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Extracellular vesicles (EVs) are small particles released by many cell types in different tissues, including the liver, and transfer specific cargo molecules from originating cells to receptor cells. This process generally culminates in activation of distant cells and inflammation and progression of certain diseases. The global chronic liver disease (CLD) epidemic is estimated at 1.5 billion patients worldwide. Cirrhosis and liver cancer are the most common risk factors for CLD. However, hepatitis C and B virus infection and obesity are also highly associated with CLD. Nonetheless, the etiology of many CLD pathophysiological, cellular, and molecular events are unclear. Changes in hepatic lipid metabolism can lead to lipotoxicity events that induce EV release. Here, we aimed to present an overview of EV features, from definition to types and biogenesis, with particular focus on the molecules related to steatosis-related liver disease, diagnosis, and therapy.
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Systemic lupus erythematosus (SLE) is a chronic pathology characterized by a bimodal mortality pattern attributed to clinical disease activity and cardiovascular disease (CVD). A complex interaction between traditional CVD risk factors such as obesity, dyslipidemia, smoking, insulin resistance, metabolic syndrome, and hypertension, as well as the presence of non-traditional CVD risk factors such as hyperhomocysteinemia, pro-inflammatory cytokines, and C-reactive protein levels, has been suggested as a cause of the high prevalence of CVD in SLE patients. On the other hand, environmental factors, such as nutritional status, could influence the disease's prognosis; several nutrients have immunomodulators, antioxidants, and anti-cardiometabolic risk properties which could reduce SLE severity and organ damage by decreasing the development of traditional and non-traditional CVD risk factors. Therefore, this critical literature review discusses the therapeutic potential of nutritional approaches that could modulate the development of the main comorbidities related to CVD risk in SLE patients.
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Doenças Cardiovasculares , Hipertensão , Lúpus Eritematoso Sistêmico , Síndrome Metabólica , Humanos , Doenças Cardiovasculares/etiologia , Fatores de Risco , Lúpus Eritematoso Sistêmico/epidemiologia , Hipertensão/complicações , Síndrome Metabólica/complicaçõesRESUMO
There are few reports in oral squamous cell carcinoma (OSCC) that indicate the expression of macrophage migration inhibitory factor (MIF) in tissues, serum, or saliva of patients with OSCC. The aim of this study was to evaluate the mRNA expression and protein of MIF in tissues and serum, respectively, in OSCC patients and its association with the TNM stage. A cross-sectional study was performed. Serum and tissues of 25 patients with OSCC and 25 healthy control subjects (HCS) were included to evaluate the MIF mRNA expression and protein serum levels by real-time PCR and ELISA, respectively. Serum MIF levels were significantly higher in OSCC compared with control subjects. Furthermore, in the OSCC group, MIF was significantly increased in accordance with tumor disease stage (TNM III-IV), as well as in poorly differentiated tumors. The mRNA showed significantly higher levels in HCS, as well as in more differentiated tumors. The results of this study suggest that MIF could be an indicator of severity and progression of OSCC. Further studies are required to explore the role of MIF as a serological biomarker for OSCC.
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Biomarcadores Tumorais/sangue , Carcinogênese/metabolismo , Carcinoma de Células Escamosas/sangue , Movimento Celular/fisiologia , Fatores Inibidores da Migração de Macrófagos/sangue , Macrófagos/metabolismo , Neoplasias Bucais/sangue , Carcinoma de Células Escamosas/patologia , Proliferação de Células/fisiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Prognóstico , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Human adenovirus 36 (HAd36) infection has been associated with obesity. Experiments using 3T3-L1 adipocyte cultured cells and human adipose stem cells (hASCc) have shown that HAd36 stimulates the expression of genes implicated in cell differentiation and increased lipid accumulation. The presence of HAd36 in adipose tissue of overweight and obese women has also been confirmed. This study aims to analyze the presence of HAd36 DNA in the adipose tissue of women undergoing surgery for weight reduction and its relationship with obesity through changes in adipocyte morphology as well as the expression of C/EBPß and HIF-1α. METHODS: Fifty-two subcutaneous adipose tissue biopsies were collected. The anthropometric parameters measured were weight, height, skin folds, body circumferences, and body fat percentage. Biochemical measures were performed for glucose, cholesterol, triglycerides, cholesterol HDL-c, and LDL-c. The presence of HAd36 DNA was performed by conventional PCR. Adipocyte morphology was analyzed in H&E-stained sections using ImageJ/Fiji software. The expression of genes C/EBPß, HIF-1α and ß-actin was determined using TaqMan probes. RESULTS: HAd36 DNA was detected in 31% of adipose tissue samples. The presence of viral DNA was not significantly associated with anthropometric, clinical, or metabolic measurements, or with changes in adipose tissue morphology. The levels of mRNA expression for C/EBPß and HIF-1α did not show significant differences between positive and negative samples for HAd36 (p>0.05). CONCLUSION: The presence of HAd36 DNA in adipose tissue was identified, but it was not related to morphological changes of adipocytes, or the expression of C/EBPß and HIF-1α. Further studies are needed to confirm these findings.
