RESUMEN
Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet and deficiencies in essential nutrients. This study aimed to assess the levels of folate and vitamin B12 (B12) and their relationship with metabolic factors in women with PCOS. Anthropometric, clinical, and genetic analyses were conducted to evaluate markers related to one-carbon metabolism in women with PCOS and in a control group. The PCOS group had a higher BMI and HOMA-IR (1.7 vs. 3.1; p < 0.0001). HDL cholesterol levels were 23% lower and triglyceride levels were 74% higher in women with PCOS. Although there were no significant differences in folate and B12 levels between the PCOS and control groups, over 60% of women with PCOS had low B12 levels (<300 pg/mL) and high homocysteine levels. In addition, the MTHFR A1298C and C677T polymorphisms were not associated with PCOS. Moreover, erythrocyte folate levels were positively correlated with fasting glucose, triglycerides, and free androgen index, and negatively correlated with SHBG and LH levels. These results suggest that B vitamins may be associated with the metabolic phenotype in PCOS. This study emphasizes the potential link between folate, vitamin B12, and metabolic and hormonal outcomes in women with PCOS.
Asunto(s)
Ácido Fólico , Síndrome del Ovario Poliquístico , Vitamina B 12 , Humanos , Femenino , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/genética , Vitamina B 12/sangre , Ácido Fólico/sangre , Adulto , Chile/epidemiología , Adulto Joven , Triglicéridos/sangre , Homocisteína/sangre , Índice de Masa Corporal , Glucemia/metabolismo , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Resistencia a la Insulina , HDL-Colesterol/sangre , Estudios de Casos y Controles , Biomarcadores/sangreRESUMEN
Changes in gut microbiota composition and in epigenetic mechanisms have been proposed to play important roles in energy homeostasis, and the onset and development of obesity. However, the crosstalk between epigenetic markers and the gut microbiome in obesity remains unclear. The main objective of this study was to establish a link between the gut microbiota and DNA methylation patterns in subjects with obesity by identifying differentially methylated DNA regions (DMRs) that could be potentially regulated by the gut microbiota. DNA methylation and bacterial DNA sequencing analysis were performed on 342 subjects with a BMI between 18 and 40 kg/m2. DNA methylation analyses identified a total of 2648 DMRs associated with BMI, while ten bacterial genera were associated with BMI. Interestingly, only the abundance of Ruminococcus was associated with one BMI-related DMR, which is located between the MACROD2/SEL1L2 genes. The Ruminococcus abundance negatively correlated with BMI, while the hypermethylated DMR was associated with reduced MACROD2 protein levels in serum. Additionally, the mediation test showed that 19% of the effect of Ruminococcus abundance on BMI is mediated by the methylation of the MACROD2/SEL1L2 DMR. These findings support the hypothesis that a crosstalk between gut microbiota and epigenetic markers may be contributing to obesity development.
Asunto(s)
Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Ruminococcus/genética , Índice de Masa Corporal , Metilación de ADN , Epigénesis Genética , Obesidad/genética , Obesidad/microbiología , ADN , Hidrolasas/genética , Enzimas Reparadoras del ADN/genéticaRESUMEN
Maternal obesity and the imbalance in linoleic acid (C18:2 n-6, LA) and alpha-linolenic acid (C18:3 n-3, ALA) levels are related with hepatic disturbances in the offspring. However, whether these alterations are present during fetal life is not well understood. Obese and normal weight pregnant women were recruited to determine fatty acids (FAs) consumption, FAs profile (in maternal erythrocytes, placenta and neonatal very low-density lipoproteins VLDL) and biomarkers of fetal liver function, such as gamma-glutamyl transferase (GGT), alpha-fetoprotein (AFP) and albumin, in umbilical cord blood. Stearic acid (C18:0, ST) was lower, and total n-3 FAs tended to be lower in umbilical cord VLDLs of obese women compared to controls. Independently of maternal obesity, GGT levels in umbilical cord blood was positively correlated with the LA content and negatively correlated with the ALA content in maternal erythrocytes. We conclude that maternal obesity and its imbalance of LA and ALA are associated with changes in biomarkers of fetal liver function.
