RESUMEN
Macrophage activation plays a central role in the development of atherosclerotic plaques. Interaction with oxidized low-density lipoprotein (oxLDL) leads to macrophage differentiation into foam cells and oxylipin production, contributing to plaque formation. 7-Ketocholesterol (7KC) is an oxidative byproduct of cholesterol found in oxLDL particles and is considered a factor contributing to plaque progression. During atherosclerotic lesion regression or stabilization, macrophages undergo a transformation from a pro-inflammatory phenotype to a reparative anti-inflammatory state. Interleukin-10 (IL-10) and PGE1 appear to be crucial in resolving both acute and chronic inflammatory processes. After coffee consumption, the gut microbiota processes non-absorbed chlorogenic acids producing various lower size phenolic acids. These colonic catabolites, including dihydroferulic acid (DHFA), may exert various local and systemic effects. We focused on DHFA's impact on inflammation and oxidative stress in THP-1 macrophages exposed to oxLDL, 7KC, and lipopolysaccharides (LPS). Our findings reveal that DHFA inhibits the release of several pro-inflammatory mediators induced by LPS in macrophages, such as CCL-2, CCL-3, CCL-5, TNF-α, IL-6, and IL-17. Furthermore, DHFA reduces IL-18 and IL-1ß secretion in an inflammasome-like model. DHFA demonstrated additional benefits: it decreased oxLDL uptake and CD36 expression induced by oxLDL, regulated reactive oxygen species (ROS) and 8-isoprostane secretion (indicating oxidative stress modulation), and selectively increased IL-10 and PGE1 levels in the presence of inflammatory stimuli (LPS and 7KC). Finally, our study highlights the pivotal role of PGE1 in foam cell inhibition and inflammation regulation within activated macrophages. This study highlights DHFA's potential as an antioxidant and anti-inflammatory agent, particularly due to its ability to induce PGE1 and IL-10.
Asunto(s)
Ácidos Cumáricos , Cetocolesteroles , Lipopolisacáridos , Lipoproteínas LDL , Macrófagos , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Lipoproteínas LDL/metabolismo , Lipopolisacáridos/farmacología , Cetocolesteroles/farmacología , Ácidos Cumáricos/farmacología , Antiinflamatorios/farmacología , Polifenoles/farmacología , Activación de Macrófagos/efectos de los fármacos , Colon/metabolismo , Colon/efectos de los fármacos , Interleucina-10/metabolismo , Estrés Oxidativo/efectos de los fármacos , Mediadores de Inflamación/metabolismoRESUMEN
INTRODUCTION: In ST-elevation myocardial infarction (STEMI), inflammation is pivotal, with early senescent CD4+CD28null cells implicated in its pathogenesis. However, the functional phenotype of these cells within the coronary circulation remains unclear. METHODS: We examined CD4+ cell subpopulations in blood samples from the coronary sinus and vena cava of 24 STEMI patients and the cephalic vein of seven healthy controls. RESULTS: Our findings revealed reduced CD4+ cell counts in STEMI patients compared to controls (1,998, 1,275-3,268 vs. 4,278, 3,595-4,449), alongside an increased proportion of CD4+ cells lacking CD28 expression (20.1 vs. 6.1%). These CD4+CD28null cells in STEMI predominantly exhibited a Th1 phenotype (47.8% vs. 6.6%). Intriguingly, no significant differences were detected in CD4+CD28null cells between coronary sinus and vena cava, and cytokine levels in these compartments remained similar. CONCLUSION: CD4+CD28null cells are increased in STEMI, mainly polarized toward a Th1 phenotype, and distributed equally between the different vascular beds.
Asunto(s)
Antígenos CD28 , Linfocitos T CD4-Positivos , Circulación Coronaria , Citocinas , Fenotipo , Infarto del Miocardio con Elevación del ST , Células TH1 , Humanos , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/inmunología , Infarto del Miocardio con Elevación del ST/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios de Casos y Controles , Antígenos CD28/metabolismo , Células TH1/inmunología , Citocinas/sangre , Citocinas/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Senescencia Celular , Seno Coronario , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Recuento de Linfocito CD4 , InmunofenotipificaciónRESUMEN
Research suggests that both tuberculosis (TB) and type 2 diabetes mellitus (T2DM) have an immuno-endocrine imbalance characterized by dysregulated proinflammatory molecules and hormone levels (high cortisol/DHEA ratio), impeding an effective immune response against Mycobacterium tuberculosis (Mtb) driven by cytokines, antimicrobial peptides (AMPs), and androgens like DHEA. Insulin, sulfonylurea derivatives, and metformin are commonly used glucose-lowering drugs in patients suffering from TB and T2DM. For this comorbidity, metformin is an attractive target to restore the immunoendocrine mechanisms dysregulated against Mtb. This study aimed to assess whether metformin influences cortisol and DHEA synthesis in adrenal cells and if these hormones influence the expression of proinflammatory cytokines and AMPs in Mtb-infected macrophages. Our results suggest that metformin may enhance DHEA synthesis while maintaining cortisol homeostasis. In addition, supernatants from metformin-treated adrenal cells decreased mycobacterial loads in macrophages, which related to rising proinflammatory cytokines and AMP expression (HBD-2 and 3). Intriguingly, we find that HBD-3 and LL-37 can modulate steroid synthesis in adrenal cells with diminished levels of cortisol and DHEA, highlighting the importance of crosstalk communication between adrenal hormones and these effectors of innate immunity. We suggest that metformin's effects can promote innate immunity against Mtb straight or through modulation of corticosteroid hormones.
