RESUMEN
BACKGROUND: Elevated liver enzyme levels have been associated with metabolic syndrome in both obese and non-obese pediatric populations. This study aims to compare the serum liver enzyme levels in obese adolescents with and without insulin resistance (IR). METHODS: A cross-sectional analysis was conducted involving obese adolescents aged 10-18. We assessed somatometry, serum insulin levels, lipid profiles, and liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyl transferase [GGT]). Statistical differences between groups were evaluated using Student's t-test or the Chi-squared test, with IR (wIR) status matched by propensity scores based on body mass index (BMI) z-scores. RESULTS: The study included 365 adolescents with obesity, 229 wIR, and 136 without (woIR). Before matching, the wIR group had a significantly higher BMI z-score (2.21 vs. 2.14, p = 0.032). After matching for BMI z-scores (n = 122 each group), the wIR group displayed significantly higher levels of AST (32.3 vs. 24.7, p < 0.001) and ALT (42.4 vs. 30.9, p < 0.001), but no significant differences were observed in GGT levels (37.4 vs. 32.5, p = 0.855). CONCLUSION: Obese adolescent's wIR exhibit higher serum ALT and AST levels, suggesting that altered AST is a potential risk factor for IR.
INTRODUCCIÓN: Se ha observado asociación entre niveles elevados de enzimas hepáticas y síndrome metabólico en población pediátrica con y sin obesidad. El objetivo del estudio fue comparar los niveles séricos de enzimas hepáticas entre adolescentes con obesidad con y sin resistencia a la insulina (RI). MÉTODOS: Se realizó un estudio transversal en adolescentes con obesidad entre 10 y 18 años. Se analizaron los datos somatometricos, insulina sérica, perfil lipídico y niveles de enzimas hepáticas (aspartato aminotransferasa [AST], alanina aminotransferasa [ALT] y gamma-glutamil transferasa [GGT]). Análisis estadístico: se utilizó t de Student o la prueba de Chi-cuadrado para evaluar diferencias entre grupos. Los pacientes con RI se emparejaron con pacientes sin RI utilizando puntuaciones de propensión basadas en la puntuación z del IMC. RESULTADOS: Se incluyeron un total de 365 adolescentes con obesidad (229 con RI y 136 sin RI). El grupo con RI tuvo un IMC mayor (con RI 2.21 vs sin RI 2.14 p = 0.032). Después de emparejar los grupos según el IMCz (n = 122 por grupo), el grupo con RI tuvo niveles de AST (24.7 vs., 32.3, p < 0.001) y ALT (30.9 vs., 42.4, p < 0.001) significativamente más altos en comparación al grupo sin RI. Sin embargo, no hubo diferencia en los niveles de GTT (37.4 vs 32.5, p = 0.855). CONCLUSIONES: Los niveles séricos de ALT y AST en adolescents con obesidad y RI fueron mayores. La AST alterada fue un factor de riesgo para presentar RI.
Asunto(s)
Alanina Transaminasa , Aspartato Aminotransferasas , Índice de Masa Corporal , Resistencia a la Insulina , Hígado , Obesidad Infantil , Puntaje de Propensión , gamma-Glutamiltransferasa , Humanos , Adolescente , Estudios Transversales , Femenino , Masculino , Alanina Transaminasa/sangre , Niño , Aspartato Aminotransferasas/sangre , gamma-Glutamiltransferasa/sangre , Hígado/enzimología , Síndrome Metabólico/sangre , Insulina/sangreRESUMEN
Live food in the initial life stages of neotropical fish is essential for their development and health; however, it can significantly increase production costs. This study uses complete diets with varying moisture contents (47%, 35%, 24%, and 8%) as a cost-effective alternative in the co-feeding phase of surubim larvae, assessing their influence on development, digestive enzymes, and liver metabolism. In a completely randomized design, 3200 three-day-old Pseudoplatystoma sp. larvae (0.001 g) were distributed evenly among 16 aquariums (20 L), with 200 individuals per aquarium. For the first five days, all larvae were fed Artemia exclusively, after which they were fed experimental diets with varying levels of humidity (47%, 35%, 24%, and 8%) six times a day across four treatments and four replicates. The 21-day feeding trial demonstrated that larvae fed with 24% and 8% moisture diets exhibited increased (p < 0.05) weight gain, final length, and protein efficiency rate. The remaining growth parameters (i.e., specific growth rate and condition factor) did not show significant differences (p > 0.05) among the dietary treatments. Enzymatic analysis revealed that the 47% moisture diet enhanced the amylase and alkaline phosphatase activities, whereas the 24% and 35% moisture diets elevated the lipase and protease activities. The 47% moisture diet also resulted in increased alanine aminotransferase, aspartate aminotransferase, and albumin levels, along with visible hepatic histopathologies in samples, such as visible lipid vacuoles, displacement of the nucleus of the hepatocyte, and increased sinusoid spaces. No significant liver changes were observed in fish fed with other diets. Principal component analysis showed that diets with 8-24% moisture content were the most beneficial during the co-feeding phase of surubim larviculture.