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Obesidad Materna , Recién Nacido , Humanos , Femenino , Embarazo , Ácido alfa-Linolénico , Ácidos Grasos , Ácidos Grasos Esenciales , Obesidad , Ácido Linoleico , Sangre Fetal , Hígado , BiomarcadoresRESUMEN
La diabetes mellitus tipo 1 (DM1) es una enfermedad autoinmune que genera dependencia exógena de insulina de forma permanente, presenta inflamación subclínica crónica lo que conlleva a una elevación de marcadores de inflamación como factor de necrosis tumoral alfa (TNF-α), proteína C reactiva (PCR) e interleuquina 6 (IL-6). OBJETIVO: determinar la relación entre el IMC sobre los marcadores de inflamación y el control metabólico en niños y jóvenes con DM1 entre 5 a 15 años de edad. METODOLOGÍA: Se realizó un estudio clínico, observacional, exploratorio. A partir de La recolección de datos de fichas clínicas y muestras de sangre en el Instituto de Investigaciones Materno Infantil (IDIMI) del Hospital San Borja Arriarán de la Universidad de Chile. Clasificación del estado nutricional utilizando datos registrados en ficha clínica. Marcadores de inflamación por medio de ELISA, hemoglobina glicosilada mediante métodos estándares. El análisis estadístico incluyó correlaciones mediante test de Spearman y diferencia de medias mediante test de Kruskal-Wallis seguido de post hoc Dunns. RESULTADOS: Un 30% de los pacientes con DM1 presentaron malnutrición por exceso. Al analizar la relación entre los niveles de marcadores inflamatorios y Hb glicosilada se observó la existencia de asociacion positiva entre usPCR y HbA1c (r= 0,30; p=0,0352) y entre IL-6 y HbA1c (r= - 0,038; p=0,0352). CONCLUSIONES: este estudio describe una posible asociación entre parámetros clásicos de inflamación con la hemoglobina glicosilada en las categorias de sobrepeso y obesidad en pacientes con DM1.
Type 1 diabetes mellitus (T1D) is an autoimmune disease that generates permanent exogenous insulin dependence, accompanied by chronic subclinical inflammation that leads to an elevation of inflammation markers such as tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP) and interleukin-6 (IL-6). OBJECTIVE: To determine the relationship between BMI on markers of inflammation and metabolic control in children and young people with T1D between 5 and 15 years of age. METHODOLOGY: A clinical, observational and exploratory study was carried out, based on the collection of data from clinical records and blood samples of children and adolescents with DM1 at the Instituto de Investigaciones Materno Infantil (IDIMI) of the Hospital San Borja Arriarán of the Universidad de Chile. Nutritional status, levels of inflammation markers and glycosylated hemoglobin were determined by standardized methods. Statistical analysis included correlations by Spearman test and mean difference by Kruskal-Wallis test followed by post hoc Dunns test. RESULTS: A total of 56 patients with T1D were analyzed, 30% of whom presented excess malnutrition. Those children or adolescents with obesity presented significantly higher usPCR levels compared to underweight patients or patients at risk of malnutrition (p=0.039). In addition, HbA1c levels were determined which were negatively associated with usPCR (r= 0.30; p=0.0352) and IL-6 (r= - 0.038; p=0.0352) levels. CONCLUSIONS: This study points out that nutritional status is associated with usPCR levels, in agreement with what is described in the literature and shows a possible association between classical parameters of inflammation with glycosylated hemoglobin in children and adolescents with nutritional diagnosis of overweight or obesity.