Asunto(s)
Citocinas , Deshidroepiandrosterona , Hidrocortisona , Macrófagos , Metformina , Mycobacterium tuberculosis , Metformina/farmacología , Humanos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Macrófagos/inmunología , Mycobacterium tuberculosis/efectos de los fármacos , Hidrocortisona/metabolismo , Deshidroepiandrosterona/farmacología , Citocinas/metabolismo , Inmunidad Innata/efectos de los fármacos , Células THP-1 , Interacciones Huésped-Patógeno , Células Cultivadas , Hipoglucemiantes/farmacología , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/microbiología , Mediadores de Inflamación/metabolismoRESUMEN
AIMS: To identify the cardiac biogenic amine profile of obese rats and associate these compounds with parameters of cardiovascular disease. MAIN METHODS: Wistar rats (n = 20) were randomly distributed into two groups: control and obese. Obesity was induced by a high-sugar fat diet. Biochemical parameters were evaluated. Doppler Echocardiography and systolic blood pressure; interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), protein carbonylation, ferric reducing antioxidant power (FRAP), and catalase activity were measured in cardiac tissue. HPLC evaluated the cardiac biogenic profile. Data were compared using the Student's T or Mann-Whitney tests and Spearman's correlation at 5% significance. The principal component analysis (PCA) was performed. KEY FINDINGS: Obesity generated hypertension, cardiac remodeling and dysfunction, and imbalanced all biochemical, inflammatory, and oxidative markers (p < 0.001). Eight biogenic amines were found in cardiac tissue. Obesity increased serotonin and decreased agmatine, putrescine, cadaverine, and spermidine. Serotonin (r = 0.534 to 0.808) was strong and positively correlated with obesity, biochemical parameters, cardiac inflammation, oxidative stress, hypertension, cardiac remodeling, and dysfunction (p < 0.001). Spermidine (r = -0.560 to -0.680), putrescine (r = -0.532 to -0.805), cadaverine (r = -0.534 to -0.860), and agmatine (r = -0.579 to -0.884) were inversely correlated with the same parameters (p < 0.001). PCA allowed for distinguishing the control and obese groups. SIGNIFICANCE: There are strong correlations between cardiac biogenic amine levels, cardiac remodeling, and dysfunction resulting from obesity. CONCLUSION: There is an association between cardiac biogenic amines and cardiovascular disease in obesity. In addition, agmatine, putrescine, cadaverine, and, mainly, serotonin may be new biomarkers for cardiovascular health in obesity and help to improve the diagnosis and treatment of CVD resulting or not from obesity. However, more research is needed to support this conclusion.
Asunto(s)
Aminas Biogénicas , Biomarcadores , Modelos Animales de Enfermedad , Miocardio , Obesidad , Estrés Oxidativo , Ratas Wistar , Animales , Obesidad/metabolismo , Aminas Biogénicas/metabolismo , Masculino , Miocardio/metabolismo , Biomarcadores/metabolismo , Biomarcadores/sangre , Remodelación Ventricular , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Mediadores de Inflamación/metabolismo , Ratas , Presión SanguíneaRESUMEN
Metabolic alterations are a common problem in people living with HIV (PLHIV), as a result of a stage of chronic inflammation that affects the homeostasis of the organism. Prolonged exposure to antiretroviral therapy has been associated with developing lipodystrophies that modify lipoprotein metabolism and inflammatory markers such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which are mediators of the immune response. The study aimed to associate TNF-α and IL-6 levels with their polymorphisms and metabolic alterations in PLIHV. We hypothesized that TNF-α and IL-6 levels and their polymorphisms are associated with metabolic alterations. In total, 185 PLHIV and 51 HIV-negative people were included. Biochemical parameters were determined by colorimetric assay, cytokine levels by immunoassay, and allelic discrimination by quantitative polymerase chain reaction. A correlation was found between TNF-α levels and the variables cholesterol (r = -0.171, P = 0.020) and high-density lipoprotein (HDL) (r = -0.245, P = 0.001). There are associations between HDL levels (P = 0.011) and GG genotype of rs1800629. The results suggest a metabolic alteration related to the constant immune response, especially the production of proinflammatory cytokines such as TNF-α and IL-6. It was observed that genetic factors may influence metabolism alteration, mainly in lipids.
