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The cytosolic enzymes N-Acetyl Transferases 1 and 2 (NATs) transfer an acetyl group from acetyl-CoA to a xenobiotic substrate. NATs are regulated at the genetic and epigenetic levels by deacetylase enzymes such as sirtuins. The enzymatic expression of NAT1, NAT2, and SIRT1 was evaluated by flow cytometry, as well as the enzymatic activity of NATs by cell culture and HPLC analysis. Six SNPs were determined through genotyping. T2D patients (n = 29) and healthy subjects (n = 25) with a median age of 57 and 50, respectively, were recruited. An increased enzyme expression and a diminished NAT2 enzymatic activity were found in cells of T2D patients compared to the control group, while NAT1 was negatively correlated with body fat percentage and BMI. In contrast, Sirtuin inhibition increased NAT2 activity, while Sirtuin agonism decreased its activity in both groups. The analysis of NAT2 SNPs showed a higher frequency of rapid acetylation haplotypes in T2D patients compared to the control group, possibly associated as a risk factor for diabetes. The enzymatic expression of CD3+NAT2+ cells was higher in the rapid acetylators group compared to the slow acetylators group. The levels and activity of NAT1 were associated with total cholesterol and triglycerides. Meanwhile, CD3+NAT2+ cells and NAT2 activity levels were associated with HbA1c and glucose levels. The results indicate that NAT2 could be involved in metabolic processes related to the development of T2D, due to its association with glucose levels, HbA1c, and the altered SIRT-NAT axis. NAT1 may be involved with dyslipidaemias in people who are overweight or obese.
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Structure-activity relationship (SAR) studies allow the evaluation of the relationship between structural chemical changes and biological activity. Fluoroquinolones have chemical characteristics that allow their structure to be modified and new analogs with different therapeutic properties to be generated. The objective of this research is to identify and select the C-7 heterocycle fluoroquinolone analog (FQH 1-5) with antibacterial activity similar to the reference fluoroquinolone through in vitro, in silico, and in vivo evaluations. First, SAR analysis was conducted on the FQH 1-5, using an in vitro antimicrobial sensibility model in order to select the best compound. Then, an in silico model mechanism of action analysis was carried out by molecular docking. The non-bacterial cell cytotoxicity was evaluated, and finally, the antimicrobial potential was determined by an in vivo model of topical infection in mice. The results showed antimicrobial differences between the FQH 1-5 and Gram-positive and Gram-negative bacteria, identifying the 7-benzimidazol-1-yl-fluoroquinolone (FQH-2) as the most active against S. aureus. Suggesting the same mechanism of action as the other fluoroquinolones; no cytotoxic effects on non-bacterial cells were found. FQH-2 was demonstrated to decrease the amount of bacteria in infected wound tissue.
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Antibacterianos , Antiinfecciosos , Animales , Ratones , Antibacterianos/farmacología , Fluoroquinolonas/farmacología , Simulación del Acoplamiento Molecular , Staphylococcus aureus , Bacterias Gramnegativas , Bacterias Grampositivas , Relación Estructura-ActividadRESUMEN
BACKGROUND/AIM: Arylamine N-acetyltransferase 1 and 2 (NAT1 and NAT2) are drug-metabolizing enzymes that play a key role in the development of acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: This study evaluated NAT1 and NAT2 mRNA and protein expression and their enzymatic activity in peripheral blood mononuclear cells (PBMC) from patients with ALL (n=20) and healthy children (n=19) and explored the mechanisms that regulate these enzymes in ALL such as microRNAs (miR-1290, miR-26b) and SNPs. RESULTS: PBMC from patients with ALL showed a decrease in NAT1 mRNA and protein expression. In addition, NAT1 enzymatic activity was decreased in patients with ALL. There was no influence of SNP 559 C>T or 560 G>A on low NAT1 activity. The lower expression of NAT1 might be related to the loss of acetylated histone H3K14 in the NAT1 gene promoter in patients with ALL and the higher relative expression of miR-1290 in the plasma of patients with relapsed ALL compared with healthy controls. There were significantly fewer CD3+/NAT1+ double-positive cells in patients who relapsed compared with control subjects. Based on a t-distributed stochastic neighbor embedding algorithm, CD19+ cells that reappeared in patients with relapse showed low NAT1 expression. In contrast, for NAT2, there were no significant results. CONCLUSION: The expression and function of NAT1 and miR-1290 levels could be involved in modulating immune cells altered in ALL.