Asunto(s)
Humanos , Niño , Adolescente , Hemoglobina Glucada/análisis , Biomarcadores/análisis , Índice de Masa Corporal , Diabetes Mellitus Tipo 1/metabolismo , Proteína C-Reactiva/análisis , Ensayo de Inmunoadsorción Enzimática , Estado Nutricional , Interleucina-6/análisis , Factor de Necrosis Tumoral alfa/análisis , Estadísticas no Paramétricas , InflamaciónRESUMEN
Rodent models in rats, mice, and guinea pigs have been extremely helpful to gain insight into pregnancy physiology and pathologies-related. Moreover, they have allowed understanding the mechanism that links an adverse intrauterine environment with the origin of adult disease. In this regard, the effects of diverse maternal conditions, such as undernutrition, obesity, hypoxia, and hyperandrogenism on placental function and its long-term consequences for the offspring, have been widely analyzed through rodents models involving dietary manipulations, modifications in environmental oxygen, surgical and pharmacological procedures that reduce uteroplacental blood flow and administrations of exogenous testosterone and dihydrotestosterone (DHT) mimicking maternal androgen excess. Both in human and in rodent models, these interventions induce modifications of placental morphology, transport of glucose, amino acid, and fatty acids, steroid synthesis, and signaling pathways control placental function. These changes are associated with the increase of pro-inflammatory and oxidative stress markers. For its part, offspring exhibit alterations in organs involved in metabolic control such as the hypothalamus, adipose tissue, liver, skeletal muscle, and pancreas altering the intake and preferences for certain foods, the metabolism of glucose and lipid, and hormonal function leading to fat accumulation, insulin resistance, fatty liver, dyslipidemia, and elevated glucose levels. Therefore, the present review discusses the evidence emerging from rodent models that relate maternal nutrition, hypoxia, and androgen exposure to the maternal mechanisms that lead to fetal programming and their metabolic consequences in postnatal life.
RESUMEN
Differentially methylated regions (DMR) are genomic regions with different methylation status. The aim of this research was to identify DMRs in subjects with obesity that predict the response to a weight-loss dietary intervention and its association with metabolic variables. Based on the change in body mass index (BMI), 201 subjects with overweight and obesity were categorized in tertiles according to their response to a hypocaloric diet: Responders (R; n = 64) and Non-Responders (NR; n = 63). The R group lost 4.55 ± 0.91 BMI units (kg/m2) and the NR group lost 1.95 ± 0.73 kg/m2 (p < 0.001). DNA methylation was analysed in buffy coat through a methylation array at baseline. DMRs were analysed using a function of ChAMP (Chip Analysis Methylation Pipeline) in R software. Baseline DNA methylation analysis between R and NR exhibited a DMR located at paraoxonase 3 gene (PON3) consisting of 13 CpG sites, eleven of them significantly hypermethylated in R. To analyse the implication of these 11 CpGs on weight loss, a z-score was performed as a measure of DMR methylation. This analysis showed a correlation between PON3 DNA methylation and BMI loss. This z-score negatively correlated with PON3 protein serum levels. Total paraoxonase activity in serum was not different between groups, but PON enzymatic activity positively correlated with oxidized LDL levels. The present study identified a DMR within PON3 gene that is related to PON3 protein levels in serum, and that could be used as a potential biomarker to predict the response to weight-loss dietary interventions.
Asunto(s)
Metilación de ADN , Dieta Reductora , Arildialquilfosfatasa/genética , Índice de Masa Corporal , Humanos , Obesidad/genética , Pérdida de Peso/genéticaRESUMEN
Scavenger receptor class B type 1 (SR-B1) is a membrane lipoprotein receptor/lipid transporter involved in the pathogenesis of atherosclerosis, but its role in obesity and fatty liver development is unclear. Here, we determined the effects of SR-B1 deficiency on plasma metabolic and inflammatory parameters as well as fat deposition in adipose tissue and liver during obesity. To induce obesity, we performed high-fat diet (HFD) exposure for 12 weeks in male SR-B1 knock-out (SR-B1-/-, n = 14) and wild-type (WT, n = 12) mice. Compared to HFD-fed WT mice, plasma from HFD-fed SR-B1-/- animals exhibited increased total cholesterol, triglycerides (TG) and tumor necrosis factor-α (TNF-α) levels. In addition, hypertrophied adipocytes and macrophage-containing crown-like structures (CLS) were observed in adipose tissue from HFD-fed SR-B1 deficient mice. Remarkably, liver from obese SR-B1-/- mice showed attenuated TG content, dysregulation in hepatic peroxisome proliferator-activated receptors (PPARs) expression, increased hepatic TG secretion, and altered hepatic fatty acid (FA) composition. In conclusion, we show that SR-B1 deficiency alters the metabolic environment of obese mice through modulation of liver and adipose tissue lipid accumulation. Our findings provide the basis for further elucidation of SR-B1's role in obesity and fatty liver, two major public health issues that increase the risk of advanced chronic diseases and overall mortality.
