surge of drug-resistant mycobacteria (MDR-TB), whose treatment becomes more aggressive, being longer and more toxic. Thus, the search for novel strategies for treatment that improves time or efficiency is of relevance. In this work, we used a murine model of pulmonary TB produced by the MDR-TB strain to test the efficiency of gene therapy with adenoviral vectors codifying TNF (AdTNF), a pro-inflammatory cytokine that has protective functions in TB by inducing apoptosis, granuloma formation and expression of other Th1-like cytokines. When compared to the control group that received an adenoviral vector that codifies for the green fluorescent protein (AdGFP), a single dose of AdTNF at the chronic active stage of the disease produced total survival, decreasing bacterial load and tissue damage (pneumonia), which correlated with an increase in cells expressing IFN-γ, iNOS and TNF in pneumonic areas and larger granulomas that efficiently contain and eliminate mycobacteria. Second-line antibiotic treatment against MDR-TB plus AdTNF gene therapy reduced bacterial load faster within a week of treatment compared to empty vector plus antibiotics or antibiotics alone, suggesting that AdTNF is a new potential type of treatment against MDR-TB that can shorten second-line chemotherapy but which requires further experimentation in other animal models (non-human primates) that develop a more similar disease to human pulmonary TB.

Effects of ivermectin on cytokine and immunoglobulin levels in sheep / Efectos de la ivermectina en los niveles de citoquinas e inmunoglobulinas en ovejas / Efeitos da ivermectina nos níveis de citocinas e imunoglobulinas em ovinos

Abstract Background: Ivermectin may affect the levels of cytokines and immunoglobulins in sheep, considering that avermectins have an effect on the immune system. Objective: To determine whether ivermectin has an effect on cytokines and immunoglobulins in sheep. Methods: After administration of ivermectin to 10 healthy sheep, sheep-specific interferon-α, tumor necrosis factor-α, interleukin-2, interleukin-6, interleukin-10, immunoglobulin G, immunoglobulin M, and immunoglobulin E levels were measured with an ELISA reader. Results: Significant (p<0.05) fluctuations were detected in interleukin-2 and interleukin-10 levels. Transient increases (p<0.05) were measured in tumor necrosis factor-α and immunoglobulin E levels (p<0.05). Conclusion: Ivermectin may affect immune system parameters in healthy sheep; however, the effects of ivermectin administration on infected sheep should be investigated.

Resumen Antecedentes: La ivermectina puede alterar los niveles de citocinas e inmunoglobulinas en ovinos, dado que las avermectinas afectan el sistema inmunológico. Objetivo: Determinar si la ivermectina tiene algún efecto sobre las citocinas e inmunoglobulinas en ovinos. Métodos: Después de la administración de ivermectina a 10 ovejas sanas los niveles de interferón-α específico de oveja, factor de necrosis tumoral-α, interleucina-2, interleucina-6, interleucina-10, inmunoglobulina G, inmunoglobulina M, e inmunoglobulina E se midieron con un lector ELISA. Resultados: Se detectaron fluctuaciones significativas (p<0,05) en los niveles de interleucina-2 e interleucina-10. También se encontraron aumentos transitorios (p<0,05) en los niveles de factor de necrosis tumoral-α e inmunoglobulina E (p<0,05). Conclusión: la ivermectina puede afectar los parámetros del sistema inmunitario en ovejas sanas.

Resumo Antecedentes: A ivermectina pode alterar os níveis de citocinas e imunoglobulinas em ovinos, visto que as avermectinas afetam o sistema imunológico. Objetivo: Determinar o efeito da ivermectina nas citocinas e imunoglobulinas em ovinos. Métodos: Após a administração de ivermectina a 10 ovelhas saudáveis, interferon-α específico de ovelha, fator de necrose tumoral-α, interleucina-2, interleucina-6 e interleucina-10, os níveis de imunoglobulina G, imunoglobulina M e imunoglobulina E foram medidos com Leitor de ELISA. Resultados: Flutuações estatisticamente significativas (p<0,05) foram detectadas nos níveis de interkeukin-2 e interkeukin-10. Aumentos transitórios (p<0,05) foram medidos nos níveis de fator de necrose tumoral-α e imunoglobulina E (p<0,05). Conclusão: A ivermectina pode afetar parâmetros do sistema imunológico em ovinos saudáveis, entretanto, os efeitos da administração de ivermectina em ovinos infectados devem ser investigados.