Asunto(s)
Alimentación Animal , Dieta , Larva , Animales , Alimentación Animal/análisis , Dieta/veterinaria , Larva/crecimiento & desarrollo , Bagres/crecimiento & desarrollo , Bagres/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales , Agua/metabolismo , Digestión/fisiología , Hígado/enzimología , Hígado/metabolismoRESUMEN
Our purpose was to evaluate the biocompatibility and hepatotoxicity of a new bioceramic intracanal medicament, Bio-C Temp (BIO). The biological properties of BIO were compared with calcium hydroxide-based intracanal medicament (Calen; CAL), used as gold pattern. Polyethylene tubes filled with BIO or CAL, and empty tubes (control group, CG) were implanted into subcutaneous tissue of rats. After 7, 15, 30 and 60 days, the samples were embedded in paraffin for morphological, quantitative and immunohistochemistry analyses. At 7 and 60 days, blood samples were collected for analysis of serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels. The data were submitted to two-way ANOVA and Tukey's test (p ≤ 0.05). No significant difference was detected in serum GOT and GPT levels among BIO, CAL and CG specimens. In all periods, BIO specimens exhibited lower number of inflammatory cells and immunoexpression of IL-6, a pro-inflammatory cytokine, than CAL specimens. The reduction of these parameters was accompanied by significant increase in the collagen content and in the immunoexpression of IL-10, a cytokine involved in the tissue repair, over time. Our findings indicate that Bio-C Temp is biocompatible and had no hepatotoxicity effect.
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Óxido de Aluminio/farmacología , Materiales Biocompatibles/farmacología , Hígado/enzimología , Tejido Subcutáneo/efectos de los fármacos , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Hidróxido de Calcio/farmacología , Hígado/efectos de los fármacos , Ensayo de Materiales , Prótesis e Implantes/efectos adversos , Ratas , Materiales de Obturación del Conducto Radicular/farmacologíaRESUMEN
Triclosan (TCS) is a synthetic broad-spectrum antimicrobial agent commonly used world-wide in a range of personal care and sanitizing products detected frequently in aquatic ecosystems. The aim of this study was to examine biochemical markers responses triggered by TCS in Danio rerio and in a native South American fish species (Corydoras paleatus). Further, an integrated approach comparing both test fish species was undertaken. These fish organisms were exposed to 100 or 189 µg TCS/L for 48 h. The activities of catalase (CAT), glutathione-s-transferase (GST), superoxide dismutase (SOD), and lipid peroxidation levels (LPO) and total antioxidant capacity against peroxyl radicals (ACAP) were determined in liver, gills, and brain. Acetylcholinesterase activity (AChE) was measured in the brain. Multivariate analysis showed that the most sensitive hepatic parameters were activities of GST and SOD for C. paleatus while LPO levels were for D. rerio. In gills the same parameters were responsive for C. paleatus but CAT in D. rerio. ACAP and GST activity were responsive parameters in brain of both species. Integrated biomarker responses (IBR) index demonstrated similar trends in both species suggesting this parameter might serve as a useful tool for quantification of integrated responses induced by TCS.