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Tejido Adiposo/patología , Antígenos CD36/deficiencia , Dieta Alta en Grasa/efectos adversos , Hígado Graso/complicaciones , Hígado Graso/metabolismo , Obesidad/complicaciones , Obesidad/etiología , Animales , Susceptibilidad a Enfermedades , Ácidos Grasos/metabolismo , Hígado Graso/patología , Inflamación/complicaciones , Hígado/metabolismo , Masculino , Ratones , Triglicéridos/metabolismoRESUMEN
La diabetes Tipo 1 (DT1) es una compleja enfermedad autoinmune con una etiología aún desconocida. La vitamina D ha sido ampliamente estudiada debido a su potencial terapéutico en los potenciales nuevos casos de DT1. Por otra parte, los microARNs (miRs) han sido propuestos como posibles biomarcadores en diversos procesos biológicos como en la apoptosis e inflamación. El objetivo de este estudio fue evaluar el efecto de la suplementación con vitamina D sobre el perfil de expresión del miR-21 y marcadores de apoptosis tales como: BCL2, STAT3, TIPE2 y DAXX, en células mononucleares periféricas provenientes de pacientes con DT1 y sujetos controles. RESULTADOS: El perfil de expresión de miR-21 se encontró disminuido en los pacientes con DT1 en comparación con los controles. La expresión relativa de BCL2 se encontró aumentada en controles al comparar con pacientes DT1 en todas las condiciones experimentales. La expresión relativa de DAXX mostró un perfil de expresión diferencial al comparar pacientes con DT1 versus controles (p=0.006). CONCLUSIÓN: El estímulo con vitamina D parece tener un posible efecto regulador sobre los genes BCL2 y DAXX.
Type 1 diabetes (T1D) is a complex chronic autoimmune disease. Vitamin D has been one of the most studied therapeutic potential outbreaks related to T1D. Specific miRNAs have been proposed as potential biomarkers in several biological processes as apoptosis and inflammation. The aim of this study was to evaluate the effect of vitamin D on the expression profiles of miR-21 and apoptotic markers BCL2, STAT3, TIPE2 and DAXX, in PBMCs from T1D patients and control subjects. RESULTS: miR-21 expression was increased in controls regarding T1D patients. BCL2 was increased in controls compared to T1D patients in all experimental conditions. DAXX showed different expression patterns between T1D patients and controls (p=0.006). CONCLUSION: Vitamin D showed a possible regulation effect on apoptosis markers mainly through the regulation of BCL2 and DAXX
Asunto(s)
Humanos , Niño , Adolescente , Vitamina D/administración & dosificación , Apoptosis , Diabetes Mellitus Tipo 1/metabolismo , Vitamina D/metabolismo , Biomarcadores , Chaperonas Moleculares/efectos de los fármacos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , MicroARNs/efectos de los fármacos , MicroARNs/genética , MicroARNs/metabolismo , Factor de Transcripción STAT3/efectos de los fármacos , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Proteínas Co-Represoras/efectos de los fármacos , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Glucosa/administración & dosificaciónRESUMEN
Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose.
