RESUMEN
BACKGROUND/AIMS: Whey proteins (WP), obtained from milk after casein precipitation, represent a heterogeneous group of proteins. WP are reported to inhibit food intake in diet-induced experimental obesity; WP have been proposed as adjuvant therapy in oxidative stress-correlated pathologies. This work evaluates the effects of WP in comparison with casein, as a source of alimentary proteins, on food intake, weight growth and some indexes of oxidative equilibrium in Zucker Rats, genetically prone to obesity. METHODS: We monitored food intake and weight of Zucker Rats during the experiment, and some markers of oxidative equilibrium. RESULTS: WP induced significant decrease of food intake in comparison to casein (WP 80.41 ± 1.069 ml/day; CAS: 88.95 ± 1.084 ml/day; p < 0.0005). Body weight growth was slightly reduced, and the difference was just significant (WP 128.2 ± 6.56 g/day; CAS 145.2 ± 3.29 g/day; p = 0.049), while plasma HNE level was significantly lower in WP than in CAS (WP 41.2 ± 6.3 vs CAS 69.61 ± 4.69 pmol/ml, p = 0.007). Mild amelioration of oxidative equilibrium was indicated by a slight increase of total glutathione both in the liver and in the blood and a significant decrease of plasma 4-hydroxynonenal in the group receiving WP. CONCLUSIONS: The effect of WP on food intake and weight growth in Zucker Rats is particularly noteworthy since the nature of their predisposition to obesity is genetic; the possible parallel amelioration of the oxidative balance may constitute a further advantage of WP since oxidative stress is believed to be interwoven to obesity, metabolic syndrome and their complications.
Asunto(s)
Obesidad , Estrés Oxidativo , Animales , Ingestión de Alimentos , Humanos , Obesidad/tratamiento farmacológico , Ratas , Ratas Zucker , Proteína de Suero de Leche/farmacologíaRESUMEN
Neuroblastoma (NB) is the second most common solid pediatric tumor and is characterized by clinical and biological heterogeneity, and stage-IV of the disease represents 50% of all cases. Considering the limited success of present chemotherapy treatment, it has become necessary to find new and effective therapies. In this context, our approach consists of identifying and targeting key molecular pathways associated with NB chemoresistance. This study has been carried out on three stage-IV NB cell lines with different status of MYCN amplification. Cells were exposed to a standard chemotherapy agent, namely etoposide, either alone or in combination with particular drugs, which target intracellular signaling pathways. Etoposide alone induced a concentration-dependent reduction of cell viability and, at very high doses, totally counteracted cell tumorigenicity and neurosphere formation. In addition, etoposide activated p38 mitogen-activated protein kinase (MAPK), AKT and c-Jun N-terminal kinase. Pre-treatment with SB203580, a p38MAPK inhibitor, dramatically sensibilized NB cells to etoposide, strongly reducing the dosage needed to inhibit tumorigenicity and neurosphere formation. Importantly, SB203580-etoposide cotreatment also reduced cell migration and invasion by affecting cyclooxygenase-2, intercellular adhesion molecule-1, C-X-C chemokine receptor-4 and matrix metalloprotease-9. Collectively, our results suggest that p38MAPK inhibition, in combination with standard chemotherapy, could represent an effective strategy to counteract NB resistance in stage-IV patients.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Etopósido/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Imidazoles/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Piridinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Apoptosis/genética , Diferenciación Celular , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/economía , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estadificación de Neoplasias , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Objetivo: Identificar la prevalencia de insatisfacción corporal y búsqueda de la delgadez en una población de estudiantes de 13 a 16 anos; exponer la correlación existente con la malnutrición por exceso y describir las diferencias por sexo. Sujetos y método: A 291 alumnos de 3 colegios mixtos, se les aplicó cuestionario EDI 2, se determinó el IMC (peso/talla²) a cada uno de ellos. Resultados: El 27,5 % de la población total (51% mujeres, 49% varones) tiene malnutrición por exceso. El 2,1% de los varones y el 13 % de las mujeres presentaron puntaje de riesgo en el ítem búsqueda de la delgadez (BD); el 11 % de los hombres y 21,9 % de las mujeres presentaron puntaje de riesgo en el item insatisfacción corporal (IC). Hubo diferencias de género estadísticamente significativas en ambos ítems BD (P < 0,001) y para IC (P < 0,011). La IC correlacionó con el IMC (Fisher's 0,006). No se observó correlación entre BD y estado nutricional (Fisher's 0,082). La IC y BD se correlacionaron con el género femenino (Fisher's 0.009. 0,000). Conclusión: Se detectan índices significativos de los factores evaluados (prevalencia y correlación entre variables), en una población no clínica. Las mujeres presentan un mayor riesgo.