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Arilamina N-Acetiltransferasa , MicroARNs , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Leucocitos Mononucleares/metabolismo , Proyectos Piloto , Arilamina N-Acetiltransferasa/genética , Arilamina N-Acetiltransferasa/metabolismo , MicroARNs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , ARN MensajeroRESUMEN
Since their discovery, arylamine N-acetyltransferases 1 and 2 (NAT1 and NAT2, respectively) have been associated with the metabolism of xenobiotics. NAT2 is the main factor in the therapeutic success of tuberculosis treatment due to its role in the biotransformation of isoniazid. However, researchers have started to investigate the possible participation of NAT1 and NAT2 (NATs) in carcinogenesis, although the mechanisms have not been elucidated fully. NATs enzymatic activity is essential in some types of cancer, such as breast cancer and acute lymphoblastic leukemia. Whether NAT1 and/or NAT2 participate in insulin resistance level in diabetes mellitus or in the immune system remains to be explored. Therefore, it is clear that its role in cell physiology has more implications than just metabolizing compounds.
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Arilamina N-Acetiltransferasa , Acetiltransferasas , Arilamina N-Acetiltransferasa/genética , Arilamina N-Acetiltransferasa/metabolismo , Sistema Inmunológico/metabolismoRESUMEN
Non-communicable diseases (NCD), are not transmitted from person to person, are long-lasting and usually of slow evolution. Worldwide cause 71% deaths, in Mexico during 2016 were the cause of 80% of registered deaths; population in socioeconomic disadvantage is more vulnerable. It is urgent to develop strategies that can prevent NCD, thus, the objective of this study was to design, implement and evaluate an educational intervention strategy (EI), to prevent and control risk factors for the development NCD in families of two vulnerable communities. The research design was mixed, the stages were developed based on a risk communication (RC) model and was performed in three stages: 1) EI Design, 2) Implementation and 3) Evaluation of the intervention. In the contextualization, risk factors were found in the participants who were integrated in the design of the educational strategy. The EI implemented was effective in increasing knowledge about NCD and practice of healthy habits, such as increasing the consumption of fruits and vegetables. Additionally, the guidance of EI at the family level has the advantage of creating a support network for these changes. However, pending issues remain, such as the design of effective strategies to reduce the consumption of sugars and sugary drinks.
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Enfermedades no Transmisibles , Humanos , México , Enfermedades no Transmisibles/epidemiología , Enfermedades no Transmisibles/prevención & control , Evaluación de Programas y Proyectos de Salud , Factores de Riesgo , VerdurasRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) causes a mild illness in most cases; forecasting COVID-19-associated mortality and the demand for hospital beds and ventilators are crucial for rationing countries' resources. OBJECTIVE: To evaluate factors associated with the severity of COVID-19 in Mexico and to develop and validate a score to predict severity in patients with COVID-19 infection in Mexico. DESIGN: Retrospective cohort. PARTICIPANTS: We included 1,435,316 patients with COVID-19 included before the first vaccine application in Mexico; 725,289 (50.5%) were men; patient's mean age (standard deviation (SD)) was 43.9 (16.9) years; 21.7% of patients were considered severe COVID-19 because they were hospitalized, died or both. MAIN MEASURES: We assessed demographic variables, smoking status, pregnancy, and comorbidities. Backward selection of variables was used to derive and validate a model to predict the severity of COVID-19. KEY RESULTS: We developed a logistic regression model with 14 main variables, splines, and interactions that may predict the probability of COVID-19 severity (area under the curve for the validation cohort = 82.4%). CONCLUSIONS: We developed a new model able to predict the severity of COVID-19 in Mexican patients. This model could be helpful in epidemiology and medical decisions.