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Glucemia , Metilación de ADN/genética , Resistencia a la Insulina/genética , Secreción de Insulina/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Regiones Promotoras Genéticas/genética , Adulto , Biomarcadores/sangre , Chile , Femenino , HumanosRESUMEN
Circulating microRNAs (miRNAs) are valuable biomarkers that may provide important insight into the pathogenesis of metabolic syndrome (MetS). Moreover, there is an association between chronotypical characteristics and MetS predisposition. Considering that expression of some miRNAs is circadian-rhythm-dependent, the aim of this study was to investigate the circulating miRNA profile in subjects with and without MetS in association with chronotype. The expression of 86 metabolic syndrome-related miRNAs was investigated in the plasma of 21 subjects with MetS and in 82 subjects without MetS using miRCURY LNA miRNA PCR System technology. Chronotype was assessed using the Horne and Östberg Morningness-Eveningness Questionnaire. Bioinformatic analyses were performed to explore the target genes and biological pathways regulated by the selected miRNAs. Subjects with MetS were more often evening chronotype compared to non-MetS controls. Additionally, four miRNAs (miR-140-3p, miR-150-5p, miR-375, and miR-29 c-3p) demonstrated interaction with MetS and chronotype. Interestingly, the target genes of these four miRNAs participate in pathways related to the circadian clock. In conclusion, we identified four circulating miRNAs whose circulating levels could interact with MetS and chronotype.
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MicroARN Circulante , Síndrome Metabólico , MicroARNs , Biomarcadores , Ritmo Circadiano/genética , MicroARN Circulante/genética , Humanos , Síndrome Metabólico/genética , MicroARNs/genéticaRESUMEN
Clinical and experimental evidences indicate that epigenetic modifications induced by the prenatal environment are related to metabolic and reproductive derangements in polycystic ovary syndrome (PCOS). Alterations in the leptin and adiponectin systems, androgen signalling and antimüllerian hormone (AMH) levels have been observed in PCOS women and in their offspring. Using a targeted Next-Generation Sequencing (NGS), we studied DNA methylation in promoter regions of the leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), adiponectin receptor 1 and 2 (ADIPOR1 and ADIPOR2), AMH and androgen receptor (AR) genes in 24 sons and daughters of women with PCOS (12 treated with metformin during pregnancy) and 24 children born to non-PCOS women during early infancy (2-3 months of age). Genomic DNA was extracted from whole blood, bisulphite converted and sequenced by NGS. Girls showed differences between groups in 1 CpG site of LEPR, 2 of LEP, 1 of ADIPOR2 and 2 of AR. Boys showed differences in 5 CpG sites of LEP, 3 of AMH and 9 of AR. Maternal metformin treatment prevented some of these changes in LEP, ADIPOR2 and partially in AR in girls, and in LEP and AMH in boys. Maternal BMI at early pregnancy was inversely correlated with the methylation levels of the ChrX-67544981 site in the whole group of girls (r = -0.530, p = 0.008) and with the global Z-score in all boys (r = -0.539, p = 0.007). These data indicate that the intrauterine PCOS environment predisposes the offspring to acquire certain sex-dependent DNA methylation patterns in the promoter regions of metabolic and reproductive genes.
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Metilación de ADN , Epigénesis Genética , Síndrome del Ovario Poliquístico/genética , Efectos Tardíos de la Exposición Prenatal/genética , Adiponectina/genética , Adiponectina/metabolismo , Adulto , Femenino , Humanos , Lactante , Leptina/genética , Leptina/metabolismo , Masculino , Embarazo , Regiones Promotoras Genéticas , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores de Leptina/genética , Receptores de Leptina/metabolismoRESUMEN
A healthy dietary pattern and high quality nutrient intake reduce atherosclerotic cardiovascular disease risk. Red wine grape pomace (RWGP)-a rich natural source of dietary fiber and antioxidants-appears to be a potential functional food ingredient. The impact of a dietary supplementation with RWGP flour was evaluated in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice, a model of lethal ischemic heart disease. SR-B1 KO/ApoER61h/h mice were fed with atherogenic (high fat, cholesterol, and cholic acid, HFC) diet supplemented with: (a) 20% chow (HFC-Control), (b) 20% RWGP flour (HFC-RWGP), or (c) 10% chow/10% oat fiber (HFC-Fiber); and survival time was evaluated. In addition, SR-B1 KO/ApoER61h/h mice were fed for 7 or 14 days with HFC-Control or HFC-RWGP diets and plasma lipid levels, inflammation, oxidative damage, and antioxidant activity were measured. Atherosclerosis and myocardial damage were assessed by histology and magnetic resonance imaging, respectively. Supplementation with RWGP reduced premature death, changed TNF-α and IL-10 levels, and increased plasma antioxidant activity. Moreover, decreased atheromatous aortic and brachiocephalic plaque sizes and attenuated myocardial infarction and dysfunction were also observed. These results suggest that RWGP flour intake may be used as a non-pharmacological therapeutic approach, contributing to decreased progression of atherosclerosis, reduced coronary heart disease, and improved cardiovascular outcomes.