Objective: To identify the prevalence ofbody dissatisfaction and search for thinness (ST) of a student population 13 to 16 years old, its correlation with overweight, and gender differences. Subjects and method: To 291 students of 3 coed schools (51% female) the EDI 2 questionnaire was applied to assess body dissatisfaction and ST and their IMC (weight/height2) were obtained. Results: The prevalence of malnutrition by excess reached 27.5 % in the total population. 2.1% of men and 13% of the women presented risk scores related to search for thinness; 11 % of men and 2.,9 % of women presented risk scores related to body dissatisfaction. There were statistically significant gender differences in both items (0.001). The body dissatisfaction was correlated with BMI (Fisher's 0,006). There was no correlation between ST and nutritional status (Fisher's 0.082). Body dissatisfaction and search for thinness was correlated with gender (Fisher's 0,009 - 0,000). Conclusion: Significant indices (prevalence and correlation) of the evaluated factors were found. Women presented increased risk compared to man.
Asunto(s)
Estudiantes , Delgadez , Imagen Corporal , Trastornos de Alimentación y de la Ingestión de Alimentos , Adolescente , Chile , Prevalencia , Factores de RiesgoRESUMEN
Molecular mechanisms relating interferon-alpha (IFN-alpha) to brain damage have recently been identified in a microarray analysis of cerebrospinal fluid lymphocytes from patients with Aicardi-Goutières Syndrome (AGS). These findings demonstrate that the inhibition of angiogenesis and the activation of neurotoxic lymphocytes are the major pathogenic mechanisms involved in the brain damage consequent to elevated interferon-alpha levels. Our previous study demonstrated that cathepsin D, a lysosomal aspartyl endopeptidase, is the primary mediator of the neurotoxicity exerted by AGS lymphocytes. Cathepsin D is a potent pro-apoptotic, neurotoxic, and demyelinating protease if it is not properly inhibited by the activities of leukocystatins. In central nervous system white matter, demyelination results from cathepsin over-expression when not balanced by the expression of its inhibitors. In the present study, we used RNA interference to inhibit cathepsin D expression in AGS lymphocytes with the aim of decreasing the neurotoxicity of these cells. Peripheral blood lymphocytes collected from an AGS patient were immortalized and co-cultured with astrocytes in the presence of interferon alpha with or without cathepsin D RNA interference probes. Cathepsin D expression was measured by qPCR, and neurotoxicity was evaluated by microscopy. RNA interference inhibited cathepsin D over-production by 2.6-fold (P<0.01) in AGS lymphocytes cultured in the presence of interferon alpha. AGS lymphocytes treated using RNA interference exhibited a decreased ability to induce neurotoxicity in astrocytes. Such neurotoxicity results in the inhibition of astrocyte growth and the inhibition of the ability of astrocytes to construct web-like aggregates. These results suggest a new strategy for repairing AGS lymphocytes in vitro by inhibiting their ability to induce astrocyte damage and leukodystrophy.