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Citocinas , Interleucina-6 , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Interleucina-6/genética , Interleucina-6/sangre , Interleucina-6/metabolismo , Citocinas/metabolismo , Infecciones por VIH/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Genotipo , Polimorfismo de Nucleótido Simple , Mediadores de Inflamación/metabolismo , Síndrome de Inmunodeficiencia Adquirida/genética , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/metabolismoRESUMEN
Despite all the scientific progress in recent decades to unravel the immune processes and the way the parasite bypasses the immune system, Chagas disease is still a major public health problem, affecting an estimated 3.5 million people. Among the components that may participate in the response against the parasite, testosterone has been gaining more and more visibility. Studies indicate that the parasite itself seems to carry out steroidogenesis, in which, in co-culture with androgen precursors, T. cruzi has been shown to produce TS, but the purpose of the TS synthesized by the parasite and how this can influence its invasion glycoproteins is still unclear unknown. The aim of this study was to evaluate the influence of testosterone in Trypanosoma cruzi infection on the immune response of bone marrow-derived macrophages. Bone marrow from male rats was extracted and cultured with RMPI medium containing 30% L929 cell supernatant for macrophage differentiation. The cells were incubated for 10 days and, after this period, they were seeded in 96 wells in the amount of 1 x 105 cells per well. TS was added at different concentrations of 20 µM, 10 µM, 5 µM and 1 µM and then infected with the Y strain of T. cruzi, at a rate of 10 parasites per cell, with the culture remaining for six, 12 and 24 h. The supernatant was collected and the production of nitric oxide (NO), tumor necrosis factor (TNF) and the number of cell parasites was assessed by staining with 4'-6'-diamino-2-phenylindole (DAPI) and ranked by high Content Screening (HSC). The parasite was then cultured with the addition of TS, at the mentioned concentrations, leaving it for six and 12 h and then performing the RT-PCR of the mucins. DAPI staining revealed a significant increase in the number of parasites in cells containing TS. The exception was observed when 1 µM of hormone/well was used. A reduction in TNF production was found with 20 and 10 µM of TS for 6 h stimulation, although increased levels were observed with 5 and 1 µM, similar to the infected control. However, there was an increase in TNF production and not after 12 h. The relative expression of parasite glycoprotein 82 was increased with the presence of TS in the medium, regardless of time. Our data suggest that TS may contribute to cellular immunosuppression, increasing parasite infection in the cell, as well as inflammatory mediators that lead to cell and tissue damage in infected individuals, as well as the possible use of TS to allow their invasion into the cell hosts.
Asunto(s)
Macrófagos , Óxido Nítrico , Testosterona , Trypanosoma cruzi , Animales , Masculino , Macrófagos/parasitología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratas , Testosterona/biosíntesis , Testosterona/farmacología , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Glicoproteínas/metabolismo , Glicoproteínas/farmacología , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Mediadores de Inflamación/metabolismo , Proteínas Protozoarias/metabolismo , Células Cultivadas , Células de la Médula Ósea/parasitología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/inmunologíaRESUMEN
Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity. Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level. Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels. Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine.
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Artritis Juvenil , Perfilación de la Expresión Génica , Inflamación , Monocitos , Transcriptoma , Adulto , Niño , Femenino , Humanos , Anticuerpos Antiproteína Citrulinada , Artritis Juvenil/clasificación , Artritis Juvenil/genética , Artritis Juvenil/inmunología , Artritis Juvenil/patología , Estudios de Casos y Controles , Enfermedad Crónica , Análisis por Conglomerados , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/inmunología , Interferón gamma/inmunología , Monocitos/inmunología , Monocitos/metabolismo , Fenotipo , Medicina de Precisión , Premenopausia , Unión Proteica , Mapas de Interacción de Proteínas , Factor Reumatoide , Análisis de Secuencia de ARN , Transcriptoma/genética , Factor de Necrosis Tumoral alfa/inmunología , Aprendizaje Automático no SupervisadoRESUMEN
OBJECTIVES: The aim of the present study was to assess the cytocompatibility of epoxy resin-based AH Plus Jet (Dentsply De Trey, Konstanz, Germany), Sealer Plus (MK Life, Porto Alegre, Brazil), calcium silicate-based Bio-C Sealer (Angelus, Londrina, PR, Brazil), Sealer Plus BC (MK Life) and AH Plus BC (Dentsply) through a tridimensional (3D) culture model of human osteoblast-like cells. METHODS: Spheroids of MG-63 cells were produced and exposed to fresh root canal sealers extracts by 24 h, and the cytotoxicity was assessed by the Lactate Dehydrogenase assay (LDH). The distribution of dead cells within the microtissue was assessed by fluorescence microscopy, and morphological effects were investigated by histological analysis. The secreted inflammatory mediators were detected in cell supernatants through flow luminometry (XMap Luminex). RESULTS: Cells incubated with AH Plus Jet, AH Plus BC, Sealer Plus BC and Bio-C Sealer extracts showed high rates of cell viability, while the Sealer Plus induced a significant reduction of cell viability, causing reduction on the spheroid structure. Sealer Plus and Seaker Plus BC caused alterations on 3D microtissue morphology. The AH Plus BC extract was associated with the downregulation of secretion of pro-inflammatory cytokines IL-5, IL-7, IP-10 and RANTES. CONCLUSIONS: The new AH Plus BC calcium silicate-based endodontic sealer did not reduce cell viability in vitro, while led to the downregulation of pro-inflammatory cytokines. CLINICAL SIGNIFICANCE: Choosing the appropriate endodontic sealer is a crucial step. AH Plus BC demonstrated high cell viability and downregulation of pro-inflammatory cytokines, appearing reliable for clinical use, while Sealer Plus presented lower cytocompatibility.
