p66shc-mediated toxicity of high-dose alfa-tocopherol in renal proximal tubule cells

α-Tocopherol (TOC) is a widely used supplement known for its role as an antioxidant. Previously, we have shown that TOC elicits adaptive responses by upregulating the ERK/CREB/HO-1 pathway, which depends on its concentration in cultured renal proximal tubule cells (RPTCs). This suggests that high-dose TOC (hTOC) may elicit adverse effects via inflicting oxidative stress. Since the pro-oxidant p66shc is a major mediator of oxidant injury in various models of renal toxicants, we tested the hypothesis that hTOC elicits renal toxicity through activation of p66shc and consequent oxidative stress. RPTCs (NRK52E) were treated with high-dose TOC (hTOC; 400 nM) in cells where expression or mitochondrial cytochrome c-binding of p66shc was manipulated by genetic means. Intracellular production of reactive oxygen species (ROS), mitochondrial depolarization, and cell viability was also determined. Additionally, activation of the pro-survival ERK/CREB/HO-1 signaling and the p66shc promoter was determined via reporter luciferase assays. hTOC decreased cell viability via increasing ROS-dependent mitochondrial depolarization and suppressing the pro-survival ERK/CREB/HO-1 pathway via transcriptional activation of p66shc. Conversely, either knockdown of p66shc, mutation of its mitochondrial cytochrome c-binding site, or overexpression of ERK or HO-1 ameliorated adverse effects of hTOC and restored the pro-survival signaling. The pro-oxidant p66shc plays dual role in toxicity of high-dose TOC: it provokes oxidative stress and suppresses adaptive responses (AU)

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Magnesium sulphate protect against propofol-induced neurotoxicity in developing rats’ cerebral cortex

Propofol-induced neurotoxicity in developing brain is an evolving problem. Magnesium is proved to be neuro-protective when administered antenatally in case of pre-eclampsia and eclampsia. The aim of this work is to investigate the protective role of magnesium sulphate (MgSO4) against propofol-induced neurotoxicity in developing rats’ cerebral cortex (CC). Forty albino rats of the Sprague-Dawley strain aged 5 to 7 days were divided into four groups; Control group (Group A); MgSO4 group (Group B) receiving MgSO4 at a dose of 270 mgkg; Propofol group (Group C) receiving propofol at a dose of 20 mgkg; and Propofol+ MgSO4 group (Group D) receiving both drugs simultaneously. All drugs were given by intra-peritoneal (IP) injection. 48 hours following exposure, blood samples were collected from rats for cytochrome-c plasma assay. Also, Specimens from rats’ CC were processed for light microscopic examination. An immune-histo-chemical study was conducted using Glial Fibrillary Acidic Protein (GFAP) and Bcl-2-associated X protein (BAX).Propofol administration led to disruption of the cortical laminar architecture, with a significant decrease in the number of pyramidal cells. Also, GFAP and BAX immune-stained sections revealed a significant increase in the area percentage of their immune-reaction as compared to the control group, together with a significant increase in the serum level of cytochrome-c. Administration of MgSO4 with propofol could improve the histological picture of the cortex, including its laminar appearance and neuronal density. Also MgSO4 could decrease GFAP and BAX immune-reaction, with no change that could be noticed in the serum level of cytochrome-c. MgSO4 could be used as neuro-protective agent against propofol-induced cortical injury in infant rats

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Sexual metabolic differences in the rat limbic brain / Diferencias metabólicas sexuales en el cerebro límbico de rata

Background: There is actually limited evidence about the influence of estrogens on neuronal energy metabolism or functional cerebral asymmetry. In order to evaluate this relationship, eight male and sixteen female adult Wistar rats, divided into estrus and diestrus phase, were used to measure basal neuronal metabolic activity in some of the structures involved in the Papez circuit, using cytochrome c oxidase (C.O.) histochemistry. Method: We used C.O. histochemistry because cytochrome oxidase activity can be considered as a reliable endogenous marker of neuronal activity. Results: We found higher C.O. activity levels in diestrus as compared to estrus and male groups in the prefrontal cortex and thalamus. Conversely, neuronal oxidative metabolism was significantly higher in estrus than in diestrus and male groups in the dorsal and ventral hippocampus (CA1 and CA3) and in the mammillary bodies. However, no hemispheric functional lateralization was found in estrus, diestrus or male groups by C.O. activity. Conclusions: These results suggest a modulatory effect of estrogens on neuronal oxidative metabolism (AU)