Asunto(s)
Astrocitos/patología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/patología , Catepsina D/antagonistas & inhibidores , Linfocitos/inmunología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Malformaciones del Sistema Nervioso/inmunología , Malformaciones del Sistema Nervioso/patología , Astrocitos/inmunología , Catepsina D/genética , Línea Celular Tumoral , Humanos , Interferón-alfa/inmunología , Proteínas del Tejido Nervioso/genética , Interferencia de ARN , ARN Interferente Pequeño/genéticaRESUMEN
T lymphocytes play a major role in counteracting cancer occurrence and development. Immune therapies against cancer are focused on eliciting a cytotoxic T cell response. This anticancer activity is related to a variety of mechanisms including the activation of cytokines and proapoptotic mediators. Interferon α is an established inhibitor of cancer cell growth. A clinical situation involving the coexistence of high interferon α levels and lymphocyte activation is the Aicardi-Goutières syndrome, a progressive encephalopathy arising usually during the first year of life characterized by intracranial basal ganglia calcifications, leukodystrophy and microcephaly. Aicardi-Goutières syndrome 1 mutation silences the TREX1 gene, a major endogenous nuclease. The in vitro study presented herein evaluates the efficacy of the TREX1 mutation in potentiating the anticancer properties of T cells. A TREX1-mutated lymphocyte cell line was derived from an Aicardi-Goutières syndrome patient and co-cultured with neuroblastoma cells and vascular endothelial cells in the presence of interferon α. TREX1-mutated lymphocytes exerted marked inhibitory action on neuroblastoma cell growth. Cathepsin D was recognized by qPCR as the main mediator produced by TREX1-mutated lymphocytes involved in the inhibition of neuroblastoma cell growth. These effects were enhanced in the presence of interferon α. Similar inhibitory effects in cell growth were exerted by TREX1-mutated lymphocytes towards vascular endothelial cell angiogenesis as evaluated on Matrigel. The results obtained provide evidence that mutations of the TREX1 gene increase the capability of T-lymphocytes to inhibit growth of neoplastic neuronal cells and related angiogenesis.
Asunto(s)
Exodesoxirribonucleasas/genética , Linfocitos/metabolismo , Mutación , Neuroblastoma/genética , Fosfoproteínas/genética , Catepsina D/genética , Línea Celular , Proliferación Celular , Expresión Génica/efectos de los fármacos , Humanos , Interferón gamma/inmunología , Interferón gamma/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Neovascularización Patológica/genética , Neovascularización Patológica/inmunología , Neuroblastoma/inmunologíaRESUMEN
4-Hydroxynonenal, a significant aldehyde end product of membrane lipid peroxidation with numerous biochemical activities, has consistently been detected in various human diseases. Concentrations actually detectable in vivo (0.1-5 microM) have been shown to up-regulate different genes and modulate various enzyme activities. In connection with the latter aspect, we show here that, in isolated rat hepatocytes, 1 microM 4-hydroxynonenal selectively activates protein kinase C-delta, involved in apoptosis of many cell types; it also induces very early activation of Jun N-terminal kinase, in parallel increasing activator protein-1 DNA-binding activity in a time-dependent manner and triggering apoptosis after only 120 min treatment. These phenomena are likely protein kinase C-delta-dependent, being significantly reduced or annulled by cell co-treatment with rottlerin, a selective inhibitor of protein kinase C-delta. We suggest that 4-hydroxynonenal may induce apoptosis through activation of protein kinase C-delta and of Jun N-terminal kinase, and consequent up-regulation of activator protein-1 DNA binding.
