RESUMO
Phenothiazines inhibit antioxidant enzymes in trypanosomatids. However, potential interferences with host cell antioxidant defenses are central concerns in using these drugs to treat Trypanosoma cruzi-induced infectious myocarditis. Thus, the interaction of thioridazine (TDZ) with T. cruzi and cardiomyocytes antioxidant enzymes, and its impact on cardiomyocytes and cardiac infection was investigated in vitro and in vivo. Cardiomyocytes and trypomastigotes in culture, and mice treated with TDZ and benznidazole (Bz, reference antiparasitic drug) were submitted to microstructural, biochemical and molecular analyses. TDZ was more cytotoxic and less selective against T. cruzi than Bz in vitro. TDZ-pretreated cardiomyocytes developed increased infection rate, reactive oxygen species (ROS) production, lipid and protein oxidation; similar catalase (CAT) and superoxide dismutase (SOD) activity, and reduced glutathione's (peroxidase - GPx, S-transferase - GST, and reductase - GR) activity than infected untreated cells. TDZ attenuated trypanothione reductase activity in T. cruzi, and protein antioxidant capacity in cardiomyocytes, making these cells more susceptible to H2O2-based oxidative challenge. In vivo, TDZ potentiated heart parasitism, total ROS production, myocarditis, lipid and protein oxidation; as well as reduced GPx, GR, and GST activities compared to untreated mice. Benznidazole decreased heart parasitism, total ROS production, heart inflammation, lipid and protein oxidation in T. cruzi-infected mice. Our findings indicate that TDZ simultaneously interact with enzymatic antioxidant targets in cardiomyocytes and T. cruzi, potentiating the infection by inducing antioxidant fragility and increasing cardiomyocytes and heart susceptibility to parasitism, inflammation and oxidative damage.
Assuntos
Antioxidantes , Cardiomiopatia Chagásica , Miócitos Cardíacos , Espécies Reativas de Oxigênio , Tioridazina , Trypanosoma cruzi , Animais , Miócitos Cardíacos/parasitologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Trypanosoma cruzi/efeitos dos fármacos , Camundongos , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tioridazina/farmacologia , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Miocardite/parasitologia , Miocardite/tratamento farmacológico , Miocardite/metabolismo , Miocardite/patologia , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Masculino , Tripanossomicidas/farmacologia , Superóxido Dismutase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Doença de Chagas/metabolismo , Doença de Chagas/patologia , Catalase/metabolismo , Ratos , NADH NADPH Oxirredutases/metabolismoRESUMO
INTRODUCTION: In children, the presence of obesity is a major risk factor for the occurrence of cardiovascular diseases on the adulthood. OBJECTIVE: To evaluate the association of anthropometry, body composition, clinical variables and biochemical profile with C-reactive protein and adiponectin levels, and insulin resistance in children in the municipality of Nova Era, Brazil. METHODS: Nested case-control study following a crosssectional study. We evaluated 178 children, 57 of them classified as obese and 121 as normal-weight from a population of 1024 schoolchildren 6 to 10 years old: Blood samples were collected after 12-hour fast to obtain serum and plasma. We collected anthropometric and body composition measures, systolic and diastolic blood pressure data. Sexual maturation was assessed according to the stage of sexual development. We performed Student's t-test, Mann-Whitney U test, Pearson's correlation, Spearman's test and multiple linear regression analysis. Independent variables with p < 0.05 were included in the multiple regression model. Residual analysis was performed to assess model validity. RESULTS: Among obese children, C-reactive protein levels were associated with triacylglycerol levels and body fat percentage estimated by skinfold thickness (R2 adjusted = 27.6%, p < 0.001). Adiponectin was associated with HOMA-IR, HOMAAD and body fat percentage estimated by skinfold thickness (R2 adjusted = 75.5%, p < 0.001). HOMA-AD index was associated with HOMA-IR, adiponectin, systolic blood pressure and weight (R2 adjusted = 90.7%, p < 0.001). CONCLUSION: Significant associations were found between body composition, anthropometry, clinical variables, biochemical profile and adiponectin and C-reactive protein levels and insulin resistance in obese and normal-weight children.
INTRODUCCIÓN: En niños, la obesidad es um factor de riesgo para enfermedades cardiovasculares en la edad adulta. OBJETIVOS: Asociaciar la antropometría, composición corporal, variables clínicas y bioquímicas con la proteína C reactiva (PCR), adiponectina y resistencia a la insulina en niños de Nova Era, Brasil. MÉTODOS: Estudio de casos y controles anidado en un transversal. Se evaluaron 178 niños, 57 obesos y 121 eutróficos en una población de 1.024 escolares de 6 a 10 años. Las muestras de sangre se recogieron después de 12 horas de ayuno. Recogimos las medidas antropométricas, de composición corporal y presión arterial. La madurez sexual fue evaluada de acuerdo con el desarrollo sexual. Se realizo las pruebas t de Student y U de Mann- Whitney, las correlaciones de Pearson y Spearman y el análisis de regresión lineal múltiple. Se incluyeron en el modelo de regresión, las variables independientes con p < 0,05. Se realizo el análisis residual para evaluar la validez del modelo. RESULTADOS: Entre los niños obesos, los niveles de PCR se asociaron con los triglicéridos y el porcentaje de grasa corporal (%GC) estimada por los pliegues cutáneos (R2 ajustado = 27,6%, p < 0,001). La adiponectina se asoció con HOMA-IR, HOMA-AD y % GC estimada por los pliegues cutáneos (R2 ajustado = 75,5%, p < 0,001). El HOMA-AD se asoció con HOMA-IR, adiponectina, presión arterial sistólica y peso (R2 ajustado = 90,7%, p < 0,001). CONCLUSIONES: Se encontraron asociaciones entre la composición corporal, antropometría, variables clínicas, perfil bioquímico, adiponectina, PCR y la resistencia a la insulina en niños obesos y eutróficos.