Antecedentes: existe poca evidencia acerca de la influencia de los estrógenos sobre el metabolismo energético cerebral o la asimetría cerebral funcional. Para evaluarlo, se utilizaron ocho machos y dieciséis hembras de rata adultas de la cepa Wistar, divididas en fase estro y diestro, con el fin de medir la actividad metabólica neuronal basal en algunas de las estructuras cerebrales del circuito de Papez. Método: utilizamos la histoquímica de la citocromo c oxidasa (C.O.) porque su actividad puede ser considerada como un relevante marcador endógeno de la actividad neuronal. Resultados: encontramos mayores niveles de C.O. en el diestro en comparación con el estro y los machos en la corteza prefrontal y el tálamo. El metabolismo oxidativo neuronal fue significativamente mayor en el estro en comparación con el grupo diestro y los machos en el hipocampo dorsal y ventral (CA1 y CA3), así como en los cuerpos mamilares. No se encontró ninguna lateralización hemisférica funcional en los grupos experimentales. Conclusiones: estos resultados sugieren un efecto modulador de los estrógenos sobre el metabolismo oxidativo neuronal (AU)

Mecanismos moleculares de muerte celular programada en la neurodegeneración dopaminérgica de la enfermedad de Parkinson / No disponible

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Avances en cardiopatía hipertensiva. Mecanismos de remodelado implicados en la transición de la hipertrofia a la insuficiencia cardiaca / Progress in hypertensive heart disease. Remodeling mechanisms involved in the transition from hypertrophy to heart failure

Desde el punto de vista molecular, la cardiopatía hipertensiva se caracteriza por un conjunto de cambios en la expresión de genes y proteínas del miocardio que provocan una serie de modificaciones en su composición, dando lugar a su remodelado estructural y geométrico, así como a alteraciones de su función, perfusión y actividad eléctrica. El remodelado es la consecuencia tanto de la sobrecarga mecánica hipertensiva como de la activación local de diversos factores humorales que afectan a los cardiomiocitos (facilitando su muerte por apoptosis) y a la matriz extracelular miocárdica (dando lugar a cambios en la cuantía y el depósito de las fibras de colágeno). La relevancia clínica de estas lesiones radica en que contribuyen a la transición de la hipertrofia ventricular izquierda a la insuficiencia cardiaca en los pacientes con cardiopatía hipertensiva. Hallazgos recientes señalan nuevos mecanismos de apoptosis y fibrosis (p. ej., alteraciones del receptor alfa activado por proliferadores de peroxisomas) en el ventrículo hipertenso que abren vías nuevas para la prevención de la insuficiencia cardiaca en los pacientes con cardiopatía hipertensiva (AU)

At the molecular level, hypertensive heart disease is characterized by a combination of changes in myocardial gene and protein expression that induce a series of alterations in the structure of the myocardium, thereby giving rise to structural and geometric remodeling as well as to changes in myocardial function, perfusion and electrical activity. Remodeling results from the effects both hypertension-induced mechanical overload and local activation of various humoral factors have on cardiomyocytes (inducing cell death by apoptosis) and on the extracellular matrix (resulting in changes in the density and deposition of collagen fibers). The clinical significance of these lesions stems from their contribution to the transition from left ventricular hypertrophy to heart failure in patients with hypertensive heart disease. Recent findings indicate that ventricular hypertension may be associated with novel apoptotic and fibrotic mechanisms (e.g., alterations in peroxisome proliferator-activated receptor-) that may lead to new approaches to the prevention of heart failure in patients with hypertensive heart disease (AU)

Mecanismos de muerte celular y relevancia en hepatología / No disponible

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Contribución de la ciclooxigenasa 2 a las afecciones del hígado: inhibición de la apoptosis en las células hepáticas / No disponible