Asunto(s)
Antiinfecciosos Locales/toxicidad , Biomarcadores , Estrés Oxidativo/efectos de los fármacos , Triclosán/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Bagres , Branquias/efectos de los fármacos , Branquias/enzimología , Hígado/efectos de los fármacos , Hígado/enzimología , Pez CebraRESUMEN
Obesogenic diets (ODs) can affect AMPK activation in several sites as the colon, liver, and hypothalamus. OD intake can impair the hypothalamic AMPK regulation of energy homeostasis. Despite consuming ODs, not all subjects have the propensity to develop or progress to obesity. The obesity propensity is more associated with energy intake than expenditure dysregulations and may have a link with AMPK activity. While the effects of ODs are studied widely, few evaluate the short-term effects of terminating OD intake. Withdrawing from OD (WTD) is thought to improve or reverse the damages caused by the intake. Therefore, here we applied an OD intake and WTD protocol aiming to evaluate AMPK protein content and phosphorylation in the colon, liver, and hypothalamus and their relationship with obesity propensity. To this end, male Wistar rats (60 days) received control or high-sugar/high-fat (HSHF) OD for 30 days. Half of the animals were OD-withdrawn and fed the control diet for 48 h. After intake, we found a reduction in AMPK phosphorylation in the hypothalamus and colon, and after WTD, we found an increase in its hepatic and hypothalamic phosphorylation. The decrease in colon pAMPK/AMPK could be linked with hypothalamic pAMPK/AMPK after HSHF intake, while the increase in hepatic pAMPK/AMPK could have prevented the increase in hypothalamic pAMPK/AMPK. In the obesity-prone rats, we found higher levels of hypothalamic and colon pAMPK/AMPK despite the higher body mass gain. Our results highlight the relevance in multi-organ investigations and animal phenotype evaluation when studying the energy metabolism regulations.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Eje Cerebro-Intestino , Colon/enzimología , Hipotálamo/enzimología , Hígado/enzimología , Obesidad/enzimología , Animales , Dieta Alta en Grasa/efectos adversos , Azúcares de la Dieta/efectos adversos , Masculino , Obesidad/etiología , Ratas WistarRESUMEN
Lipids excess from an uterine environment can increase free radicals production of and thus induce oxidative status imbalance, a key factor for progression of non-alcoholic fatty liver disease (NAFLD) in offspring. Food antioxidant components in maternal diet may play an important role in preventing offspring metabolic disorders. The objective of the study was to evaluate the effects of açaí pulp supplementation on maternal high-fat diet, by assessing activity and expression of antioxidant enzymes and biomarkers of oxidative stress in the liver. Female Fisher rats were divided into four groups and fed a control diet (C), a high-fat diet (HF), a control diet supplemented with açaí (CA) and a high-fat diet supplemented with açaí (HFA) before mating, during gestation and lactation. The effects of açaí supplementation on oxidative stress biomarkers and antioxidant enzymes expression were evaluated in dams and male offspring after weaning. HFA diet increased body weight in dams, however reduced absolute and relative liver weight. There was a reduction in liver biomarkers of oxidative stress, malondialdehyde and carbonyl protein, as well as in catalase, glutathione peroxidase and superoxide dismutase activity. In offspring, HFA diet reduced liver weight and increased Gpx1, Gpx4 and Sod1 mRNA expression. These results suggest that açaí is able to restore redox status, preventing oxidative damage in dams by a direct mechanism and to promote beneficial effects on expression of antioxidant defences related genes in offspring.
Asunto(s)
Antioxidantes/metabolismo , Euterpe/química , Hígado/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa , Suplementos Dietéticos , Femenino , Expresión Génica/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Lactancia , Hígado/efectos de los fármacos , Hígado/enzimología , Ratones , Enfermedad del Hígado Graso no Alcohólico , Tamaño de los Órganos/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Embarazo , Ratas , Ratas Endogámicas F344 , Superóxido Dismutasa-1/metabolismo , Glutatión Peroxidasa GPX1RESUMEN
Childhood obesity is a global and increasing health issue. Inflammation and dysregulated adipose tissue secretion are common findings in obesity and have been related to poor metabolic function. Given that DNA methylation impacts gene expression and is responsive to environmental changes, we aimed, in addition to characterize the patients in anthropometric and biochemical terms, to determine the expression of cytokines and adipokines, assess the methylation on regulatory regions of the genes that code for these molecules, and investigate the association of the expression and gene methylation with anthropometric and biochemical parameters in childhood obesity. Obese children present dyslipidemia, dysregulated serum levels of adipokines and their ratios, altered leukocytic expression of cytokines, and higher methylation at the CXCL8 promoter as compared to the control group. However, no significant results were observed in the fasting plasma glucose levels or the methylation of TGFB1, LEP, and the enhancer region of ADIPOQ. We also found negative correlations of CXCL8 expression with anthropometric and biochemical parameters, and positive correlation of CXCL8 promoter methylation and the serum levels of hepatic enzymes. Our results indicate that changes in metabolic parameters observed in childhood obesity are associated with the expression of adipokines and cytokines, and the methylation status at the CXCL8 promoter. CXCL8 may be a key factor for these alterations, as it correlates with many of the parameters assessed in the present study.