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COVID-19 , Hospitalización , Humanos , Masculino , México/epidemiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2RESUMEN
Research on glutamatergic neurotransmission has focused mainly on the function of presynaptic and postsynaptic neurons, leaving astrocytes with a secondary role only to ensure successful neurotransmission. However, recent evidence indicates that astrocytes contribute actively and even regulate neuronal transmission at different levels. This review establishes a framework by comparing glutamatergic components between neurons and astrocytes to examine how astrocytes modulate or otherwise influence neuronal transmission. We have included the most recent findings about the role of astrocytes in neurotransmission, allowing us to understand the complex network of neuron-astrocyte interactions. However, despite the knowledge of synaptic modulation by astrocytes, their contribution to specific physiological and pathological conditions remains to be elucidated. A full understanding of the astrocyte's role in neuronal processing could open fruitful new frontiers in the development of therapeutic applications.
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The exposure to air pollutants causes significant damage to health, and inefficient cooking and heating practices produce high levels of household air pollution, including a wide range of health-damaging pollutants such as fine particles, carbon monoxide and PAHs. The exposure to PAHs has been associated with the development of neoplastic processes, asthma, genotoxicity, altered neurodevelopment and inflammation. The effects on the induction of proinflammatory cytokines are attributed to the activation of AhR. However, the molecular mechanisms by which the PAHs produce proinflammatory effects are unknown. This study was performed on a group of 41 Mexican women from two rural communities who had stoves inside their houses, used wood as biomass fuel, and, thus, were vulnerable. According to the urinary 1-OHP concentration, the samples were stratified into two groups for determination of the levels of TNF-α, AhR, CYP1B1, miR-125b and miR-155 expression. Our results showed that the CYP1B1, TNF-α, miR-125b and miR-155 expression levels were not statistically different between women with the lowest and highest levels of 1-OHP. Interestingly, high levels of PAHs promoted augmented expression of AhR, which is a protein involved in the modulation of inflammatory pathways in vivo, suggesting that cell signaling of AhR may be implicated in several pathogenesis processes.
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INTRODUCTION: Background: prediabetes is a state observed before type-2 diabetes. Nowadays the obesity epidemic could be due to a rise in the incidence of prediabetes. Mexico has public policies for the management of non-communicable diseases. However, obesity rates continue to increase. The aim of this study was to elaborate on a diagnosis of prediabetes in the pediatric Mexican population, and compare the proportions of comorbidities that children with and without prediabetes had. Methods: a cross-sectional study was performed with 569 participants of 4 to 19 years of age from public schools. Anthropometric (weight, height, and waist circumference), clinical (blood pressure), and biochemical (fasting glucose, lipidic profile, and uric acid) variables were collected. Results: in all, 8.6 % of the population had prediabetes. Variables with the highest altered prevalence included triglycerides and systolic blood pressure. Boys had higher rates of prediabetes, altered BP, and hyperuricemia than girls. Children with prediabetes had a greater risk of elevated waist circumference, blood pressure, and uric acid measures. Conclusions: the Mexican pediatric population had elevated rates of prediabetes. Furthermore, the group with prediabetes had a higher risk of presenting high values of triglycerides, blood pressure, uric acid, and total cholesterol.
INTRODUCCIÓN: Objetivo: la prediabetes es un estado que se observa antes de la diabetes de tipo 2. La actual epidemia de obesidad puede ser una causa del aumento de la incidencia de la prediabetes. En México existen políticas públicas para el manejo de las enfermedades no comunicables. Sin embargo, la obesidad continúa aumentando. Nuestro objetivo fue elaborar un diagnóstico de prediabetes en la población pediátrica mexicana y contrastar la proporción de comorbilidades que presentaban los niños con y sin prediabetes. Metodología: se realizó un estudio transversal analítico de 569 participantes de 4 a 19 años de edad procedentes de escuelas públicas. Se tomaron variables antropométricas (peso, talla y circunferencia de la cintura) y clínicas (presión arterial), así como indicadores bioquímicos (glucosa, perfil lipídico y ácido úrico). Resultados: el 8,6 % de la población presentaba prediabetes. Las variables de mayor prevalencia de alteración fueron los triglicéridos, seguidos de la presión arterial sistólica. Los hombres tenían prevalencias más altas de prediabetes, presión arterial elevada e hiperuricemia. Los niños con prediabetes tenían mayor riesgo de presentar cifras elevadas de circunferencia de la cintura, presión arterial y ácido úrico. Conclusiones: la población pediátrica mexicana tiene una prevalencia elevada de prediabetes. Además, se encontró que el grupo con prediabetes tiene mayor riesgo de presentar cifras elevadas de triglicéridos, presión arterial, ácido úrico y colesterol total.