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Antioxidantes/administración & dosificación , Aorta/metabolismo , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Suplementos Dietéticos , Frutas/química , Isquemia Miocárdica/prevención & control , Miocardio/metabolismo , Estrés Oxidativo , Extractos Vegetales/administración & dosificación , Vitis/química , Alimentación Animal , Animales , Antioxidantes/aislamiento & purificación , Antioxidantes/metabolismo , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Biomarcadores/sangre , Dieta Aterogénica , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/sangre , Interleucina-10/sangre , Lípidos/sangre , Masculino , Ratones Noqueados para ApoE , Isquemia Miocárdica/sangre , Isquemia Miocárdica/genética , Isquemia Miocárdica/patología , Miocardio/patología , Extractos Vegetales/sangre , Extractos Vegetales/aislamiento & purificación , Placa Aterosclerótica , Receptores Depuradores de Clase B/deficiencia , Receptores Depuradores de Clase B/genética , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Aging is the main risk factor for most chronic diseases. Epigenetic mechanisms, such as DNA methylation (DNAm) plays a pivotal role in the regulation of physiological responses that can vary along lifespan. The aim of this research was to analyze the association between leukocyte DNAm in genes involved in longevity and the occurrence of obesity and related metabolic alterations in an adult population. Subjects from the MENA cohort (n=474) were categorized according to age (<45 vs 45>) and the presence of metabolic alterations: increased waist circumference, hypercholesterolemia, insulin resistance, and metabolic syndrome. The methylation levels of 58 CpG sites located at genes involved in longevity-regulating pathways were strongly correlated (FDR-adjusted< 0.0001) with BMI. Fifteen of them were differentially methylated (p<0.05) between younger and older subjects that exhibited at least one metabolic alteration. Six of these CpG sites, located at MTOR (cg08862778), ULK1 (cg07199894), ADCY6 (cg11658986), IGF1R (cg01284192), CREB5 (cg11301281), and RELA (cg08128650), were common to the metabolic traits, and CREB5, RELA, and ULK1 were statistically associated with age. In summary, leukocyte DNAm levels of several CpG sites located at genes involved in longevity-regulating pathways were associated with obesity and metabolic syndrome traits, suggesting a role of DNAm in aging-related metabolic alterations.
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Envejecimiento/genética , Metilación de ADN , Longevidad/genética , Adulto , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Resistencia a la Insulina/genética , Masculino , Síndrome Metabólico/genética , Persona de Mediana Edad , Obesidad/genéticaRESUMEN
BACKGROUND: The high-density lipoprotein receptor SR-B1 mediates cellular uptake of several lipid species, including cholesterol and vitamin E. During early mouse development, SR-B1 is located in the maternal-fetal interface, where it facilitates vitamin E transport towards the embryo. Consequently, mouse embryos lacking SR-B1 are vitamin E-deficient, and around half of them fail to close the neural tube and show cephalic neural tube defects (NTD). Here, we used transcriptomic profiling to identify the molecular determinants of this phenotypic difference between SR-B1 deficient embryos with normal morphology or with NTD. RESULTS: We used RNA-Seq to compare the transcriptomic profile of three groups of embryos retrieved from SR-B1 heterozygous intercrosses: wild-type E9.5 embryos (WT), embryos lacking SR-B1 that are morphologically normal, without NTD (KO-N) and SR-B1 deficient embryos with this defect (KO-NTD). We identified over 1000 differentially expressed genes: down-regulated genes in KO-NTD embryos were enriched for functions associated to neural development, while up-regulated genes in KO-NTD embryos were enriched for functions related to lipid metabolism. Feeding pregnant dams a vitamin E-enriched diet, which prevents NTD in SR-B1 KO embryos, resulted in mRNA levels for those differentially expressed genes that were more similar to KO-N than to KO-NTD embryos. We used gene regulatory network analysis to identify putative transcriptional regulators driving the different embryonic expression profiles, and identified a regulatory circuit controlled by the androgen receptor that may contribute to this dichotomous expression profile in SR-B1 embryos. Supporting this possibility, the expression level of the androgen receptor correlated strongly with the expression of several genes involved in neural development and lipid metabolism. CONCLUSIONS: Our analysis shows that normal and defective embryos lacking SR-B1 have divergent expression profiles, explained by a defined set of transcription factors that may explain their divergent phenotype. We propose that distinct expression profiles may be relevant during early development to support embryonic nutrition and neural tube closure.
