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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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Discrepancies between the measurement of body mass index (BMI) and metabolic health status have been described for the onset of metabolic diseases. Studying novel biomarkers, some of which are associated with metabolic syndrome, can help us to understand the differences between metabolic health (MetH) and BMI. A group of 1469 young adults with pre-specified anthropometric and blood biochemical parameters were selected. Of these, 80 subjects were included in the downstream analysis that considered their BMI and MetH parameters for selection as follows: norm weight metabolically healthy (MHNW) or metabolically unhealthy (MUNW); overweight/obese metabolically healthy (MHOW) or metabolically unhealthy (MUOW). Our results showed for the first time the differences when the MetH status and the BMI are considered as global MetH statures. First, all the evaluated miRNAs presented a higher expression in the metabolically unhealthy group than the metabolically healthy group. The higher levels of leptin, IL-1b, IL-8, IL-17A, miR-221, miR-21, and miR-29 are directly associated with metabolic unhealthy and OW/OB phenotypes (MUOW group). In contrast, high levels of miR34 were detected only in the MUNW group. We found differences in the SIRT1-PGC1α pathway with increased levels of SIRT1+ cells and diminished mRNA levels of PGCa in the metabolically unhealthy compared to metabolically healthy subjects. Our results demonstrate that even when metabolic diseases are not apparent in young adult populations, MetH and BMI have a distinguishable phenotype print that signals the potential to develop major metabolic diseases.
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Índice de Masa Corporal , MicroARNs , Femenino , Humanos , Masculino , Adulto Joven , Biomarcadores/sangre , Leptina/sangre , Leptina/genética , Leptina/metabolismo , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , MicroARNs/genética , MicroARNs/sangre , MicroARNs/metabolismo , Obesidad/genética , Obesidad/metabolismo , Fenotipo , Sirtuina 1/genética , Sirtuina 1/metabolismoRESUMEN
Establishing the infant's gut microbiota has long-term implications on health and immunity. Breastfeeding is recognized as the best practice of infant nutrition in comparison with formula feeding. We evaluated the effects of the primary feeding practices by analyzing the infant growth and the potential association with gut diseases. A cross-sectional and observational study was designed. This study included 55 mothers with infants, who were divided according to their feeding practices in breastfeeding (BF), formula feeding (FF), and combined breast and formula feeding (CF). Anthropometric measurements of the participants were recorded. Additionally, non-invasive fecal samples from the infants were collected to analyze the microbiota by sequencing, immunoglobulin A (IgA) concentration (ELISA), and volatile organic compounds (gas chromatography with an electronic nose). Results showed that the microbiota diversity in the BF group was the highest compared to the other two groups. The IgA levels in the BF group were twice as high as those in the FF group. Moreover, the child´s growth in the BF group showed the best infant development when the data were compared at birth to the recollection time, as noted by the correlation with a decreased concentration of toxic volatile organic compounds. Interestingly, the CF group showed a significant difference in health status when the data were compared with the FF group. We conclude that early health practices influence children's growth, which is relevant to further research about how those infants' health evolved.
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Microbioma Gastrointestinal , Compuestos Orgánicos Volátiles , Recién Nacido , Lactante , Femenino , Niño , Humanos , Estudios Transversales , Lactancia Materna , Inmunoglobulina A , Fórmulas InfantilesRESUMEN
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
CONTEXT: Periodontitis is a chronic multifactorial inflammatory disease linked to oral microbiota dysbiosis. This disease progresses to infection that stimulates a host immune/inflammatory response, with progressive destruction of the tooth-supporting structures. OBJECTIVE: This systematic review aims to present a robust critical evaluation of the evidence of salivary protein profiles for identifying oral diseases using proteomic approaches and summarize the use of these approaches to diagnose chronic periodontitis. DATA SOURCES: A systematic literature search was conducted from January 1st, 2010, to December 1st, 2022, based on PICO criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and by searching the three databases Science Direct, Scopus, and Springer Link. STUDY SELECTION: According to the inclusion criteria, eight studies were identified to analyze the proteins identified by proteomics. RESULTS: The protein family S100 was identified as the most abundant in patients with chronic periodontitis. In this family, an increased abundance of S100A8 and S100A9 from individuals with the active disease was observed, which strongly relates to the inflammatory response. Moreover, the ratio S100A8/S100A9 and the metalloproteinase-8 in saliva could differentiate distinct periodontitis groups. The changes in protein profile after non-surgical periodontal therapy improved the health of the buccal area. The results of this systematic review identified a set of proteins that could be used as a complementary tool for periodontitis diagnosis using salivary proteins. CONCLUSION: Biomarkers in saliva can be used to monitor an early stage of periodontitis and the progression of the disease following therapy.