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Comorbilidad/tendencias , Estado Prediabético/diagnóstico , Adolescente , Antropometría/instrumentación , Antropometría/métodos , Índice de Masa Corporal , Niño , Preescolar , Estudios Transversales , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Masculino , México/epidemiología , Obesidad/epidemiología , Estado Prediabético/epidemiología , Prevalencia , Adulto JovenRESUMEN
PURPOSE: Resistance to neoadjuvant chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) in some patients with locally advanced breast cancer remains one of the main obstacles to first-line treatment. We investigated clinical and pathological responses to FAC neoadjuvant chemotherapy in Mexican women with breast cancer and their possible association with SNPs present in ABC transporters as predictors of chemoresistance. MATERIALS: A total of 102 patients undergoing FAC neoadjuvant chemotherapy were included in the study. SNP analysis was performed by RT-PCR from genomic DNA. Two SNPs were analyzed: ABCB1 rs1045642 (3435 C > T) and ABCG2 rs2231142 (421 G > T). RESULTS: In clinical response evaluation, significant associations were found between the ABCB1 C3435T genotype and breast cancer chemoresistant and chemosensitive patients (p < 0.05). In the early clinical response, patients with genotype C/C or C/T were more likely to be chemosensitive to neoadjuvant therapy than patients with genotype T/T (OR = 4.055; p = 0.0064). Association analysis between the ABCB1 gene polymorphism and the pathologic response to FAC chemotherapy showed that the C/C + C/T genotype was a protective factor against chemoresistance (OR = 3.714; p = 0.0104). Polymorphisms in ABCG2 indicated a lack of association with resistance to chemotherapy (p = 0.2586) evaluating the clinical or pathological response rate to FAC neoadjuvant chemotherapy. CONCLUSION: The early clinical response and its association with SNPs in the ABCB1 transporter are preserved until the pathological response to neoadjuvant chemotherapy; therefore, it could be used as a predictor of chemoresistance in locally advanced breast cancer patients of the Mexican population.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Proteínas de Neoplasias/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Genotipo , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Polimorfismo de Nucleótido Simple/genética , Estudios RetrospectivosRESUMEN
Breast cancer (BRCA) is the most frequent cancer type that afflicts women. Unfortunately, despite all the current therapeutic strategies, many patients develop chemoresistance hampering the efficacy of treatment. Hence, an early indicator of therapy efficacy might aid in the search for better treatment and patient survival. Although emerging evidence indicates a key role of the purinergic receptors P2X7 and A2A in cancer, less is known about their involvement in BRCA chemoresistance. In this sense, as the chemotherapeutic treatment stimulates immune system response, we evaluated the expression and function of P2X7 and A2A receptors in CD8+ T cells before and four months after BRCA patients received neoadjuvant chemotherapy. The results showed an increase in the levels of expression of P2X7 and a decrease in the expression of A2A in CD8+ T cells in non-chemoresistant (N-CHR) patients, compared to chemoresistant (CHR) patients. Interestingly, in CHR patients, reduced expression of P2X7 occurs along with a decrease in the CD62L shedding and the production of IFN-γ. In the case of the A2A function, the inhibition of IFN-γ production was not observed after chemotherapy in CHR patients. A possible relationship between the modulation of the expression and function of the P2X7 and A2A receptors was found, according to the molecular subtypes, where the patients that were triple-negative and human epidermal growth factor receptor 2 (HER2)-enriched presented more alterations. Comorbidities such as overweight/obesity and type 2 diabetes mellitus (T2DM) participate in the abnormalities detected. Our results demonstrate the importance of purinergic signaling in CD8+ T cells during chemoresistance, and it could be considered to implement personalized therapeutic strategies.