Asunto(s)
Antropometría , Metilación de ADN/genética , Interleucina-8/genética , Obesidad Infantil/genética , Obesidad Infantil/metabolismo , Adipoquinas/sangre , Adiponectina/sangre , Proteína C-Reactiva/metabolismo , Niño , Dislipidemias/genética , Femenino , Humanos , Interleucina-8/sangre , Interleucina-8/metabolismo , Leptina/sangre , Hígado/enzimología , Masculino , Obesidad Infantil/sangre , Regiones Promotoras Genéticas/genéticaRESUMEN
SUMMARY: Amiodarone (AMD), an orally powerful antidysrhythmic medication that has caused hepatotoxicity on long-term administration, is commonly used across the world. Silymarin ameliorative effects (SLM); this research elucidated the magnitude of the damage to the liver tissue in AMD. We divided 24 albino rats evenly into four groups given daily doses by gastric tube for eight weeks as follows; the 1st group acted as a control group; the 2nd group received SLM; the 3rd group received AMD; and the 4th group received AMD parallel to SLM. Liver tissues prepared for light, electron microscopic and serum samples screened for biomarkers (I)liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST); (II) oxidative and antioxidant stress, malondialdehyde (MDA) and superoxide dismutase (SOD); and (III) inflammatory markers, tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6). The findings showed that AMD caused hepatic histological changes that included congestion of the blood vessels, leucocytic infiltration and cytoplasmic vacuolation. Ultrastructural degeneration of the mitochondria, endoplasmic reticulum swelling, nuclear pyknosis and increased fat droplets and lysosomes were observed. The biochemical findings showed an increase in the AMD group's ALT and AST activities. The group of rats treated with AMD and SLM, increased the improvements in histology and ultrastructure, while the ALT and AST levels were reduced. Our findings collectively agreed that SLM has a protective impact on AMD hepatotoxicity which can be due to its antioxidant properties.
RESUMEN: La amiodarona (AMD) es un fuerte medicamento antiarrítmico administrado por vía oral que ha causado hepatotoxicidad en la administración a largo plazo utilizado con frecuencia en todo el mundo. Efectos de mejora de la silimarina (SLM); esta investigación analizó la magnitud del daño al tejido hepático en la DMAE. Dividimos 24 ratas albinas de manera uniforme en cuatro grupos que recibieron dosis diarias por sonda gástrica durante ocho semanas de la siguiente manera; el primer grupo fue designado como grupo control; el segundo grupo recibió SLM; el tercer grupo recibió AMD; y el cuarto grupo recibió AMD en paralelo a SLM. Se prepararon tejidos hepáticos para muestras de suero, microscopía de luz y electrónica y se analizaron para biomarcadores (I) enzimas de daño hepático, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST); (II) estrés oxidativo y antioxidante, malondialdehído (MDA) y superóxido dismutasa (SOD); y (III) marcadores inflamatorios, factor de necrosis tumoral alfa (TNF-a) e interleucina-6 (IL-6). Los hallazgos mostraron que la DMAE genera cambios histológicos hepáticos que incluyen congestión de los vasos sanguíneos, infiltración leucocítica y vacuolación citoplásmica. Se observó una degeneración ultraestructural de las mitocondrias, aumento del retículo endoplásmico, picnosis nuclear y aumento de gotitas de grasa y lisosomas. Los hallazgos bioquímicos mostraron un aumento en las actividades de ALT y AST del grupo AMD. El grupo de ratas tratadas con AMD y SLM, aumentó las mejoras en histología y ultraestructura, mientras que se redujeron los niveles de ALT y AST. Nuestros hallazgos coincidieron colectivamente en que SLM tiene un impacto protector sobre la hepatotoxicidad de AMD debido a sus propiedades antioxidantes.
Asunto(s)
Animales , Femenino , Ratas , Silimarina/administración & dosificación , Sustancias Protectoras/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Amiodarona/toxicidad , Hígado/efectos de los fármacos , Aspartato Aminotransferasas/análisis , Ratas Endogámicas , Silimarina/farmacología , Superóxido Dismutasa , Microscopía Electrónica , Interleucina-6 , Factor de Necrosis Tumoral alfa , Estrés Oxidativo , Sustancias Protectoras/farmacología , Alanina Transaminasa/análisis , Hígado/enzimología , Hígado/ultraestructura , Malondialdehído , Antiarrítmicos/toxicidadRESUMEN
Cancer cells exhibit an altered metabolic phenotype, consuming higher levels of the amino acid glutamine. This metabolic reprogramming depends on increased mitochondrial glutaminase activity to convert glutamine to glutamate, an essential precursor for bioenergetic and biosynthetic processes in cells. Mammals encode the kidney-type (GLS) and liver-type (GLS2) glutaminase isozymes. GLS is overexpressed in cancer and associated with enhanced malignancy. On the other hand, GLS2 is either a tumor suppressor or an oncogene, depending on the tumor type. The GLS structure and activation mechanism are well known, while the structural determinants for GLS2 activation remain elusive. Here, we describe the structure of the human glutaminase domain of GLS2, followed by the functional characterization of the residues critical for its activity. Increasing concentrations of GLS2 lead to tetramer stabilization, a process enhanced by phosphate. In GLS2, the so-called "lid loop" is in a rigid open conformation, which may be related to its higher affinity for phosphate and lower affinity for glutamine; hence, it has lower glutaminase activity than GLS. The lower affinity of GLS2 for glutamine is also related to its less electropositive catalytic site than GLS, as indicated by a Thr225Lys substitution within the catalytic site decreasing the GLS2 glutamine concentration corresponding to half-maximal velocity (K0.5). Finally, we show that the Lys253Ala substitution (corresponding to the Lys320Ala in the GLS "activation" loop, formerly known as the "gating" loop) renders a highly active protein in stable tetrameric form. We conclude that the "activation" loop, a known target for GLS inhibition, may also be a drug target for GLS2.