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Compuestos de Calcio , Supervivencia Celular , Resinas Epoxi , Ensayo de Materiales , Materiales de Obturación del Conducto Radicular , Silicatos , Materiales de Obturación del Conducto Radicular/farmacología , Humanos , Compuestos de Calcio/farmacología , Silicatos/farmacología , Supervivencia Celular/efectos de los fármacos , Técnicas de Cultivo Tridimensional de Células/métodos , Mediadores de Inflamación/metabolismo , Microscopía Fluorescente , Osteoblastos/efectos de los fármacosRESUMEN
By uncoupling oxidative phosphorylation, 2,4-dinitrophenol (DNP) attenuates reactive oxygen species (ROS) biosynthesis, which are known to aggravate infectious myocarditis in Chagas disease. Thus, the impact of DNP-based chemotherapy on Trypanosoma cruzi-induced acute myocarditis was investigated. C56BL/6 mice uninfected and infected untreated and treated daily with 100 mg/kg benznidazole (Bz, reference drug), 5 and 10 mg/kg DNP by gavage for 11 days after confirmation of T. cruzi infection were investigated. Twenty-four hours âafter the last treatment, the animals were euthanized and the heart was collected for microstructural, immunological and biochemical analyses. T. cruzi inoculation induced systemic inflammation (e.g., cytokines and anti-T. cruzi IgG upregulation), cardiac infection (T. cruzi DNA), oxidative stress, inflammatory infiltrate and microstructural myocardial damage in untreated mice. DNP treatment aggravated heart infection and microstructural damage, which were markedly attenuated by Bz. DNP (10 mg/kg) was also effective in attenuating ROS (total ROS, H2O2, and O2-), nitric oxide (NO), lipid (malondialdehyde - MDA) and protein (protein carbonyl - PCn) oxidation, TNF, IFN-γ, IL-10, and MCP-1/CCL2, anti-T. cruzi IgG, cardiac troponin I levels, as well as inflammatory infiltrate and cardiac damage in T. cruzi-infected mice. Our findings indicate that DNP aggravated heart infection and microstructural cardiomyocytes damage in infected mice. These responses were related to the antioxidant and anti-inflammatory properties of DNP, which favors infection by weakening the pro-oxidant and pro-inflammatory protective mechanisms of the infected host. Conversely, Bz-induced cardioprotective effects combined effective anti-inflammatory and antiparasitic responses, which protect against heart infection, oxidative stress, and microstructural damage in Chagas disease.
Asunto(s)
2,4-Dinitrofenol , Cardiomiopatía Chagásica , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Estrés Oxidativo , Trypanosoma cruzi , Animales , 2,4-Dinitrofenol/farmacología , Estrés Oxidativo/efectos de los fármacos , Cardiomiopatía Chagásica/tratamiento farmacológico , Cardiomiopatía Chagásica/metabolismo , Cardiomiopatía Chagásica/parasitología , Cardiomiopatía Chagásica/patología , Trypanosoma cruzi/efectos de los fármacos , Masculino , Especies Reactivas de Oxígeno/metabolismo , Desacopladores/farmacología , Desacopladores/toxicidad , Ratones , Miocardio/patología , Miocardio/metabolismo , Nitroimidazoles/farmacología , Enfermedad Aguda , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Antiinflamatorios/farmacología , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Miocarditis/parasitología , Miocarditis/metabolismo , Miocarditis/tratamiento farmacológico , Miocarditis/patología , Miocarditis/inducido químicamente , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/metabolismo , Enfermedad de Chagas/patología , Enfermedad de Chagas/parasitologíaRESUMEN
BACKGROUND: Cytokine storm and oxidative stress are present in chronic obstructive pulmonary disease (COPD). Individuals with COPD present high levels of NF-κB-associated cytokines and pro-oxidant agents as well as low levels of Nrf2-associated antioxidants. This condition creates a steroid-resistant inflammatory microenvironment. Lacticaseibacillus rhamnosus (Lr) is a known anti-cytokine in lung diseases; however, the effect of Lr on lung inflammation and oxidative stress in steroid-resistant COPD mice remains unknown. OBJECTIVE: Thus, we investigated the Lr effect on lung inflammation and oxidative stress in mice and macrophages exposed to cigarette smoke extract (CSE) and unresponsive to steroids. METHODS: Mice and macrophages received dexamethasone or GLPG-094 (a GPR43 inhibitor), and only the macrophages received butyrate (but), all treatments being given before CSE. Lung inflammation was evaluated from the leukocyte population, airway remodeling, cytokines, and NF-κB. Oxidative stress disturbance was measured from ROS, 8-isoprostane, NADPH oxidase, TBARS, SOD, catalase, HO-1, and Nrf2. RESULTS: Lr attenuated cellularity, mucus, collagen, cytokines, ROS, 8-isoprostane, NADPH oxidase, and TBARS. Otherwise, SOD, catalase, HO-1, and Nrf2 were upregulated in Lr-treated COPD mice. Anti-cytokine and antioxidant effects of butyrate also occurred in CSE-exposed macrophages. GLPG-094 rendered Lr and butyrate less effective. CONCLUSIONS: Lr attenuates lung inflammation and oxidative stress in COPD mice, suggesting the presence of a GPR43 receptor-dependent mechanism also found in macrophages.