Abdominal Obesity May Play a Significant Role in inflammation Exacerbation in Polycystic Ovary Syndrome Patients.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is an endocrine disorder that seems to be pro-inflammatory at many levels, abdominal obesity (AO) is a prevalent pro-inflammatory phenotype in PCOS patients, and it seems to contribute to the initiation or worsening of inflammation in PCOS patients. In this study, we investigated the role of the AO phenotype in the occurrence of other obesity indicators (neck and arm) and augmentation of inflammation in the follicular fluid (FF) of PCOS patients. METHODS: 40 patients under the age of 35 were divided into four groups: PCOS with AO, PCOS without AO, non-PCOS with AO, and non-PCOS without AO. The FF samples were collected from each patient. Clinical and anthropometric characteristics of the participants, as well as tumor necrosis factor-α (TNF-α) concentration in the FF samples, were quantitatively assessed using enzyme-linked immunosorbent assays. The number of retrieved cumulus-oocyte complexes (COC) and their quality were scored. RESULTS: The PCOS+AO+ group had significantly increased neck circumference, compared to the other groups (p<0.001). The concentration of TNF-α was significantly higher in the PCOS+AO+ group than in the other groups (p<0.001). There were no significant differences in the number of retrieved COC per patient and the quality of oocytes between the groups (p>0.05). CONCLUSIONS: Given the significant role of inflammation in the development of PCOS, managing AO in PCOS patients may aid in reducing inflammation and could potentially help in the design of customized treatment approaches.

The Expression and Activation of the NF-κB Pathway Correlate with Methotrexate Resistance and Cell Proliferation in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although its prognosis continually improves with time, a significant proportion of patients still relapse from the disease because of the leukemia's resistance to therapy. Methotrexate (MTX), a folic-acid antagonist, is a chemotherapy agent commonly used against ALL and as an immune-system suppressant for rheumatoid arthritis that presents multiple and complex mechanisms of action and resistance. Previous studies have shown that MTX modulates the nuclear factor kappa B (NF-κB) pathway, an important family of transcription factors involved in inflammation, immunity, cell survival, and proliferation which are frequently hyperactivated in ALL. Using a gene set enrichment analysis of publicly available gene expression data from 161 newly diagnosed pediatric ALL patients, we found the Tumor necrosis factor α (TNF-α) signaling pathway via NF-κB to be the most enriched Cancer Hallmark in MTX-poor-responder patients. A transcriptomic analysis using a panel of ALL cell lines (six B-cell precursor acute lymphoblastic leukemia and seven T-cell acute lymphoblastic leukemia) also identified the same pathway as differentially enriched among MTX-resistant cell lines, as well as in slowly dividing cells. To better understand the crosstalk between NF-κB activity and MTX resistance, we genetically modified the cell lines to express luciferase under an NF-κB-binding-site promoter. We observed that the fold change in NF-κB activity triggered by TNF-α (but not MTX) treatment correlated with MTX resistance and proliferation across the lines. At the individual gene level, NFKB1 expression was directly associated with a poorer clinical response to MTX and with both an increased TNF-α-triggered NF-κB activation and MTX resistance in the cell lines. Despite these results, the pharmacological inhibition (using BAY 11-7082 and parthenolide) or stimulation (using exogenous TNF-α supplementation) of the NF-κB pathway did not alter the MTX resistance of the cell lines significantly, evidencing a complex interplay between MTX and NF-κB in ALL.