Asunto(s)
Activación Enzimática , Glutaminasa/química , Hígado/enzimología , Sustitución de Aminoácidos , Catálisis , Glutaminasa/genética , Glutaminasa/metabolismo , Humanos , Mutación Missense , Estructura Cuaternaria de Proteína , Relación Estructura-ActividadRESUMEN
In the current study, chemical composition of cultivated Salvia canariensis L was determined. Carnosol was the main product isolated. We prepared more lipophilic derivatives from carnosol, and both isolated and semisynthetic abietane diterpenes were evaluated in vitro as inhibitors of squalene synthase. Among the compounds tested, carnosol was the most potent inhibitor (IC50 = 17.6 µM). These results highlight the great potential of this species for the production of new ingredients in nutritional supplements for the treatment of hyperlipidemia.
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Abietanos/farmacología , Diterpenos , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Salvia , Abietanos/aislamiento & purificación , Animales , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Hígado/enzimología , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Ratas , Salvia/químicaRESUMEN
Cirrhotic cardiomyopathy is a condition where liver cirrhosis is associated with cardiac dysfunction. Triggers and blockers of cirrhotic cardiomyopathy are poorly understood, which might compromise the prognosis of chronic liver disease patients. We tested whether exercise training would reduce liver damage induced by thioacetamide and prevent liver cirrhosis-associated cardiomyopathy. Wistar rats were divided into three groups: control, thioacetamide (TAA), or TAA plus exercise. Thioacetamide increased liver weight and serum alanine aminotransferase and aspartate aminotransferase levels. Also, TAA treatment was involved with hepatic nodule formation, fibrotic septa, inflammatory infiltration, and hepatocyte necrosis. The exercise group presented with a reduction in liver injury status. We found that liver injury was associated with disordered cardiac hypertrophy as well as diastolic and systolic dysfunction. Exercise training attenuated cirrhosis-associated cardiac remodeling and diastolic dysfunction and prevented systolic impairment. These results provided insights that exercise training can mitigate cirrhotic cardiomyopathy phenotype. Graphical Abstract Exercise training attenuated liver injury as well as cirrhosis-associated cardiac remodeling and diastolic dysfunction and prevented systolic impairment.
Asunto(s)
Cardiomiopatías/prevención & control , Terapia por Ejercicio , Cirrosis Hepática/terapia , Acondicionamiento Físico Humano , Animales , Función del Atrio Izquierdo , Biomarcadores/sangre , Cardiomiopatías/inducido químicamente , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Modelos Animales de Enfermedad , Tolerancia al Ejercicio , Humanos , Hígado/enzimología , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Masculino , Miocardio/patología , Ratas Wistar , Tioacetamida , Función Ventricular IzquierdaRESUMEN
OBJECTIVE: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration-approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD. CONCLUSIONS: Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Eritrocitos/efectos de los fármacos , Febuxostat/farmacología , Hemodinámica/efectos de los fármacos , Hemólisis/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Xantina Oxidasa/antagonistas & inhibidores , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/enzimología , Anemia de Células Falciformes/fisiopatología , Animales , Modelos Animales de Enfermedad , Eritrocitos/enzimología , Hígado/enzimología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Arteria Pulmonar/enzimología , Arteria Pulmonar/fisiopatología , Función Ventricular/efectos de los fármacos , Xantina Oxidasa/genética , Xantina Oxidasa/metabolismoRESUMEN