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Lacticaseibacillus rhamnosus , Macrófagos , Estrés Oxidativo , Enfermedad Pulmonar Obstructiva Crónica , Receptores Acoplados a Proteínas G , Animales , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Ratones , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Humo/efectos adversos , Dexametasona/farmacología , Butiratos/farmacología , Pulmón/efectos de los fármacos , Pulmón/metabolismoRESUMEN
Periodontitis, characterized by persistent inflammation in the periodontium, is intricately connected to systemic diseases, including oral cancer. Bacteria, such as Porphyromonas gingivalis and Fusobacterium nucleatum, play a pivotal role in periodontitis development because they contribute to dysbiosis and tissue destruction. Thus, comprehending the interplay between these bacteria and their impacts on inflammation holds significant relevance in clinical understanding and treatment advancement. In the present work, we explored, for the first time, their impacts on the expressions of pro-inflammatory mediators after infecting oral keratinocytes (OKs) with a co-culture of pre-incubated P. gingivalis and F. nucleatum. Our results show that the co-culture increases IL-1ß, IL-8, and TNF-α expressions, synergistically augments IL-6, and translocates NF-kB to the cell nucleus. These changes in pro-inflammatory mediators-associated with chronic inflammation and cancer-correlate with an increase in cell migration following infection with the co-cultured bacteria or P. gingivalis alone. This effect depends on TLR4 because TLR4 knockdown notably impacts IL-6 expression and cell migration. Our study unveils, for the first time, crucial insights into the outcomes of their co-culture on virulence, unraveling the role of bacterial interactions in polymicrobial diseases and potential links to oral cancer.
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Neoplasias de la Boca , Periodontitis , Humanos , Técnicas de Cocultivo , Interleucina-6 , Receptor Toll-Like 4 , Inflamación , Mediadores de Inflamación , QueratinocitosRESUMEN
BACKGROUND: Physical exercise (PE) may improve plasma concentration of interleukin- 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and adiponectin (adpN) in heart transplant (HT) patients. However, no consistent data is available on this population. AIM: Thus, we aimed to conduct a systematic review and meta-analysis on the effects of PE over these pro- and anti-inflammatory biomarkers in HT patients. METHODS: Following the guidelines established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, we conducted a systematic literature search in the PubMed, Cochrane, and Scopus databases. Outcomes included IL-6, TNF-alpha, and adpN. Effect size (ES) was calculated using the standardized mean difference with a 95% confidence interval (CI). RESULTS: The PE group (aerobic modality) was associated with reduced IL-6 compared to the control group (ES: -0.53; 95% CI: -0.99 to -0.06 pg/mL; P = 0.026). However, the PE group did not show a significant effect on TNF-alpha and adpN levels (ES: -0.33; 95% CI: -0.79 to 0.13; P = 0.16 and ES: -0.20; 95% CI: -0.70 to 0.30 pg/mL; P = 0.444, respectively). CONCLUSION: PE is associated with IL-6 reductions, although TNF alpha and adpN did not change after this intervention in HT patients. Therefore, PE is an effective intervention to downregulate IL-6 in post-HT patients.
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Biomarcadores , Ejercicio Físico , Trasplante de Corazón , Inflamación , Humanos , Adiponectina/sangre , Biomarcadores/sangre , Ejercicio Físico/fisiología , Terapia por Ejercicio/métodos , Trasplante de Corazón/rehabilitación , Inflamación/sangre , Inflamación/fisiopatología , Mediadores de Inflamación/sangre , Interleucina-6/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND AND AIMS: Research into the relationship between an Energy-adjusted Diet-Inflammatory Index (E-DII) and a wider health-related biomarkers profile is limited. Much of the existing evidence centers on traditional metabolic biomarkers in populations with chronic diseases, with scarce data on healthy individuals. Thus, this study aims to investigate the association between an E-DII score and 30 biomarkers spanning metabolic health, endocrine, bone health, liver function, cardiovascular, and renal functions, in healthy individuals. METHODS AND RESULTS: 66,978 healthy UK Biobank participants, the overall mean age was 55.3 (7.9) years were included in this cross-sectional study. E-DII scores, based on 18 food parameters, were categorised as anti-inflammatory (E-DII < -1), neutral (-1 to 1), and pro-inflammatory (>1). Regression analyses, adjusted for confounding factors, were conducted to investigate the association of 30 biomarkers with E-DII. Compared to those with an anti-inflammatory diet, individuals with a pro-inflammatory diet had increased levels of 16 biomarkers, including six cardiometabolic, five liver, and four renal markers. The concentration difference ranged from 0.27 SD for creatinine to 0.03 SD for total cholesterol. Conversely, those on a pro-inflammatory diet had decreased concentrations in six biomarkers, including two for endocrine and cardiometabolic. The association range varied from -0.04 for IGF-1 to -0.23 for SHBG. CONCLUSION: This study highlighted that a pro-inflammatory diet was associated with an adverse profile of biomarkers linked to cardiometabolic health, endocrine, liver function, and renal health.