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The aim of this study was to develop a population pharmacokinetic model of rifampicin (RMP) in Mexican patients with tuberculosis (TB) to evaluate the influence of anthropometric and clinical covariates, as well as genotypic variants associated with MDR1 and OATP1B1 transporters. A prospective study approved by Research Ethics Committee was performed at Hospital Central in San Luis Potosí, Mexico. TB patients under DOTS scheme and who signed informed consent were consecutively included. Anthropometric and clinical information was retrieved from medical records. Single nucleotide polymorphisms in MDR1 (C3435T) and SLCO1B1 (A388G and T521C) genes were evaluated. RMP plasma concentrations and time data were assessed with NONMEM software. A total of 71 Mexican TB patients from 18 to 72 years old were included for RMP quantification from 0.3 to 12 h after dose; 329 and 97 plasma concentrations were available for model development and validation, respectively. Sequential process includes a typical lag time of 0.25 h prior to absorption start with a Ka of 1.24 h-1 and a zero-order absorption of 0.62 h to characterize the gradual increase in RMP plasma concentrations. Final model includes total body weight in volume of distribution (0.7 L/kg, CV = 26.8%) and a total clearance of 5.96 L/h (CV = 38.5%). Bioavailability was modified according to time under treatment and generic formulation administration. In conclusion, a population pharmacokinetic model was developed to describe the variability in RMP plasma concentrations in Mexican TB patients. Genetic variants evaluated did not showed significant influence on pharmacokinetic parameters. Final model will allow therapeutic drug monitoring at early stages.
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Antibióticos Antituberculosos/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Modelos Biológicos , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Rifampin/farmacocinética , Tuberculosis/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adolescente , Adulto , Anciano , Antibióticos Antituberculosos/administración & dosificación , Teorema de Bayes , Disponibilidad Biológica , Esquema de Medicación , Cálculo de Dosificación de Drogas , Femenino , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , México/epidemiología , Persona de Mediana Edad , Farmacogenética , Estudios Prospectivos , Reproducibilidad de los Resultados , Rifampin/administración & dosificación , Resultado del Tratamiento , Tuberculosis/diagnóstico , Tuberculosis/etnología , Tuberculosis/microbiología , Adulto JovenRESUMEN
The first degree relatives of rheumatoid arthritis (RA) patients have a higher risk of developing RA, which is related to the expression of autoantibodies against citrullinated proteins (ACPA). Remarkably, prior to the onset of RA, cartilage damage is already initiated, whereas ACPA autoantibodies are already expressed. Here we show that both TNF-α and IL-6 are also increased prior to the onset of RA. Furthermore, when the levels of DKK1 and Sclerostin were evaluated in first degree relatives of RA patients, we found that the serum levels of TNF- α correlate with the expression levels of both DKK1 and Sclerostin. Interestingly, when the disease is already established, the correlation of TNF- α with DKK1 is lost in RA patients, whereas the correlation of Sclerostin with both TNF- α and IL-6 is further increased. Our data suggest a subclinical inflammation in patients at high risk of developing RA, which might lead to an increase in the levels of both DKK1 and Sclerostin, contributing to joint damage in the preclinical phase of the disease linked to the expression of ACPA autoantibodies.
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Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Enfermedades Asintomáticas , Cartílago Articular/inmunología , Cartílago Articular/patología , Familia , Proteínas Adaptadoras Transductoras de Señales/sangre , Adulto , Anticuerpos Antiproteína Citrulinada/sangre , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inflamación/inmunología , Péptidos y Proteínas de Señalización Intercelular/sangre , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Background The standardized doses of isoniazid in therapy against tuberculosis are determined based on total body weight, without considering genetic polymorphisms of the metabolic enzyme N-acetyltransferase-2 that contribute to the wide pharmacokinetic variability of isoniazid. Objective The aim of this work was to build a population pharmacokinetic model of isoniazid in Mexican patients with tuberculosis to characterize typical estimates of pharmacokinetics, as well as inter-individual and residual variability of isoniazid considering the genetic factors associated with the N-acetyltransferase-2 enzyme. Setting A prospective study was conducted at the Department of Internal Medicine in Hospital Central, San Luis Potosí, México. Methods Plasma concentrations of isoniazid were measured by high performance liquid chromatography. The acetylator phenotype was predicted through single nucleotide polymorphisms in the N-acetyltransferase-2 gene. Genetic, anthropometric and clinical covariates were used to develop a pharmacokinetic model. Main outcome measure Isoniazid plasma concentration. Results A total of 69 patients with tuberculosis were included. Blood samples were drawn from 20 min to 12 h post dose to determinate the isoniazid plasma concentration. Typical pharmacokinetics parameters were characterized through two-compartment open model with first-order absorption and linear elimination. Clearance was different for each predicted N-acetyltransferase-2 phenotype being 11.4, 19.2 and 27.4 L/h for slow, intermediate and rapid acetylators, respectively. Central volume of distribution was determined as 1.5 * body mass index (L). Through the application of the model, external validation was performed and initial dose regimen of isoniazid is proposed based on stochastic simulations. Conclusion A validated population pharmacokinetic model of isoniazid was developed in Mexican patients with tuberculosis. Through the application of the final model, initial dose recommendations were provided considering body mass index and N-acetyltransferase-2 phenotype.