Two microcystins, MC-LR and [D-Leu1]MC-LR, present in La Plata Basin blooms, are differentiated by substitution of D-Alanine for D-Leucine at position 1. Our objective was to evaluate acute toxicity of [D-Leu1]MC-LR and MC-LR in mice (N:NIH Swiss) and beans (Phaseolus vulgaris). We observed variations in [D-Leu1]MC-LR lethal doses with respect to those reported for MC-LR (100 µg/kg), with an increased liver/body weight ratio and intrahepatic hemorrhages in mice exposed to 50-200 µg [D-Leu1]MC-LR/kg and slight steatosis after a single 25 µg [D-Leu1]MC-LR/kg i.p. dose. Our study in the plant model showed alterations in germination, development, morphology and TBARs levels after a single contact with the toxins during imbibition (3.5 and 15 µg/mL), those treated with [D-Leu1]MC-LR being more affected than those treated with the same concentration of MC-LR. Protein phosphatase 1 (PP1) IC50 values were 40.6 nM and 5.3 nM for [D-Leu1]MC-LR and MC-LR, respectively. However, the total phosphatase activity test in root homogenate showed 60% inhibition for [D-Leu1]MC-LR and 12% for MC-LR. In mouse liver homogenate, 50% inhibition was observed for [D-Leu1]MC-LR and 40% for MC-LR. Our findings indicate the need for further research into [D-Leu1]MC-LR toxicity since together with oxidative stress, the possible inhibition of other phosphatases could explain the differences detected in the potency of the two toxins.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Inhibidores Enzimáticos/toxicidad , Hígado/efectos de los fármacos , Toxinas Marinas/toxicidad , Microcistinas/toxicidad , Phaseolus/efectos de los fármacos , Proteínas de Plantas/antagonistas & inhibidores , Proteína Fosfatasa 1/antagonistas & inhibidores , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Relación Dosis-Respuesta a Droga , Hígado/enzimología , Hígado/patología , Masculino , Ratones , Phaseolus/enzimología , Proteínas de Plantas/metabolismo , Proteína Fosfatasa 1/metabolismoRESUMEN
Leishmania spp. parasites have a complex biological cycle presenting basically two different morphological stages, the amastigote and promastigote forms. In vitro cultivation allows a more complete study of the biological aspects of these parasites, indicating better conditions for infection, immunoassay tests, drug evaluations, and vaccines. Thus, we evaluated the three most used culture media for Leishmania spp., Grace's insect cell culture medium (Grace's), liver infusion tryptose (LIT), and Schneider's insect medium (Schneider's), without supplementation or supplemented with fetal calf serum (FCS) and bovine serum albumin (Albumin) to evaluate the growth, viability, and infectivity of the L. infantum promastigotes. It was observed that promastigote forms have a better growth in LIT and Schneider's with or without FCS when compared to that in Grace's. The supplementation with albumin promoted greater viability of the parasites independent of the medium. For in vitro infection of J774.A1 macrophages using light microscopy and flow cytometry analyses, FCS-supplemented LIT and Grace's promoted higher percentage of infected macrophages and parasite load compared with Schneider's media. Taken together, our results demonstrated that the supplementation of LIT culture medium with FCS is the most suitable strategy to cultivate Leishmania infantum parasites enabling the maintenance of growth and infective parasites for research uses.
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Leishmania infantum/efectos de los fármacos , Leishmania infantum/crecimiento & desarrollo , Hígado/enzimología , Parasitología/métodos , Animales , Células Cultivadas , Medios de Cultivo/química , Medios de Cultivo/farmacología , Leishmania infantum/fisiología , Estadios del Ciclo de Vida/efectos de los fármacos , Macrófagos/parasitología , Ratones , Compuestos Orgánicos/análisis , Compuestos Orgánicos/farmacologíaRESUMEN
The dusky grouper Epinephelus marginatus is predator fish subjected to be impacted due to the contamination of their habitats. A viable source of metal contamination, i.e., copper (Cu), in this species is the ingestion of contaminated food. The objective of this work was to verify the toxic effects of Cu contaminated feed in dusky grouper. A 15 days trial was conducted with three treatments: control, 1 g and 2 g Cu/kg of fish feed. After the trial, the gut was analyzed for Cu concentration and the liver for SOD and GST activity. The Cu concentration in the intestinal tract was significantly greater in fish from contaminated treatments when compared with control. The SOD was significantly lower in contaminated fish, and the GST did not show differences among treatments. Copper showed to be toxic for the species, as evidenced by gut accumulation and suggested by SOD response.