Analysis of confounding caused by creatinine and age in the correlation between soluble tumor necrosis factor a receptor 1 (sTNFR1) levels and estimated glomerular filtration rate (eGFR) in Colombian patients with type 2 diabetes / Análisis de la confusión producida por la creatinina y la edad en la correlación entre los niveles del receptor soluble 1 del factor de necrosis tumoral a (sTNFR1) y la tasa de filtración glomerular estimada (TFGe) en pacientes colombianos con diabetes mellitus tipo 2

Abstract Introduction. Tumor necrosis factor a (TNF-α) is a cytokine involved in inflammatory processes associated with type 2 diabetes mellitus (DM2). Although the correlation between soluble TNF-a receptor 1 (sTNFRI) levels and estimated glomerular filtration rate (eGFR) has been already described in Colombian population with DM2, the influence of sTNFR1 on eGFR in a model adjusted for age and creatinine level has not yet been evaluated. Objectives. To identify and evaluate the linear correlations between sTNFR1 levels, routine clinical variables, and eGFR in Colombian patients with DM2. Materials and methods. Cross-sectional study conducted in March 2020 in 69 patients with DM2 who were enrolled in the Program for the Prevention of Diabetes Complications and Dyslipidemias of the Faculty of Medicine of the Universidad Nacional de Colombia. Medical records were reviewed in order to obtain sociodemographic, anthropometric and clinical data. Serum sTNFR1 levels were determined by means of an ELISA test. A multiple linear regression model (stepwise regression) was performed to evaluate correlations between sTNFR1, clinical variables, and eGFR. Results. The final multiple linear regression model, which includes creatinine levels, sTNFR1 levels, and age, explained 72% of the variance of eGFR (p=0.023). Furthermore, sTNFR1 levels explained 20% of the variance of eGFR independently (standardized ß coefficient: -0.2; 95%CI: [-0.008]-[-0.001]; p=0.02). Conclusion. In the final multiple linear regression model, an inversely proportional and statistically significant linear correlation was found between sTNFR1 levels and eGFR, independent of serum creatinine levels and age. Compared with age, sTNFR1 levels have a superior effect in terms of changes in eGFR.

Resumen Introducción. El factor de necrosis tumoral a (TNF-α) es una citoquina involucrada en los procesos inflamatorios de la diabetes mellitus tipo 2 (DM2). Aunque la correlación entre los niveles del receptor soluble 1 del TNF-a (sTNFR1) y la tasa de filtración glomerular estimada (TFGe) ya ha sido descrita previamente en población colombiana con DM2, la influencia del sTNFR1 en la TFGe en un modelo ajustado a edad y creatinina no ha sido evaluada. Objetivos. Identificar y evaluar las correlaciones lineales entre los niveles del sTNFR1, las variables clínicas de uso rutinario y la TFGe en pacientes colombianos con DM2. Materiales y métodos. Estudio transversal realizado en marzo de 2020 en 69 pacientes con DM2 que estaban inscritos en el Programa para la prevención de las complicaciones de la diabetes y las dislipidemias de la Facultad de Medicina de la Universidad Nacional de Colombia. Los datos sociodemográficos, antropométricos y clínicos se recolectaron a partir de la revisión de las historias clínicas. Los niveles séricos del sTNFR1 se determinaron mediante prueba de ELISA. Se realizó un modelo de regresión lineal múltiple (regresión paso a paso) para evaluar las correlaciones entre el sTNFR1, las variables clínicas y la TFGe. Resultados. El modelo final de regresión lineal múltiple, que incluye niveles de creatinina, niveles del sTNFR1 y edad, explica el 72% de la varianza de la TFGe (p=0.023); además, los niveles del sTNFR1 explican el 20% de la varianza de la TFGe de forma independiente (coeficiente ß estandarizado: -0.2; IC95%: [-0.008]-[-0.001]; p=0.02). Conclusión. En el modelo final de regresión lineal múltiple se encontró una correlación lineal inversamente proporcional y estadísticamente significativa entre los niveles del sTNFR1 y la TFGe, independientemente de los niveles séricos de creatinina y la edad. Comparado con la edad, los niveles del sTNFR1 tienen un efecto superior en términos de cambios en la TFGe.