Asunto(s)
Aldehídos/farmacología , Apoptosis/efectos de los fármacos , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Proteína Quinasa C-delta/metabolismo , Aldehídos/metabolismo , Animales , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Activación Enzimática/efectos de los fármacos , Glutatión/metabolismo , Hepatocitos/metabolismo , Técnicas In Vitro , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Factor de Transcripción AP-1/metabolismoRESUMEN
Sexual dimorphism exists in the response of rats to lead nitrate, liver hyperplasia occuring earlier and being more pronounced in males. Excess dietary choline in females shifted the growth pattern towards that of males. To determine whether phosphatidylcholine-induced growth modulations could be related to a derangement of cholesterol metabolism, liver accumulation of cholesterol esters and plasma lipoprotein patterns were investigated. In males, lead-induced liver hyperplasia was associated with increased total cholesterol hepatic content, accumulated cholesterol esters and reduced concentration of plasma High Density Lipoprotein (HDL) cholesterol. Females were less responsive to the liver mitogenic signal of lead nitrate; there was no elevation of cholesterol content nor any marked accumulation of cholesterol esters. This is consistent with the lack of change in the plasma levels of HDL cholesterol. Continuous choline feeding displaced the liver cholesterol ester pattern and plasma HDL cholesterol levels in females, and in parallel that of DNA synthesis, towards those of males. Choline was not observed to have any effect in males. These results suggest that the derangement of phosphatidylcholine metabolism induces growth-related changes in cholesterol turnover; they are consistent with the proposal that the intracellular content of cholesterol esters may have a role in regulating liver growth rates.
Asunto(s)
Ésteres del Colesterol/metabolismo , Colina/farmacología , Lipoproteínas HDL/sangre , Hígado/patología , Animales , Femenino , Hiperplasia/inducido químicamente , Hiperplasia/metabolismo , Plomo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Nitratos , Ratas , Ratas Wistar , Caracteres SexualesRESUMEN
In previous studies, we reported that fasting/refeeding has a role in sustaining the initiation of liver cancer by a subnecrogenic (noninitiating) dose of diethylnitrosamine (DENA). This research investigated whether the metabolic alterations imposed by fasting/refeeding provide an imbalance between the generation of carcinogenic molecules and the scavenger defense mechanisms in rat liver. Metabolism of DENA, levels of reduced glutathione (GSH) and GSH transferase (GST) activity, as well as basal and stimulated malondialdehyde (MDA) production, were examined. Rats fasted for 4 days showed a decrease in the liver levels of GSH, GST activity, monounsaturated fatty acids and % of labeled nuclei. After 1 day of refeeding, at which point DENA was administered, the levels of GSH recovered, GST activity remained below control values, basal and stimulated MDA production and content of total polyunsaturated fatty acids in liver phospholipids decreased. One day after DENA treatment, MDA production further decreased, although the % of labeled nuclei increased. No significant changes in the content of arachidonic acid, the main target of peroxidation, were observed at any time. The results indicated that the induction of the hepatocellular carcinoma was associated with a depression of GST activity and lipid peroxidation when rats were given 20 mg/kg of DENA after 1 day of refeeding after 4-day fasting.
Asunto(s)
Carcinógenos/toxicidad , Dietilnitrosamina/toxicidad , Glutatión Transferasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Neoplasias Hepáticas Experimentales/etiología , Neoplasias Hepáticas Experimentales/metabolismo , Animales , Antioxidantes/metabolismo , Carcinógenos/administración & dosificación , Cocarcinogénesis , Dietilnitrosamina/administración & dosificación , Ingestión de Alimentos , Ayuno , Ácidos Grasos/análisis , Depuradores de Radicales Libres/metabolismo , Radicales Libres/metabolismo , Glutatión/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Fosfolípidos/química , Fosfolípidos/metabolismo , Ratas , Ratas Endogámicas F344RESUMEN
Expone que el tratamiento quirúrgico del cáncer de mama sigue su evolución en un intento de definir la pauta ideal entre al eficacia terapéutica y las complicaciones. El cáncer mencionado engloba un grupo biológico heterogéneo de enfermedades y ninguna sola hipótesis explica su conducta. Las opciones quirúrgicas propuestas a la paciente individual debe ser producto de la experiencia de estudios clínicos retrospectivos y otros prospectivos con asignación aleatoria, en un intento de optimizar el plan terapéutico. Muchas mujeres sin metástasis a distancia son idóneas para la mastestomía, con la cual se puede lograr un control local excelente y mejoría notable de la supervivencia en caso de que la enfermedad esté en etapas incipientes. Sin embargo, la conservación del seno sigue siendo aun alternativa apropiada en un subgrupo perfectamente definido de pacientes...