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Alimentación Animal , Cobre/toxicidad , Contenido Digestivo/química , Perciformes/metabolismo , Contaminantes Químicos del Agua/toxicidad , Animales , Cobre/análisis , Ecosistema , Hígado/efectos de los fármacos , Hígado/enzimología , Modelos Teóricos , Alimentos Marinos , Superóxido Dismutasa/metabolismo , Contaminantes Químicos del Agua/análisisRESUMEN
The purpose of this study was to identify the long-term effect of chemical exposure on the liver. Laboratory tests included alanine aminotransferase (ALT) dosage and oxidative stress tests, such as thiobarbituric acid reactive substances in plasma and superoxide dismutase (SOD) and glutathione S-transferase analysis in erythrocytes. The cross-sectional study comprised 70 workers, 30 of them exposed to organic solvents and 40 not exposed. All those exposed presented at least 5 years of exposure to solvents. Hepatitis B and C, known hepatic disease, comorbidities, use of alcohol, illicit drugs or hepatotoxic medications, smoking, body mass index >30, female sex and age (<18 or >65) were excluded from the sample. Results indicated that elevated ALT was more frequent in the exposed group compared to controls: 33% vs. 10.5%, with a statistical significance (p < 0.05). Thiobarbituric acid reactive substances were significantly elevated (p < 0.01) in the exposed group in comparison to controls. Antioxidant enzymes were more elevated in the exposed group compared to controls: SOD 7.29 (4.30-8.91) USOD/mg of protein vs. 3.48 (2.98-5.28) USOD/mg of protein and GST 2.57 µmol/min/mg of protein (1.80-4.78) vs. 1.81 µmol/min/mg of protein (1.45- 2.30) µM/min/mg of protein. The results suggest an association between exposure to organic solvents and hepatotoxicity.
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Antioxidantes/metabolismo , Hidrocarburos Aromáticos/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Exposición Profesional/efectos adversos , Solventes/toxicidad , Alanina Transaminasa/sangre , Animales , Brasil , Estudios Transversales , Femenino , Glutatión Transferasa/sangre , Humanos , Hidrocarburos Aromáticos/análisis , Industrias , Hígado/enzimología , Hígado/metabolismo , Masculino , Exposición Profesional/análisis , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Solventes/análisis , Superóxido Dismutasa/sangreRESUMEN
Non-pharmacological early weaning (NPEW) induces liver damage in male progeny at adulthood; however, pharmacological early weaning (PEW) does not cause this dysfunction. To elucidate this difference in liver dysfunction between these two models and determine the phenotype of female offspring, de novo lipogenesis, ß-oxidation, very low-density lipoprotein (VLDL) export, and gluconeogenesis in both sexes were investigated in the adult Wistar rats that were weaned after a normal period of lactation (control group) or early weaned either by restriction of access to the dams' teats (NPEW group) or by reduction of dams' milk production with bromocriptine (PEW group). The offspring received standard diet from weaning to euthanasia (PN180). NPEW males had higher plasma triglycerides and TyG index, liver triglycerides, and cholesterol by de novo lipogenesis, which leads to intracellular lipids accumulation. As expected, hepatic morphology was preserved in PEW males, but they showed increased liver triglycerides. The only molecular difference between PEW and NPEW males was in acetyl-CoA carboxylase-1 (ACC-1) and stearoyl-CoA desaturase-1 (SCD-1), which were lower in PEW animals. Both early weaning (EW) females had no changes in liver cholesterol and triglyceride contents, and the hepatic cytoarchitecture was preserved. The expression of microsomal triglyceride transfer protein was increased in both the female EW groups, which could constitute a protective factor. The changes in hepatic lipid metabolism in EW offspring were less marked in females. EW impacted in the hepatic cytoarchitecture only in NPEW males, which showed higher ACC-1 and SCD-1 when compared to the PEW group. As these enzymes are lipogenic, it could explain a worsened liver function in NPEW males.