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Biomarcadores , Mediadores de Inflamación , Inflamación , Riñón , Hígado , Humanos , Estudios Transversales , Masculino , Persona de Mediana Edad , Biomarcadores/sangre , Femenino , Reino Unido/epidemiología , Anciano , Riñón/fisiopatología , Inflamación/sangre , Inflamación/diagnóstico , Adulto , Mediadores de Inflamación/sangre , Hígado/metabolismo , Factores de Riesgo Cardiometabólico , Dieta/efectos adversos , Medición de Riesgo , Bancos de Muestras Biológicas , Huesos/metabolismo , Biobanco del Reino UnidoRESUMEN
Although multiple myeloma (MM) is a neoplasm that leads affected individuals to death, little is known about why some patients survive much longer than others. In this context, we investigated the transcriptomic profile of bone marrow hematopoietic stem cells obtained from MM patients and compared the clinical outcomes of death and survival six months after bone marrow transplantation. The leukapheresis products of 39 patients with MM eligible for autologous transplantation were collected and analyzed. After extraction, the RNA was analyzed using the GeneChip Human Exon 1.0 Array method. The transcriptome profile was analyzed in silico, and the differentially expressed signaling pathways of interest were validated. The results showed a difference in the expression of inflammation-related genes, immune response processes, and the oxidative stress pathway. The in silico study also pointed out the involvement of the NFκB transcription factor in the possible modulation of these genes. We chose to validate molecules participating in these processes, including the cytokines TNF-α, IFN-γ, and TGF-ß1; in addition, we measured the levels of oxidative stress mediators (pro-oxidant profile and the total antioxidant capacity). TNF-α levels were significantly reduced in patients who died and were over 50 years old at diagnosis, as well as in patients with plasmacytoma. Increased TNF-α was detected in patients with very high levels of ß2-microglobulin. IFN-γ reduction was observed in patients with a complete response to treatment compared to those with a very good response. Patients with plasmacytoma who died also had an increased pro-oxidant profile. These data show the profile of inflammatory response markers that are altered in patients with MM who die quickly and serve as a basis for the development of future studies of markers to predict better survival in this disease.
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Mediadores de Inflamación , Mieloma Múltiple , Transcriptoma , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/metabolismo , Persona de Mediana Edad , Masculino , Femenino , Transcriptoma/genética , Mediadores de Inflamación/metabolismo , Anciano , Estrés Oxidativo , Adulto , Células de la Médula Ósea/metabolismo , Análisis de Supervivencia , FN-kappa B/metabolismo , Inflamación/metabolismo , Inflamación/genética , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Background/Aims: Extracellular vesicles (EVs) are promising as a biomarker of metabolic dysfunction associated steatotic liver disease (MASLD). The objective is to study EVs and their involvement in MASLD concerning the disease's pathogenesis and progression characteristics. Methods: Male adult Sprague Dawley rats were randomly assigned into two experimental models of MASLD: MASLD-16 and MASLD-28, animals received a choline-deficient high-fat diet (CHFD) and Control-16 and Control-28, animals received a standard diet (SD) for 16 and 28 weeks, respectively. Biological samples from these animal models were used, as well as previously registered variables. EVs from hepatic tissue were characterized using confocal microscopy. EVs were isolated through differential ultracentrifugation from serum and characterized using NanoSight. The data from the EVs were correlated with biochemical, molecular, and histopathological parameters. Results: Liver EVs were identified through the flotillin-1 protein. EVs were isolated from the serum of all groups. There was a decrease of EVs concentration in MASLD-28 in comparison with Control-28 (P < 0.001) and a significant increase in EVs concentration in Control-28 compared with Control-16 (P < 0.001). There was a strong correlation between serum EVs concentration with hepatic gene expression of interleukin (Il)6 (r2 = 0.685, P < 0.05), Il1b (r2 = 0.697, P < 0.05) and tumor necrosis factor-alpha (Tnfa; r2 = 0.636, P < 0.05) in MASLD-16. Moreover, there was a strong correlation between serum EVs size and Il10 in MASLD-28 (r2 = 0.762, P < 0.05). Conclusion: The concentration and size of EVs correlated with inflammatory markers, suggesting their involvement in the systemic circulation, cellular communication, and development and progression of MASLD, demonstrating that EVs have the potential to serve as noninvasive biomarkers for MASLD diagnosis and prognosis.
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Dieta Alta en Grasa , Modelos Animales de Enfermedad , Vesículas Extracelulares , Ratas Sprague-Dawley , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patología , Animales , Masculino , Ratas , Hígado/metabolismo , Hígado/patología , Biomarcadores/sangre , Biomarcadores/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Hígado Graso/patología , Hígado Graso/metabolismo , Hígado Graso/etiología , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/sangre , Inflamación/patología , Inflamación/metabolismo , Deficiencia de Colina/complicacionesRESUMEN
Saliva measurements serve as a noninvasive tool for clinically monitoring newborns (NB) and children, a vulnerable population with promising potential for both research and clinical practice. Saliva acts as a repository for various inflammatory biomarkers involved in diverse biological functions. Particularly for children, it offers numerous advantages when compared to plasma and urine sampling. Nevertheless, there is a significant knowledge gap regarding detectable levels of cytokines in the saliva of newborns and children, as well as studies aiming to assess the relationship of this content with physiological and pathological processes. OBJECTIVES: To characterize the levels of 11 inflammatory mediators (IFNg, IL1b, IL2, IL4, IL6, IL8, IL10, IL12, IL17, TNF, and VEGF) in saliva samples from NB on the first and second day of hospitalization in the Neonatal Intensive Care Unit (NICU). METHOD: Exploratory study, descriptive, nested within a primary clinical, observational, and prospective study, conducted in the NICU of a public hospital in São Paulo, Brazil. Demographic data and vital signs were recorded in the clinical records of 90 NB, and five saliva samples from 5 NB were collected between the first and second day of life (D1-D2) at approximately 8-hr intervals (8-9 am, 4-5 pm, and 11-12 pm). Saliva samples were used for the measurement of 11 cytokines (IFNg, IL1b, IL2, IL4, IL6, IL8, IL10, IL12, IL17, TNF, and VEGF). RESULTS: Five NBs participated in this exploratory study, and the vital signs showed variability from the first (D1) to the second day (D2) of hospitalization, variability similar to that of the total population of the primary study. The presence and levels of the 11 cytokines were detected in the saliva samples, as well as a statistical correlation between 10 cytokines (IFNg, IL1b, IL2, IL4, IL6, IL10, IL12, IL17, TNF, and VEGF) and vital signs. CONCLUSIONS: The novelty of measuring inflammatory mediators in saliva samples from hospitalized NBs in the NICU is highlighted, providing support and new perspectives for the development of clinical and experimental research and an opportunity for developing and implementing new salivary biomarkers in different population segments.