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Periodontitis Crónica , Humanos , Periodontitis Crónica/diagnóstico , Periodontitis Crónica/terapia , Proteómica , Saliva , Periodoncio , Ligamento Periodontal , Calgranulina A , Calgranulina BRESUMEN
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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BACKGROUND: There has been a global increase in the prevalence of obesity in pregnant women in recent years. Animal studies have shown that intrauterine environment associated with maternal obesity leads to epigenetic changes. However, the effects of epigenetic changes occurring before birth in response to maternal conditions have not been clearly characterized in humans. OBJECTIVE: The aim of the study was to analyze peroxisome proliferator-activated receptor (PPAR)-γ expression in cell cultures from newborns from mothers with overweight and obesity, in response to in vitro metabolic challenges and their relationship with microRNA profile and cytokine expression. Methods/Study design: The profile of circulating microRNAs from 72 mother-child pairs (including healthy infants born to normal weight [n = 35], overweight [n = 25], and obese [n = 12] mothers) was determined through real-time PCR, and the PPAR-γ expression in peripheral blood mononuclear cell cultures from offspring was analyzed after in vitro challenges. RESULTS: miR-146a, miR-155, and miR-378a were upregulated in overweight mothers, while miR-378a was upregulated in obese mothers compared to normal weight mothers. In children from overweight mothers, miR-155 and miR-221 were downregulated and miR-146a was upregulated, while offspring of mothers with obesity showed downregulation of miR-155, miR-221, and miR-1301. These microRNAs have direct or indirect relation with PPAR-γ expression. In vitro exposure to high triglyceride and exposure to miR-378a induced a higher expression of PPAR-γ in cells from offspring of mothers with overweight and obesity. In contrast, cells from offspring of mothers with obesity cultured with high glucose concentrations showed PPAR-γ downregulation. IL-1ß, IL-6, and TNF-α expression in cells of offspring of overweight and obese mothers differed from that of offspring of normal weight mothers. Limitation of our study is the small sample size. CONCLUSION: The blood microRNA profile, and in vitro PPAR-γ and inflammatory cytokine expression in cells of newborn infants are associated with maternal obesity indicating that epigenetic marks may be established during intrauterine development. Key Message: Neonatal microRNA profile is associated with maternal weight. Neonatal microRNA profile is independent of maternal microRNA profile. PPAR-γ expression in newborn cell cultures is affected by maternal weight.
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MicroARNs , PPAR gamma , Animales , Femenino , Desarrollo Fetal , Humanos , Leucocitos Mononucleares , MicroARNs/genética , Obesidad/genética , Sobrepeso/genética , PPAR gamma/genética , EmbarazoRESUMEN
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
Methotrexate is the gold standard treatment in rheumatoid arthritis. Once absorbed, it is internalized in cells, where glutamate residues are added to produce polyglutamated forms, which are responsible for the effect of methotrexate. The aim of the current study is to determine the relationship between methotrexate triglutamate concentrations and the clinical evolution in rheumatoid arthritis patients, as well as to characterize the variability in both features to propose strategies for low-dose methotrexate optimization. The quantification of methotrexate triglutamate concentration in red blood cells was performed through ultra-performance liquid chromatography coupled with mass spectrometry. Polymorphisms of genes involved in the formation of polyglutamates were determined by real-time polymerase chain reaction. A multivariate regression was performed to determine the covariates involved in the variability of methotrexate triglutamate concentrations and a population pharmacokinetics model was developed through nonlinear mixed-effects modeling. Disease activity score changed according to methotrexate triglutamate concentrations; patients with good response to treatment had higher concentrations than moderate or nonresponding patients. The methotrexate triglutamate concentrations were related to time under treatment, dose, red blood cells, and body mass index. A 1-compartment open model was selected to estimate the pharmacokinetic parameters; the typical total clearance (L/day) was determined as 1.45 * (body mass index/28 kg/m2 ) * (red blood cells/4.6 × 106 cells/µL) and the volume of distribution was 52.4 L, with an absorption rate of 0.0346/day and a fraction metabolized of 1.03%. Through the application of the model, the initial dose of methotrexate is proposed on the basis of stochastic simulations and considering methotrexate triglutamate concentrations found in responders patients.