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Antituberculosos/administración & dosificación , Isoniazida/administración & dosificación , Modelos Biológicos , Tuberculosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antituberculosos/farmacocinética , Arilamina N-Acetiltransferasa/genética , Índice de Masa Corporal , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Isoniazida/farmacocinética , Masculino , México , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Adulto JovenRESUMEN
Obesity is characterized by immune cell infiltration and inflammation. Purinergic receptors such as P2X1, 4 and 7 are expressed on immune cells and their activation contributes with an inflammatory response. However, the simultaneous expression of P2X1, 4 and 7 during overweight or obesity have not been described. Therefore, the aim of this study was to determine single and simultaneously expression and function of the P2X1, 4 and 7 receptors in lymphocytes and CD4â¯+â¯T cells from peripheral blood (PB) and adipose tissue (AT). Our results showed a higher expression of the P2X4 receptor on CD4â¯+â¯T cells from PB regarding P2X7 and P2X1 receptor expression. In addition, P2X4 receptor expression on CD4â¯+â¯T cells from PB and AT was increased in individuals with BMIâ¯≥â¯25 Kg/m2. Moreover, a higher simultaneous expression of the P2X4 and P2X7 receptors on CD4â¯+â¯T cells from AT compared to CD4â¯+â¯T cells expressing P2X1 and P2X7 receptors simultaneously. Besides, CD4â¯+â¯T cells expressing P2X4 and P2X7 receptors from PB and AT were augmented in individuals with BMIâ¯≥â¯25 Kg/m2. In addition, the percentage of lymphocytes and also CD4â¯+â¯T cells expressing P2X4 receptor were elevated both in PB and AT compared to cells expressing P2X7 or P2X1. However, CD4â¯+â¯T cells expressing P2X4 and P2X7 were augmented in AT compared to PB. The function of the receptors showed a lower shedding of CD62â¯L in adipose tissue mononuclear cells (ATMC) compared with peripheral blood mononuclear cells (PBMC) and a greater participation of P2X4 in the mobilization of intracellular calcium. We concluded that it was possible to determine for the first time the simultaneous expression of purinergic receptors in ATMC, where the P2X4 receptor has a greater participation in the activation of CD4â¯+â¯T cells possibly modulating the function of the other two receptors.
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Tejido Adiposo/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Leucocitos Mononucleares/metabolismo , Receptores Purinérgicos P2X1/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Adenosina Trifosfato/metabolismo , Adulto , Calcio/metabolismo , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Background and objectives: To identify the relationship between neck circumference (NC) and cardiometabolic risk factors in children. Materials and Methods: Children and adolescents 6-18 years old (n = 548) from five counties of San Luis Potosí, México were included. Data was collected for biological markers (glucose and lipid profile) and anthropometric and clinical measurements-weight, height, NC, waist circumference (WC), and blood pressure (BP). Body mass index (BMI) was calculated using Quetelet formula (kg/m2). Descriptive analysis, correlation tests, and receiver operating characteristic (ROC) analysis were performed. Results: NC was highly correlated with BMI and WC in both genders (p <0.0001). The most frequent risk factor was high BMI (38.7%). Sensitivity and specificity analysis of NC and high BMI showed an area under the ROC curve of 0.887. Conclusions: According to our findings, NC is a simple, low-cost, and non-invasive measurement, which has a high association with high BMI and increased WC.