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Biomarcadores , Citocinas , Unidades de Cuidado Intensivo Neonatal , Saliva , Humanos , Saliva/química , Recién Nacido , Biomarcadores/análisis , Biomarcadores/metabolismo , Masculino , Femenino , Citocinas/análisis , Citocinas/metabolismo , Estudios Prospectivos , Brasil , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/análisis , HospitalizaciónRESUMEN
PURPOSE: Osteoarthritis (OA) is a degenerative joint disease which is categorized via destruction of joint cartilage and it also affects the various joints, especially knees and hips. Sinomenine active phytoconstituents isolated from the stem of Sinomenium acutum and already proof anti-inflammatory effect against the arthritis model of rodent. In this experimental protocol, we scrutinized the anti-osteoarthritis effect of sinomenine against monosodium iodoacetate (MIA) induced OA in rats. METHODS: MIA (3 mg/50 µL) was used for inducing the OA in the rats, and rats received the oral administration of sinomenine (2.5, 5 and 7.5 mg/kg body weight) up to the end of the experimental study (four weeks). The body and organs weight were estimated. Aggrecan, C-terminal cross-linked telopeptide of type II collagen (CTX-II), glycosaminoglycans (GCGs), monocyte chemoattractant protein-1 (MCP-1), Interferon gamma (IFN-γ), antioxidant, inflammatory cytokines, inflammatory mediators and matrix metalloproteinases (MMP) were analyzed. RESULTS: Sinomenine significantly (P < 0.001) boosted the body weight and reduced the heart weight, but the weight of spleen and kidney remain unchanged. Sinomenine significantly (P < 0.001) reduced the level of nitric oxide, MCP-1 and improved the level of aggrecan, IFN-γ and GCGs. Sinomenine remarkably upregulated the level of glutathione, superoxide dismutase and suppressed the level of malonaldehyde. It effectually modulated the level of inflammatory cytokines and inflammatory mediators and significantly (P < 0.001) reduced the level of MMPs, like MMP-1, 2, 3, 9 and 13. CONCLUSIONS: Sinomenine is a beneficial active agent for the treatment of OA disease.
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Cartílago Articular , Morfinanos , Osteoartritis , Ratas , Animales , Ácido Yodoacético/metabolismo , Ácido Yodoacético/farmacología , Osteoartritis/metabolismo , Agrecanos/metabolismo , Agrecanos/farmacología , Modelos Animales de Enfermedad , Cartílago Articular/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Peso CorporalRESUMEN
Arthritis and periodontitis are inflammatory diseases that share several immunopathogenic features. The expansion in the study of virus-induced arthritis has shed light on how this condition could impact other parts of the human body, including the mouth. Viral arthritis is an inflammatory joint disease caused by several viruses, most notably the alphaviruses Chikungunya virus (CHIKV), Sindbis virus (SINV), Ross River virus (RRV), Mayaro virus (MAYV), and O'nyong'nyong virus (ONNV). These viruses can induce an upsurge of matrix metalloproteinases and immune-inflammatory mediators such as Interleukin-6 (IL6), IL-1ß, tumor necrosis factor, chemokine ligand 2, and receptor activator of nuclear factor kappa-B ligand in the joint and serum of infected individuals. This can lead to the influx of inflammatory cells to the joints and associated muscles as well as osteoclast activation and differentiation, culminating in clinical signs of swelling, pain, and bone resorption. Moreover, several data indicate that these viral infections can affect other sites of the body, including the mouth. The human oral cavity is a rich and diverse microbial ecosystem, and viral infection can disrupt the balance of microbial species, causing local dysbiosis. Such events can result in oral mucosal damage and gingival bleeding, which are indicative of periodontitis. Additionally, infection by RRV, CHIKV, SINV, MAYV, or ONNV can trigger the formation of osteoclasts and upregulate pro-osteoclastogenic inflammatory mediators, interfering with osteoclast activation. As a result, these viruses may be linked to systemic conditions, including oral manifestations. Therefore, this review focuses on the involvement of alphavirus infections in joint and oral health, acting as potential agents associated with oral mucosal inflammation and alveolar bone loss. The findings of this review demonstrate how alphavirus infections could be linked to the comorbidity between arthritis and periodontitis and may provide a better understanding of potential therapeutic management for both conditions.