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Macrophage migration Inhibitory Factor (MIF) is a cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive-feedback-loop with proinflammatory cytokines and could perpetuate the inflammatory process in Systemic Lupus Erythematosus (SLE).The aim of this study was to assess the effect of recombinant-human-MIF (rhMIF) on the expression of Th1, Th2 and Th17 cytokines in Peripheral Blood Mononuclear Cells (PBMC) from Healthy Subjects (HS) and SLE patients. The PBMC were isolated from SLE patients classified according to the 1997 SLE ACR criteria and HS donors; all subjects included were women from an unrelated Mexican-Mestizo population. The PBMC isolated were stimulated with rhMIF, LPS and ISO-1 in different combinations; Th1, Th2 and Th17cytokine profiles levels were determined by MAGPIX Bio-plex assay in supernatants from cell cultures. We observed in supernatants of PBMCs from HS treated with rhMIF a predominance of Th17 cytokine profile with an increase of IL-17A, IL-17F and IL-21 versus PBMCs from SLE patients, which showed an inflammatory profile represented by increase of IL-6 cytokine. According to SLE remission/activity presented at enrollment in the study (Mex-SLEDAI index), the PBMC from active SLE patients showed higher levels of TNF-α and IL-6 versus PBMC from remission SLE patients. In conclusion, our results suggest that MIF can induce a differential inflammatory response in physiological and pathological conditions with a predominance of a Th17 cytokine profile in PBMC from HS and an increase in TNF-α and IL-6 expression in PBMC from active SLE patients.
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Interleucina-6/imunologia , Oxirredutases Intramoleculares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto , Estudos de Casos e Controles , Citocinas/imunologia , Feminino , Humanos , Interleucina-17/imunologia , Interleucina-6/sangue , Oxirredutases Intramoleculares/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Lúpus Eritematoso Sistêmico/sangue , Fatores Inibidores da Migração de Macrófagos/farmacologia , Pessoa de Meia-Idade , Cultura Primária de Células , Proteínas Recombinantes/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Macrophage migration inhibitory factor (MIF) is an immunoregulatory cytokine that plays a crucial role as a regulator of the innate and adaptive immune responses and takes part in the destructive process of the joint in rheumatoid arthritis (RA) by promoting angiogenesis and inducing proinflammatory cytokines and matrix metalloproteinases (MMP). We evaluated if recombinant human MIF (rhMIF) induces the production of TNF-α, IFN-γ, IL-1ß, IL-6, IL-10, IL-17A, and IL- 17F in peripheral blood mononuclear cells (PBMC) from RA patients and control subjects (CS). METHODS: The PBMC from RA patients and CS were stimulated for 24 hours with combinations of LPS, rhMIF or the MIF antagonist ISO-1. Cytokine profiles were measured using a multiplex immunoassay and, macrophage migration inhibitory factor (MIF) was determined by ELISA kit. RESULTS: The PBMC of CS and RA produced Th1 and Th17 cytokines under stimulation with rhMIF, however, this effect was higher in the cells of RA patients. The rhMIFstimulated PBMC from RA patients produced higher levels of Th1 and Th17 cytokines in comparison with unstimulated cells: TNF-α (538.81 vs. 5.02 pg/mL, p<0.001), IFN-γ (721.90 vs. 8.40 pg/mL, p<0.001), IL-1ß (150.14 vs. 5.17 pg/mL, p<0.05), IL-6 (19769.70 vs. 119.85 pg/mL, p<0.001), IL-17A (34.97 vs. 0.90 pg/mL, p<0.01) and IL-17F (158.43 vs. 0.92 pg/mL, p<0.001). CONCLUSION: These results highlight the potential role of MIF in the establishment of the chronic inflammatory process in RA via Th1 and Th17 cytokine profile induction and provide new evidence of the role of MIF to stimulate the IL-17A and IL-17F expression in PBMC from RA and CS.