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Antropometría/métodos , Enfermedades Metabólicas/clasificación , Cuello , Pesos y Medidas/normas , Adolescente , Antropometría/instrumentación , Índice de Masa Corporal , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Enfermedades Metabólicas/fisiopatología , México , Pediatría/instrumentación , Pediatría/métodos , Medición de Riesgo/métodos , Medición de Riesgo/normas , Factores de Riesgo , Pesos y Medidas/instrumentaciónRESUMEN
BACKGROUND: Chronic inflammation has critical role in Type 2 diabetes (T2D), in which IL-1ß contributes in insulin resistance and beta cell dysfunction. The activation of NLRP3 and AIM2 by endogens ligands, such as mtDNA can lead to the release of active form of IL-1ß. OBJECTIVE: To evaluate AIM2 expression and activation as well as circulating mtDNA levels in T2D patients. METHODS: AIM2 expression was analyzed by flow cytometry, it's activity was assessed by measuring in vitro release of IL-1ß induced by Poly (dA:dT), and mtDNA copy number was determined by quantitative real-time polymerase chain reaction. RESULTS: Increased percent of AIM2+ cells were detected in monocytes from patients with T2D. Moreover, increased levels of IL-1ß in monocytes cultures from T2D patients compared to healthy controls were observed. Also, association between AIM2+ cells and hyperglycemia (r=0.4385, P=0.0095) and triglycerides levels (r=0.5112, P=0.002) and waist-hip ratio (r=0.4710, P=0.0049) were detected. Likewise, the mtDNA copy number was augmented in T2D patients compared to control group. The mtDNA copies number was associated with body mass index (r=0.4231, P=0.0008) and TNF-α levels (r=0.5231, P=0.0005). In addition, increased levels of IL-12p70, TNF-a, IL-10, IL-6, IL-8 and IL-1ß were detected in a serum from T2D patients. CONCLUSION: These results suggest the involvement of AIM2 and mtDNA in the inflammatory process seen in T2D.
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Ácidos Nucleicos Libres de Células , ADN Mitocondrial , Proteínas de Unión al ADN/genética , Diabetes Mellitus Tipo 2/genética , Expresión Génica , Adulto , Biomarcadores , Estudios de Casos y Controles , ADN Mitocondrial/sangre , Proteínas de Unión al ADN/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Citometría de Flujo , Humanos , Inflamasomas/metabolismo , Mediadores de Inflamación/sangre , Interleucina-1beta/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismoRESUMEN
It has been reported that an increased function of the P2X7 purinergic receptor is associated with an increase in both insulin sensitivity and secretion. Accordingly, we explored the possible effect of the 1068 G>A polymorphism of the gene P2RX7 on glucose homeostasis and the levels of the anti-inflammatory cytokine IL-1Ra in T2D patients. The presence of the 1068 G>A polymorphism in T2D patients (nâ¯=â¯100) and healthy subjects (nâ¯=â¯100) was determined by DNA sequencing, and serum levels of IL-1Ra were measured by ELISA. Pancreatic ß-cell function, insulin resistance, blood glucose levels and glycated hemoglobin (HbA1c) were also analyzed. We detected a significant negative association between T2D and the 1068 G>A SNP (Odds ratio 0.3916, pâ¯=â¯0.0045). In addition, we observed that T2D patients bearing the 1068 G>A variant showed higher serum levels of IL-1Ra compared to both, patients with the GG genotype or healthy individuals (GG or G>A). Moreover, T2D patients bearing the 1068 G>A SNP showed increased insulin levels and a better pancreatic ß-cell function (pâ¯<â¯0.05 in both cases) compared to patients with the wild type genotype. However, the HbA1c levels, fasting glucose levels and the degree of insulin resistance were similar in T2D patients carrying or not the G>A SNP. Our results suggest that although the 1068 G>A polymorphism of the P2RX7 gene is associated with an increased ß-cell function and IL-1Ra release in T2D patients, the glycemic control is not significantly affected by the presence of this SNP.