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Infecciones por Alphavirus , Artritis , Virus Chikungunya , Periodontitis , Humanos , Infecciones por Alphavirus/tratamiento farmacológico , Infecciones por Alphavirus/patología , Virus Chikungunya/fisiología , Mediadores de Inflamación/uso terapéutico , Ligandos , Virus del Río Ross/fisiologíaRESUMEN
OBJECTIVE: The objective of the study was to evaluate the expression of oxytocin receptors in normal and inflamed gingiva, as well as the effects of systemic administration of oxytocin in bone loss and gum inflammatory mediators in a rat model of experimental periodontitis. BACKGROUND DATA: Current evidence supports the hypothesis of a disbalance between the oral microbiota and the host's immune response in the pathogenesis of periodontitis. Increased complexity of the microbial biofilm present in the periodontal pocket leads to local production of nitrogen and oxygen-reactive species, cytokines, chemokines, and other proinflammatory mediators which contribute to periodontal tissue destruction and bone loss. Oxytocin has been suggested to participate in the modulation of immune and inflammatory processes. We have previously shown that oxytocin, nitric oxide, and endocannabinoid system interact providing a mechanism of regulation for systemic inflammation. Here, we aimed at investigating not only the presence and levels of expression of oxytocin receptors on healthy and inflamed gingiva, but also the effects of oxytocin treatment on alveolar bone loss, and systemic and gum expression of inflammatory mediators involved in periodontal tissue damage using ligature-induced periodontitis. Therefore, anti-inflammatory strategies oriented at modulating the host's immune response could be valuable adjuvants to the main treatment of periodontal disease. METHODS: We used an animal model of ligature-induced periodontitis involving the placement of a linen thread (Barbour flax 100% linen suture, No. 50; size 2/0) ligature around the neck of first lower molars of adult male rats. The ligature was left in place during the entire experiment (7 days) until euthanasia. Animals with periodontitis received daily treatment with oxytocin (OXT, 1000 µg/kg, sc.) or vehicle and/or atosiban (3 mg/kg, sc.), an antagonist of oxytocin receptors. The distance between the cement-enamel junction and the alveolar bone crest was measured in stained hemimandibles in the long axis of both buccal and lingual surfaces of both inferior first molars using a caliper. TNF-α levels in plasma were determined using specific rat enzyme-linked immunosorbent assays (ELISA). OXT receptors, IL-6, IL-1ß, and TNF-α expression were determined in gingival tissues by semiquantitative or real-time PCR. RESULTS: We show that oxytocin receptors are expressed in normal and inflamed gingival tissues in male rats. We also show that the systemic administration of oxytocin prevents the experimental periodontitis-induced increased gum expression of oxytocin receptors, TNF-α, IL-6, and IL-1ß (p < .05). Furthermore, we observed a reduction in bone loss in rats treated with oxytocin in our model. CONCLUSIONS: Our results demonstrate that oxytocin is a novel and potent modulator of the gingival inflammatory process together with bone loss preventing effects in an experimental model of ligature-induced periodontitis.
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Pérdida de Hueso Alveolar , Periodontitis , Ratas , Masculino , Animales , Oxitocina/uso terapéutico , Oxitocina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Receptores de Oxitocina/metabolismo , Modelos Animales de Enfermedad , Periodontitis/metabolismo , Encía/metabolismo , Pérdida de Hueso Alveolar/tratamiento farmacológico , Pérdida de Hueso Alveolar/prevención & control , Pérdida de Hueso Alveolar/etiología , Proceso Alveolar/metabolismo , Mediadores de Inflamación/metabolismoRESUMEN
Nurr1 is a member of the orphan nuclear receptor family NR4A (nuclear receptor subfamily 4 group A) that modulates inflammation in several cell lineages, both positively and negatively. Macrophages are key regulators of inflammatory responses, yet information about the role of Nurr1 in human macrophages is scarce. Here we examined Nurr1 expression and activity in steady state and activated human macrophages. Pro- and anti-inflammatory macrophages were generated in vitro by culture of blood monocytes with granulocyte/macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), respectively. Nurr1 expression was predominant in macrophages with the pro-inflammatory phenotype. Nurr1 activation with the agonists 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) or isoxazolo-pyridinone 7e (IP7e) did not globally modify the polarization status of pro-inflammatory macrophages, but they decreased their production of TNF, IL-1ß, IL-6, IL-8, IL-12 p40, CCL2, IFN-ß, and reactive oxygen species, with variable potencies. Conversely, Nurr1 deficient macrophages increased the expression of transcripts encoding inflammatory mediators, particularly that of IL6, IFNB1, and CCL2. Mechanistically, endogenous Nurr1 interacted with NF-κB p65 in basal conditions and upon lipopolysaccharide (LPS)-mediated activation. C-DIM12 stabilized those complexes in cells exposed to LPS and concurrently decreased NF-κB transcriptional activity and p65 nuclear translocation. Expression of high levels of Nurr1 was associated with a subset of dermal macrophages that display enhanced levels of TNF and lower expression of the anti-inflammatory marker CD163L1 in skin lesions from patients with bullous pemphigoid (BP), a chronic inflammatory autoimmune blistering disorder. These results suggest that Nurr1 expression is linked with the pro-inflammatory phenotype of human macrophages, both in vivo and in vitro, where it may constitute a brake to attenuate the synthesis of inflammatory mediators.