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Antígenos CD36/deficiencia , Antígenos CD36/genética , Perfilación de la Expresión Génica , Técnicas de Inactivación de Genes , Redes Reguladoras de Genes , Tubo Neural/embriología , Transcripción Genética , Animales , Humanos , Ratones , Tubo Neural/metabolismo , Defectos del Tubo Neural/genética , Defectos del Tubo Neural/metabolismo , Fenotipo , DesteteRESUMEN
INTRODUCTION: Type 1 diabetes (T1D) has a complex etiology in which genetic and environmental factors are involved, whose interactions have not yet been completely clarified. In this context, the role in PD-1 pathway and its ligands 1 and 2 (PD-L1 and PD-L2) have been proposed as candidates in several autoimmune diseases. The aim of this work was to determine the allele and haplotype frequency of six gene polymorphisms of PD-ligands (PD-L1 and PD-L2) in Chilean T1D patients and their effect on serum levels of PD-L1 and autoantibody profile (GAD65 and IA2). METHODS: This study cohort comprised 205 T1D patients and 205 normal children. We performed genotypic analysis of PD-L1 and PD-L2 genes by TaqMan method. Determination of anti-GAD65 and anti-IA-2 autoantibodies was performed by ELISA. The PD-L1 serum levels were measured. RESULTS: The allelic distribution of PD-L1 variants (rs2297137 and rs4143815) showed differences between T1D patients and controls (p = 0.035 and p = 0.022, respectively). No differences were detected among the PD-L2 polymorphisms, and only the rs16923189 showed genetic variation. T1D patients showed decreased serum levels of PD-L1 compared to controls: 1.42 [0.23-7.45] ng/mL versus 3.35 [0.49-5.89] ng/mL (p < 0.025). In addition, the CGG haplotype in PD-L1 associated with T1D (constructed from rs822342, rs2297137 and rs4143815 polymorphisms) showed an OR = 1.44 [1.08 to 1.93]. Finally, no association of these genetic variants was observed with serum concentrations of PD ligands or auto-antibody profile, although a correlation between PD-L1 ligand serum concentration and the age at disease onset was detected. CONCLUSION: Two polymorphism of PD-L1 are presented in different allelic variants between T1D and healthy subjects, also PDL-1 serum levels are significantly lowered in diabetics patients. Moreover, the age of onset of the disease determine differences between serum ligand levels in diabetics, being lower in younger. These results points to a possible establishment of PDL-1 as a genetic and biochemical marker for T1D onset, at least in Chilean population.