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Diabetes Mellitus Tipo 2/genética , Células Secretoras de Insulina/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/genética , Polimorfismo de Nucleótido Simple , Receptores Purinérgicos P2X7/genética , Adulto , Glucemia/metabolismo , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Femenino , Expresión Génica , Genotipo , Hemoglobina Glucada/metabolismo , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Secreción de Insulina , Células Secretoras de Insulina/patología , Proteína Antagonista del Receptor de Interleucina 1/sangre , Masculino , Persona de Mediana Edad , Receptores Purinérgicos P2X7/sangreRESUMEN
Tuberculosis (Tb) is an infectious disease in which the immune system plays an important role. MicroRNAs are involved in the development and maintenance of CD4 + T lymphocyte subpopulations. miR-326 regulates the differentiation to Th17 cells and miR-29 correlates with the Th1 response. The aim of this study was to determine the role of microRNAs, Transcription Factors, and cytokines in Th differentiation before and after the directly observed treatment short-course (DOTS). Peripheral blood mononuclear cells and serum from Tb patients were collected at times 0 (before therapy), 2 (after the intensive phase), and 6 months (after the holding phase). The cells were cultivated in presence or absence of ESAT-6 (10 µg/ml) and CFP-10 (10 µg/ml). Transcription Factor and microRNA expressions were analyzed by qPCR and cytokine production in both serum and culture supernatant using ELISA. A decrease in Th1 response with a diminishing in the relative expression of TBET and miR-29a at 2 and 6 months after the anti-Tb therapy (p < 0.01) were found. The miR-326 levels decreased after the intensive phase of the DOTS scheme. However, subdivision of the Tb patients according to gender, showed increased levels of miR-29a and miR-155 in females after the intensive phase of the therapeutic treatment when compared to time 0 and similar increased levels of miR-326 at time 6 versus time 0. In contrast, we observed a decrease in miR-326 levels in males at 6 months when compared to before therapy (time 0). In addition, high production of IL-17 in the culture supernatant was found at 2 and 6 months (p < 0.05) while in serum IL-17 was decreased. A positive correlation between IL-17 and RORC2 at time 6 was detected (p = 0.0202, r = 0.7880). In conclusion, these data suggest a reduction in Th1 and an induction of Th17 response after the anti-Tb therapy.
Asunto(s)
Antituberculosos/uso terapéutico , Diferenciación Celular , Citocinas/sangre , Terapia por Observación Directa , MicroARNs/sangre , Mycobacterium tuberculosis/efectos de los fármacos , Células TH1/efectos de los fármacos , Células Th17/efectos de los fármacos , Factores de Transcripción/sangre , Tuberculosis/tratamiento farmacológico , Adulto , Células Cultivadas , Citocinas/genética , Femenino , Interacciones Huésped-Patógeno , Humanos , Interleucina-17/sangre , Masculino , MicroARNs/genética , Persona de Mediana Edad , Mycobacterium tuberculosis/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/sangre , Estudios Prospectivos , Proteínas de Dominio T Box/sangre , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/microbiología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/microbiología , Factores de Tiempo , Factores de Transcripción/genética , Resultado del Tratamiento , Tuberculosis/sangre , Tuberculosis/inmunología , Tuberculosis/microbiologíaRESUMEN
Dichlorodiphenyldichloroethylene (p,p'-DDE), the most persistent metabolite of dichlorodiphenyltrichloroethane (DDT), is still present in the human population. Both are present in the bone marrow of patients with bone marrow disorders, but thus far there are no studies that assess the capability of p,p'-DDE to affect myeloid cells. The aim of this study was to determine the effect of p,p'-DDE on promyelocytic cell differentiation and intracellular pathways related to this event. p,p'-DDE induced morphological changes compatible with promyelocytic differentiation in a concentration-dependent manner. The p,p'-DDE effect on [Ca2+]i, C/EBPß protein levels, PKCα and p38 activation, and the role of oxidative stress or PLA2 was assayed. Exposure to 1.9 µg/mL of p,p'-DDE increased [Ca2+]i, PKCα, p38, and C/EBPß protein levels; the increase of nuclear C/EBPß protein was dependent on p38. PKCα phosphorylation was dependent on PLA2 and p,p'-DDE-induced oxidative stress. p38 phosphorylation induced by p,p'-DDE was dependent on PLA2, PKC activation, and oxidative stress. These effects of p,p'-DDE at concentrations found in human bone marrow may induce alterations in immature myeloid cells and could affect their cellular homeostasis. In order to establish the risk from exposure to p,p'-DDE on the development of bone marrow disorders in humans, these effects deserve further study.