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Antirreumáticos/farmacocinética , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/análogos & derivados , Ácido Poliglutámico/análogos & derivados , Factores de Edad , Antirreumáticos/sangre , Antirreumáticos/uso terapéutico , Índice de Masa Corporal , Peso Corporal , Relación Dosis-Respuesta a Droga , Eritrocitos , Genotipo , Humanos , Estudios Longitudinales , Tasa de Depuración Metabólica , Metotrexato/sangre , Metotrexato/farmacocinética , Metotrexato/uso terapéutico , México , Modelos Biológicos , Ácido Poliglutámico/sangre , Ácido Poliglutámico/farmacocinética , Ácido Poliglutámico/uso terapéutico , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The aim of the present work was to evaluate MTX treatment (0.1, 1 and 10 µg mL-1) in vitro in order to characterize its effects on cell proliferation alterations in cell cycle of HaCaT keratinocytes and wound healing in a Skh1 mice treated with MTX (low doses 30 mg kg-1, high doses 200 mg kg-1 and repeated doses at 1.5 mg kg-1). We analyzed the cytotoxic effect of methotrexate by a resazurin assay. The effects in the proliferation, cell cycle and apoptosis of HaCaT cells were analyzed by flow cytometry. The effects of MTX on wound healing in vivo were also analyzed. A trend toward reduction in the resazurin assay was found (p > 0.05). Reduced proliferation was also identified in a clonogenic assay and a CFSE assay (p < 0.05) due to the MTX treatment. A reduction in the G2/M and S phases was observed accompanied by apoptosis induction with increased sub G0 phase and annexin V FITC staining. Effect of MTX was evidenced in vivo on the wound closure process after day 10 (p < 0.05) with alterations in tissue architecture and remodeling. There is a marked effect of MTX on wound healing in vivo in Skh1 mice with implications for long-term therapy and surgical interventions.
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Proliferación Celular/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Metotrexato/farmacología , Cicatrización de Heridas/efectos de los fármacos , Análisis de Varianza , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones , Estadísticas no ParamétricasRESUMEN
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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Silver nanoparticles (AgNPs) have been widely employed or incorporated into different materials in biological application, due to their antibacterial properties. Therefore, antimicrobial capacity and cytotoxicity have been highly studied. However, most of these reports do not consider the possible corrosion of the nanomaterials during their exposure to atmospheric conditions since AgNPs undergo a transformation when they come in contact with a particular environment. Derived from this, the functionality and properties of the nanoparticles could decrease noticeably. The most common silver corrosion process occurs by the interaction of AgNPs with sulfur species (H2S) present in the atmospheric air, forming a corrosion layer of silver sulfide around the AgNPs, thus inhibiting the release of the ions responsible for the antimicrobial activity. In this work, AgNPs were synthesized using two different methods: one of them was based on a plant extract (Brickellia cavanillesii), and the other one is the well-known method using sodium borohydride (NaBH4). Chemical stability, corrosion, antibacterial activity, and toxic activity were evaluated for both sets of prepared samples, before and after exposition to atmospheric air for three months. The structural characterization of the samples, in terms of crystallinity, chemical composition, and morphology, evidenced the formation of link structures with nanobridges of Ag2S for non- "green" AgNPs after the air exposition and the intact preservation of silver core for the "green" sample. The antibacterial activity showed a clear improvement in the antimicrobial properties of silver in relation to the "green" functionalization, particle size control, and size reduction, as well as the preservation of the properties after air exposition by the effective "green" protection. The cytotoxicity effect of the different AgNPs against mononuclear cells showed a notable increment in the cell viability by the "green" functionalization.
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The purpose of this study was to generate novel chitosan hydrogels (CHs) loaded with silver nanoparticles (AgNPs) and ampicillin (AMP) to prevent early formation of biofilms. AgNPs and CHs were characterized by UV-Vis, DLS, TEM, rheology, FT-IR, Raman, and SEM. The antibiofilm effect of the formulations was investigated against four multidrug-resistant and extensively drug-resistant pathogens using a colony biofilm, a high cell density and gradients model. Also, their hemostatic properties and cytotoxic effect were evaluated. Rheology results showed that CHs with AgNPs and AMP are typical non-Newtonian pseudoplastic fluids. The CH with 25 ppm of AgNPs and 50 ppm AMP inhibited the formation of biofilms of Acinetobacter baumannii, Enterococcus faecium and Staphylococcus epidermidis, while a ten-fold increase of the antimicrobial's concentration was needed to inhibit the biofilm of the ß-lactamase positive Enterobacter cloacae. Further, CH with 250 ppm of AgNPs and 500 ppm AMP showed anticoagulant effect, and it was shown that all formulations were biocompatible. Besides to previous reports that described the bioadhesion properties of chitosan, these results suggest that AgNPs and AMP CHs loaded could be used as prophylactic treatment in patients with central venous catheter (CVC), inhibiting the formation of biofilms in their early stages, in addition to their anticoagulant effect and biocompatibility, those properties could keep the functionality of CVC helping to prevent complications such as sepsis and thrombosis.
Asunto(s)
Catéteres Venosos Centrales , Quitosano , Nanopartículas del Metal , Ampicilina , Antibacterianos/farmacología , Biopelículas , Humanos , Hidrogeles , Pruebas de Sensibilidad Microbiana , Plata , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
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.