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Artrite Reumatoide/imunologia , Citocinas/imunologia , Oxirredutases Intramoleculares/farmacologia , Fatores Inibidores da Migração de Macrófagos/farmacologia , Células Th1/imunologia , Células Th17/imunologia , Adulto , Artrite Reumatoide/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Células Th1/patologia , Células Th17/patologiaRESUMO
The presence of childhood obesity predisposes to the development of cardio vascular and metabolic diseases, such as coronary artery disease and type 2 diabetes mellitus, in adulthood. The polymorphisms described in PAI-1 gene have been linked with obesity and metabolic syndrome in several populations. The aim of this study was to investigate the as sociation of the -844 G/A (rs2227631), -675 4G/5G (rs1799889) and HindIII C/G (rs757716) PAI-1 polymorphisms with obesity and dyslipidemia in a sample of Mexican children. A cross-sectional study was performed in 222 children with an age range between 6-11 years; 104 children were classified as obese and 118 children with normal-weight. The PAI-1 poly morphisms were analyzed by PCR-RFLP. Linkage disequilibrium (LD) and haplogenotype analysis among the three polymorphisms were determined. The results showed significant as sociations with obesity of the -844 G/A genotype and the A allele (OR= 2.75, p<0.001 and OR= 1.76, p=0.01, respectively). The -844 G/A polymorphism was found in LD with -675 4G/5G PAI-1 polymorphism (D= 0.77). We found that G-4G-C/A-5G-G is a risk haplogeno type for obesity [OR=2.6; 95% confidence interval (CI) 1.17-4.22; p= 0.01] and with marginal association with hypertriglyceridemia(OR= 2.6; 95% CI 1.04-6.35; p= 0.05). The G-4G-C/A 5G-G PAI-1 haplogenotype may be a genetic marker of susceptibility for obesity and hypertri glyceridemia in Mexican children.
La presencia de la obesidad en la infancia predispone al desarrollo de enfermedades cardiovasculares y metabólicas, como la enfermedad arterial coronaria y la diabetes mellitus tipo 2 en la edad adulta. Algunos polimorfismos en el gen PAI-1 se han relacionado con la obesidad y el síndrome metabólico en varias poblaciones. El objetivo del estudio fue investigar la asociación de los polimorfismos -844 G/A (rs2227631), -675 4G/5G (rs1799889) y HindIII C/G (rs757716) en el gen PAI-1 con la obesidad y las dislipidemias en una muestra de niños mexicanos. Se realizó un estudio transversal en 222 niños con un rango de edad de 6-11 años, de los cuales 104 niños fueron clasificados con obesidad y 118 con peso normal. Los poli morfismos en el gen PAI-1 fueron analizados por PCR-RFLP. También se determinó el desequilibrio de ligamiento y el análisis de haplogenotipos de los tres polimorfismos. Los resultados mostraron la asociación significativa de la obesidad con el genotipo -844 G/A y el alelo A (OR= 2,75, p<0,001 y OR= 1,76, p=0,01, respectivamente). El polimorfismo -844 G/A se encontró en desequilibrio de ligamiento con el -675 4G/5G (D= 0.77). También se encontró que el haplogenotipo G-4G-C/A-5G-G es un marcador de riesgo para la obesidad [OR=2,6; 95% intervalo de confianza (CI) 1,17-4,22; p= 0,01], además de que este haplogenotipo presentó una asociación marginal con la hipertrigliceridemia (OR= 2,6; 95% CI 1,04-6,35; p= 0,05). El haplogenotipo G-4G-C/A-5G-G en el gen PAI-1 puede ser un marcador genético de susceptibilidad para obesidad e hipertrigliceridemia en niños mexicanos.