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Expresión diferencial de proteínas en el corazón de ratas espontáneamente hipertensas con hipertrofia cardíaca / Differential protein expression in hearts of spontaneously hypertensive rats with cardiac hypertrophy

Introducción. La hipertensión arterial afecta a alrededor del 20% de la población del mundo occidental. A pesar de la disponibilidad de excelentes fármacos antihipertensivos, la repercusión orgánica sobre los órganos diana (corazón, cerebro y riñón) sigue siendo elevada. La hipertrofia ventricular izquierda es un hallazgo común en pacientes hipertensos. Aunque se han asociado diversos patrones transcripcionales celulares y genéticos con la hipertrofia cardíaca, sus mecanismos siguen siendo desconocidos. Los objetivos de este trabajo son: a) estudiar el perfil proteico de ratas hipertensas con hipertrofia cardíaca en comparación con animales normotensos, y b) identificar las proteínas de interés. Materiales y métodos. Los estudios se realizaron en ratas macho espontáneamente hipertensas (SHR) y se utilizaron como controles ratas normotensas Wistar Kyoto (WKY). Después de 48 semanas de vida se sacrificó a los animales y se les extrajo el corazón. Para detectar cambios proteicos en la hipertensión grave, analizamos el patrón de expresión de las proteínas cardíacas por electroforesis bidimensional. Resultados. De los más de 1.000 spots resueltos en el rango de pH 4 a 7 del ventrículo izquierdo, nos centramos en 432 bien definidos. En la comparación con los corazones normotensos, de los 432 spots analizados 360 permanecieron invariables y 72 se encontraron alterados en el corazón de las ratas SHR. La identificación de los spots alterados se está realizando mediante espectrometría de masas (MALDI-TOF). Por el momento se han identificado algunos spots tales como la tropomiosina 1-α y el polipéptido Va de la citocromo C oxidasa. Conclusiones. A través de un enfoque proteómico hemos analizado las diferencias entre los proteomas del corazón hipertrófico de animales hipertensos y de controles sanos. En el corazón hipertrófico se observó un cierto número de proteínas sobre o infraexpresadas. Estos datos ilustran un uso inexplorado de la proteómica como herramienta para el descubrimiento de nuevas dianas terapéuticas (AU)

Introduction. Arterial hypertension affects approximately 20% of the Western world. Despite the availability of excellent antihypertensive drugs, damage to target organs (heart, brain and kidney) remains significant. Left ventricular hypertrophy is a common finding in hypertensive patients. Although different cellular and gene transcription patterns have been associated with cardiac hypertrophy, the molecular mechanisms of this process remain mostly unknown. The aims of the present work were: a) to analyze the differential cardiac protein expression in spontaneously hypertensive rats (SHR) with cardiac hypertrophy compared with normotensive rats, and b) identify proteins of interest. Materials and methods. Studies were conducted in male spontaneously hypertensive rats (SHR), with normotensive Wistar-Kyoto rats (WKY) used as controls. At 48 weeks of age, rats were euthanized and hearts removed on block. Analysis of protein expression patterns by two-dimensional polyacrylamide gel electrophoresis (2-DE) was performed to detect changes in heart proteins associated to severe hypertension. Results. From the more than 1000 spots resolved in the 4-7 pH range by 2-DE of myocardial tissue from WKY and SHR rats, we focused on 432 well-defined spots. In comparison with those obtained in normotensive rat hearts, 360 spots remained invariable, 43 increased and 29 decreased or were absent. The identification by mass spectrometry (MALDI-TOF) of altered spots is under study. To date, few spots such as alphatropomyosin and the Va polypeptide of cytochrome c-oxidase have been identified. Conclusions. Via a proteomic approach, we analyzed the difference between proteomes of hypertrophic hearts of hypertensive and normotensive rats and observed a number of over or under expressed proteins in damaged hearts. These data illustrate a hitherto unexplored use of proteomics to discover new therapeutic targets for antihypertensive drugs (AU)

Bases moleculares de la apoptosis / Molecular Bases of the apoptosis

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