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Antígeno B7-H1/genética , Diabetes Mellitus Tipo 1/genética , Regulación hacia Abajo , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Adolescente , Edad de Inicio , Alelos , Autoinmunidad , Antígeno B7-H1/sangre , Antígeno B7-H1/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Chile/epidemiología , Estudios de Cohortes , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Lactante , Desequilibrio de Ligamiento , Masculino , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismoRESUMEN
INTRODUCTION: It is well established that type 1 diabetes (T1D) is an autoimmune disease. Controversial data exists regarding the differential control of the immune system in T1D patients compared to unaffected individuals. MicroRNAs (miRNAs) are involved in the control of gene expression (by negative regulation of gene expression at post-transcriptional level, by mediating translational repression or degradation of the mRNA targets). Their potential role in T cell activation and autoimmunity is controversial. AIM: We investigated the expression profile of miR-21a and miR-93 in PMC samples of 20 T1D patients and 20 healthy controls by means of qPCR in different glucose concentrations (basal, 11 nM and 25 mM), and we analyzed the possible relationship of this expression pattern with autoimmunity. RESULTS: MiR-21a was significantly underexpressed in T1D samples (media values expression 0.23 ± 0.05, p < 0.01) compared to controls (values less than 1 indicate a decrease in gene expression). When the PMCs were incubated with glucose 11 mM and 25 mM, miR-21a expression decreased in controls and increased in T1D samples (0.506 ± 0.05, p < 0.04). MiR-93 was underexpressed in T1D patients (0.331 ± 0.05, p < 0.02) compared to control samples. However, when the PBMCs were incubated with glucose, no changes were observed. No association with autoimmunity was observed. CONCLUSION: We demonstrated that miRNAs have a differential expression in PBMCs from T1D patients compared to controls, suggesting that these miRNAs or others could be involved in T cell regulation.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Glucosa/metabolismo , Leucocitos Mononucleares/metabolismo , MicroARNs/genética , Adolescente , Adulto , Estudios de Casos y Controles , Células Cultivadas , Niño , Preescolar , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/patología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/patología , Activación de Linfocitos/efectos de los fármacos , Masculino , MicroARNs/sangreRESUMEN
UNLABELLED: Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by a progressive destruction of pancreatic ß cells. It has been reported that patients with autoimmune diseases exhibit decreased expression of caspase 3 and other pro-apoptotic markers in peripheral blood mononuclear cells (PBMC). AIM: To estimate the expression of apoptosis markers in PBMC from T1D patients cultured with high glucose concentration. RESULTS: At 11 mM of glucose, the pro-apoptotic gene fas showed a 7-fold decreased expression in the T1D group compared to controls, while bax showed a 50-fold decreased expression (medians 0.14 and 0.02, respectively, considering patients as 1). At 44 mM of glucose, there is a decreased expression of the same genes, but less abrupt (medians 0.75 and 0.47). Only the anti-apoptotic gene xiap showed a 2-fold increased expression at 11 mM of glucose (median 2.3). Regarding the clinical history, no relationships were observed with age of diagnosis, ketoacidosis, glucose at debut or GAD-65 and IA-2 titles. CONCLUSION: We can conclude that the apoptotic mechanisms in PBMC of T1D patients under high glucose conditions are altered, and this is proved by the decreased expression of the pro-apoptotic genes fas and bax and by the increased expression of the anti-apoptotic gene xiap.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Glucosa/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína X Asociada a bcl-2/genética , Receptor fas/genética , Adolescente , Adulto , Apoptosis/efectos de los fármacos , Biomarcadores/metabolismo , Células Cultivadas , Niño , Preescolar , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Regulación hacia Abajo , Femenino , Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Humanos , Lactante , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Masculino , Persona de Mediana Edad , Regulación hacia Arriba , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Receptor fas/metabolismoRESUMEN
Background: A genetic polymorphism called C1858T of protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene has been associated with autoimmune diseases Aim: To describe the association between two autoimmune diseases, namely type 1 diabetes (T1D) and celiac disease (CD)and tyrosine phosphatase gene polymorphisms (variant C1858T of PTPN22). Subjects and Methods: C1858T single-nucleotide polymorphism within the PTPN22 gene was genotyped in 209 patients with T1D, 43 celiac patients and 100 healthy controls. Results: CC gene frequency was 0.906 and 0.790 in CD patients and controls respectively ( p < 0.01). All analyzed groups had a low frequency of the TT genotype. Compared with the other study groups, patients with T1D had a low frequency of CC genotype (0.636). Also, in these patients, there was a non-significant association between CC genotype and islet cell IA-2 auto antibodies (p < 0.065). Among CD patients, CC genotype was significantly associated with anti-transglutaminase or anti endomysial antibodies (p < 0.03). Conclusions: These results confirm the association of the genetic variant C1858T of PTPN22 with CD. In contrast to published data, this association was not found in T1D patients.