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Criança , Feminino , Humanos , Masculino , Hipertrigliceridemia/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Obesidade Infantil/genética , Estudos Transversais , Predisposição Genética para Doença , Genótipo , MéxicoRESUMO
Macrophage migration inhibitory factor (MIF) and tumor necrosis factor alpha (TNFα) play a pivotal role in rheumatoid arthritis (RA). MIF is considered a relevant cytokine because it appears before TNFα in the inflammatory cascade thus stimulating TNFα production and MIF's relationship with traditional synthetic disease modifying antirheumatic drugs (sDMARDs) is unknown. In this cross-sectional study, we investigated the association of MIF and TNFα serum levels with methotrexate (MTX) and in combination with chloroquine (CLQ) and sulfasalazine (SSZ) in RA patients classified according to the ACR/EULAR 2010 criteria. Patients were divided into three groups: MTX-monotherapy group (n = 40), MTX combination therapy groups: MTX + CLQ (n = 41), and MTX + CLQ + SSZ (n = 42). MIF and TNFα serum levels were determined by ELISA. We found high levels of ESR, CRP, RF, and anti-CCP in all therapy groups. Furthermore, we subclassified 97 patients with established RA (≥2 years of disease duration) and found that TNFα serum levels were lower in the combination therapy group (MTX + CLQ + SSZ) in comparison with the monotherapy MTX group (16.7 pg/mL versus 13.6 pg/mL, p = 0.02). However, we did not find differences between sDMARD therapies in MIF serum levels. We did find a significant reduction in MIF serum levels in patients treated with oral steroids compared with patients without oral steroids (1.7 ng/mL versus 4.3 ng/mL, p < 0.001). In conclusion, this study supports the role of sDMARDs in modifying TNFα serum levels and oral steroids MIF serum levels. Nevertheless, we found that MIF serum levels are not modified by sDMARD treatment.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Oxirredutases Intramoleculares/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Psoriatic arthritis (PsA) is an autoimmune disease with a complex interaction of gene and with a dysregulation of pro-inflammatory cytokine such as Macrophage migration Inhibitory Factor (MIF) and Tumor Necrosis Factor-alpha (TNFα). Two polymorphisms identified in the promoter region of the MIF gene have been described: the STR-794 CATT5-8 (rs5844572) and the SNP-173 G>C (rs755622), which are associated with increased MIF levels in circulation and with autoimmune diseases in several populations. In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with PsA susceptibility and clinical variables as well as with MIF and TNFα serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 and -173 G>C MIF polymorphisms was performed by PCR and PCR-RFLP respectively in 50 PsA patients and 100 healthy subjects (HS). MIF and TNFα serum levels were determined by ELISA. A significant increase of MIF (PsA: 7.8 vs. HS: 5.25 ng/mL; p < 0.001) and TNFα (PsA: 24.6 vs. HS: 9.9 pg/mL; p < 0.001) levels was found in PsA patients, a significant correlation was observed between MIF and TNFα (r = 0.41; p < 0.01). The 5,6 repeats genotype of the -794 CATT5-8 MIF was associated with protection to PsA (OR = 0.29; CI 0.77-0.98; p = 0.03), and the G/C genotype (OR = 7.5; CI 2.92-21.64; p < 0.001) and the -173*C allele (OR = 2.45; CI 1.43-4.20; p < 0.001) of the -173 G>C MIF were associated with susceptibility to PsA. In conclusion the -173*C allele is associated with susceptibility to PsA in Mexican-Mestizo population, whereas the correlation between MIF and TNFα soluble levels provided evidence that both cytokines are closely related in the pathophysiology of the PsA.
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En diversos estudios se ha identificado que la obesidad y principalmente el aumento de adiposidad en la región abdominal, se asocia con inflamación de grado bajo, resistencia a la insulina (RI), homeostasis alterada de la glucosa y con sus comorbilidades tales como la diabetes mellitus tipo 2 (DMT2), la hipertensión, las dislipidemias y las enfermedades cardiovasculares. El factor inhibidor de la migración de macrófagos (MIF) es una citocina proinflamatoria involucrada en enfermedades autoinmunes e inflamatorias. Sin embargo, actualmente, se sugiere que el MIF está involucrado en el proceso inflamatorio que acompaña a la obesidad, así como en el control metabólico de las complicaciones asociadas a la obesidad. Los diferentes estudios muestran de manera consistente, el aumento en los niveles séricos del MIF en personas con obesidad, diabetes tipo 2 y en los diabéticos que presentan complicaciones microvasculares (la nefropatía, la retinopatía y el síndrome de pie diabético). La relación del MIF con la regulación del metabolismo de la glucosa y la apoptosis de las células β pancreáticas, así como la asociación de algunos polimorfismos funcionales en el promotor del gen del MIF con la obesidad y la diabetes. Esta revisión resume conocimientos basados en estudios clínicos y epidemiológicos sobre el papel del MIF en la obesidad y la diabetes tipo 2.
Several studies have found that obesity and increased adiposity mainly in the abdominal region, are associated with low-grade inflammation, insulin resistance (IR), impaired glucose homeostasis and comorbidities such as type 2 diabetes mellitus (T2D) and cardiovascular disease. The macrophage migration inhibitory factor (MIF), is a proinflammatory cytokine involved in autoimmune and inflammatory diseases. However, currently it is suggested that MIF is involved in the inflammatory process associated with obesity and the metabolic control of the complications associated with obesity. Different studies show consistently, increased serum levels of MIF in subjects with obesity, type 2 diabetes and diabetics with microvascular complications (nephropathy, retinopathy and diabetic foot syndrome). The relationship of the MIF to the regulation of glucose metabolism and apoptosis of pancreatic β cells, and the association of some functional polymorphisms in the promoter of the MIF gene with obesity and diabetes.This review summarizes, the knowledge based on clinical and epidemiological studies on the role of MIF in obesity and type 2 diabetes.