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Lipogénesis/fisiología , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Acetiltransferasas/análisis , Acetiltransferasas/metabolismo , Animales , Bromocriptina/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Antagonistas de Hormonas/administración & dosificación , Humanos , Lactancia/efectos de los fármacos , Lactancia/fisiología , Lipoproteínas VLDL/metabolismo , Hígado/enzimología , Hígado/crecimiento & desarrollo , Masculino , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Oxidación-Reducción , Prolactina/antagonistas & inhibidores , Prolactina/metabolismo , Ratas , Ratas Wistar , Factores Sexuales , Estearoil-CoA Desaturasa/análisis , Estearoil-CoA Desaturasa/metabolismo , Factores de Tiempo , Triglicéridos/análisis , Triglicéridos/metabolismo , DesteteRESUMEN
N-acetylcysteine (NAC) is a pharmacological alternative with great potential for reducing the deleterious effects of surgical procedures on patients with steatohepatitis. We evaluated the effect of NAC on hepatic ischemia/reperfusion (I/R) injury in C57BL/6J mice, 8 weeks-old, weighing 25-30 g, with steatohepatitis induced by a methionine- and choline-deficient (MCD) diet. Groups: MCD group (steatohepatitis), MCD-I/R group (steatohepatitis plus 30 min of 70% liver ischemia and 24 h of reperfusion), MCD-I/R+NAC group (same as MCD-I/R group plus 150 mg/kg NAC 15 min before ischemia), and control group (normal AIN-93M diet). Liver enzymes and histopathology; nitrite and TBARS (thiobarbituric acid reactive substances) levels; pro-inflammatory cytokines; antioxidants enzymes; Nrf2 (nuclear factor erythroid-2-related factor 2) expression; and apoptosis were evaluated. In the group treated with NAC, reductions in inflammatory infiltration; AST (aspartate aminotransferase), nitrite, and TBARS levels; GPx (gutathione peroxidase) activity; cytokines synthesis; and number of apoptotic cells were observed while the GR (glutathione reductase) activity was increased. No differences were observed in Nfr2 expression or in SOD (superoxide dismutase), CAT (catalase), and GST (glutathione S-transferase) activities. Thus, it may be concluded that NAC exerts beneficial effects on mice livers with steatohepatitis submitted to I/R by reducing oxidative stress, inflammatory response, and cell death.
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Acetilcisteína/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Daño por Reperfusión/tratamiento farmacológico , Alanina Transaminasa/metabolismo , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Aspartato Aminotransferasas/metabolismo , Muerte Celular/efectos de los fármacos , Citocinas/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patologíaRESUMEN
The accumulation of red ketocarotenoids is an important component of coloration in many organisms, but the underlying mechanisms are poorly understood. In some organisms, ketocarotenoids are sequestered from the diet and can accumulate when enzymes responsible for carotenoid breakdown are disrupted. In other organisms, ketocarotenoids are formed endogenously from dietary precursors via oxidation reactions carried out by carotenoid ketolase enzymes. Here, we study the genetic basis of carotenoid coloration in an amphibian. We demonstrate that a red/yellow polymorphism in the dendrobatid poison frog Ranitomeya sirensis is due to the presence/absence of ketocarotenoids. Using whole-transcriptome sequencing of skins and livers, we found that a transcript encoding a cytochrome P450 enzyme (CYP3A80) is expressed 3.4-fold higher in livers of red frogs versus yellow. As CYP3A enzymes are known carotenoid ketolases in other organisms, our results point to CYP3A80 as a strong candidate for a carotenoid ketolase in amphibians. Furthermore, in red frogs, the transcript encoding the carotenoid cleavage enzyme BCO2 is expressed at a low level or as a splice variant lacking key catalytic amino acids. This suggests that BCO2 function may be disrupted in red frogs, providing a mechanism whereby the accumulation of ketocarotenoids and their dietary precursors may be enhanced.
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Anuros/genética , Carotenoides , Pigmentación , Animales , Sistema Enzimático del Citocromo P-450/genética , Dieta/veterinaria , Hígado/enzimología , Pigmentación/genéticaRESUMEN
AIM: To investigate the effects of linagliptin treatment on hepatic energy metabolism and ER stress in high-fat-fed C57BL/6 mice. METHODS: Forty male C57BL/6 mice, three months of age, received a control diet (C, 10% of lipids as energy, n = 20) or high-fat diet (HF, 50% of lipids as energy, n = 20) for 10 weeks. The groups were randomly subdivided into four groups to receive linagliptin, for five weeks, at a dose of 30 mg/kg/day added to the diets: C, C-L, HF, and HF-L groups. RESULTS: The HF group showed higher body mass, total and hepatic cholesterol levels and total and hepatic triacylglycerol levels than the C group, all of which were significantly diminished by linagliptin in the HF-L group. The HF group had higher hepatic steatosis than the C group, whereas linagliptin markedly reduced the hepatic steatosis (less 52%, P < 0.001). The expression of Sirt1 and Pgc1a was more significant in the HF-L group than in the HF group. Linagliptin also elicited enhanced GLP-1 concentrations and a reduction in the expression of the lipogenic genes Fas and Srebp1c. Besides, HF-L showed a reduction in the genes related to endoplasmic reticulum stress Chop, Atf4, and Gadd45 coupled with reduced apoptotic nuclei immunostaining. CONCLUSION: Linagliptin caused a marked reduction in hepatic steatosis as a secondary effect of its glucose-lowering property. NAFLD countering involved reduced lipogenesis, increased beta-oxidation, and relief in endoplasmic reticulum stress, leading to reduced apoptosis and better preservation of the hepatic structure. Therefore, linagliptin may be used, preferably in diabetic patients, to avoid the progression of hepatic steatosis.