Synapsin Is a Novel Rab3 Effector Protein on Small Synaptic Vesicles

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Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells

Hypoxia is a key driver of tumor adaptation promoting tumor progression and resistance to therapy. Hypoxia related pathways might represent attractive targets for the treatment of Glioblastoma Multiforme (GBM), that up to date is characterized by a poor prognosis. Primary aim of this study was to investigate the role of hypoxia and hypoxia-related modifications in the effect of temozolomide (TMZ) given alone or in association with the antidiabetic agent Metformin (MET) or the PI3K/mTOR blocker, BEZ235. The study was conducted in the TMZ responsive U251 and resistant T98 GBM cells. Our results showed that during hypoxia, TMZ plus MET reduced viability of U251 cells affecting also CD133 and CD90 expressing cells. This effect was associated with a reduction of HIF-1α activity, VEGF release and AKT activation. In T98 TMZ-resistant cells, TMZ plus MET exerted similar effects on HIF-1α. However, in this cell line, TMZ plus MET failed to reduce CD133 positive cells and AKT phosphorylation. Nevertheless, the administration of the dual PI3K/mTOR inhibitor BEZ235 potentiated the effect of TMZ plus MET on cell viability, inducing a pro-apoptotic phenotype during hypoxic condition also in T98 cells, suggesting the block of the PI3K/AKT/mTOR pathway as a complementary target to further overcome GBM resistance during hypoxia. In conclusion, we proposed TMZ plus MET as suitable treatment to revert TMZ-resistance also during hypoxia, an effect potentiated by the inhibition of PI3K/mTOR axis

Nuevos enfoques para calcular la evaporación y la transpiración

En este trabajo se presenta un modelo matemático desarrollado por F. I. Morton, en Canadá, para calcular la evaporación en grandes áreas, obviando las conocidas dificultades que se encuentran en este tipo de cálculos. El modelo se basa en algunas suposiciones simplificativas con respecto a la disponibilidad de agua en el suelo, así cano soslaya para ciertas condiciones del entorno, las complejas interrelaciones entre el suelo, la vegetación y la atmósfera. La técnica utilizada permite la aplicación de un modelo simple para calcular la evapotranspiración real cano función de la temperatura del aire y la humedad, tal coro se miden en un abrigo meteorológico. Se presenta, también, un ensayo de aplicación de este modelo a diferentes regiones climáticas de la Argentina.This paper present a mathematical model developed by F. I. Marton, in Canada, to calculate the evaporation on large areas obviating the known difficulties found in this type of conputations. The model is based on sane simplifying assumptions regarding the soil water availability as well as on the bypassing, under certain environmental conditions, of the complex interrel at ions between the ground, the vegetation cover and the atmosphere. The technique used enables the application of a simple model to compute the real evapotranspiration as a function of the air temperature and humidity as measured in a normal meteorological shelter. An essay of the application of this model to various different climatic regions of Argentina is also presented.Asociación Argentina de Geofísicos y Geodesta

Distribución de las precipitaciones en Rafaela y Esperanza, Santa Fe

p.85-89Para determinar el modelo estadístico que provea el mejor ajuste para la distribución de precipitaciones en las localidades de Rafaela y Esperanza (Santa Fe), se utilizaron los registros de precipitaciones mensuales de Esperanza (1929 - 1975) y Rafaela (1937 - 1998). Las distribuciones empíricas se compararon con las teóricas Normal y Logaritmica (LN), Normal Raíz Cúbica (NR) y Gamma Incompleta (GI). Según la prueba de Lilliefors, NR y GI presentaron el mejor ajuste para todos los meses (p menor 0,01). LN presentó buen ajuste (p menor 0,05) para todas las estaciones del año, excepto el invierno

Caracterización del régimen agroclimático de heladas para la provincia de Santa Fe durante el período 1979 - 2004

p.53-62El conocimiento del régimen de las temperaturas consideradas limitantes para los cultivos, es indispensable para la toma de decisiones respecto al calendario agrícola de una región. Con datos de temperatura mínima diaria de seis localidades de la provincia de Santa Fe, donde existen estaciones del SMN (período 1979-2004) se caracterizó el régimen agroclimático de heladas meteorológicas y agronómicas. Se determinaron las fechas medias de primeras y últimas heladas, las respectivas fechas extremas, el período libre de heladas, y los índices de peligrosidad. Por medio de estadísticos simples se analizó las frecuencias de días con heladas mensuales y anuales. Las fechas medias de primeras y últimas heladas meteorológicas están comprendidas entre 27 de junio y el 2 de septiembre. El período medio con heladas meteorológicas en ningún caso supera los 90 días. Las heladas agronómicas comienzan en mayo y terminan en septiembre. El período medio con heladas agronómicas aumenta hasta 150 días en el SE de la provincia

Specificity of the binding of synapsin I to Src homology 3 domains.

Synapsins are synaptic vesicle-associated phosphoproteins involved in synapse formation and regulation of neurotransmitter release. Recently, synapsin I has been found to bind the Src homology 3 (SH3) domains of Grb2 and c-Src. In this work we have analyzed the interactions between synapsins and an array of SH3 domains belonging to proteins involved in signal transduction, cytoskeleton assembly, or endocytosis. The binding of synapsin I was specific for a subset of SH3 domains. The highest binding was observed with SH3 domains of c-Src, phospholipase C-gamma, p85 subunit of phosphatidylinositol 3-kinase, full-length and NH(2)-terminal Grb2, whereas binding was moderate with the SH3 domains of amphiphysins I/II, Crk, alpha-spectrin, and NADPH oxidase factor p47(phox) and negligible with the SH3 domains of p21(ras) GTPase-activating protein and COOH-terminal Grb2. Distinct sites in the proline-rich COOH-terminal region of synapsin I were found to be involved in binding to the various SH3 domains. Synapsin II also interacted with SH3 domains with a partly distinct binding pattern. Phosphorylation of synapsin I in the COOH-terminal region by Ca(2+)/calmodulin-dependent protein kinase II or mitogen-activated protein kinase modulated the binding to the SH3 domains of amphiphysins I/II, Crk, and alpha-spectrin without affecting the high affinity interactions. The SH3-mediated interaction of synapsin I with amphiphysins affected the ability of synapsin I to interact with actin and synaptic vesicles, and pools of synapsin I and amphiphysin I were shown to associate in isolated nerve terminals. The ability to bind multiple SH3 domains further implicates the synapsins in signal transduction and protein-protein interactions at the nerve terminal level

Regional Differences in Cerebral Glucose Metabolism After Cardiac Arrest and Resuscitation in Rats Using [(18)F]FDG Positron Emission Tomography and Autoradiography.

BACKGROUND Cardiac arrest is an important cause of morbidity and mortality. Brain injury severity and prognosis of cardiac arrest patients are related to the cerebral areas affected. To this aim, we evaluated the variability and the distribution of brain glucose metabolism after cardiac arrest and resuscitation in an adult rat model. METHODS Ten rats underwent 8-min cardiac arrest, induced with a mixture of potassium and esmolol, and resuscitation, performed with chest compressions and epinephrine. Eight sham animals received anesthesia and experimental procedures identical to the ischemic group except cardiac arrest induction. Brain metabolism was assessed using [(18)F]FDG autoradiography and small animal-dedicated positron emission tomography. RESULTS The absolute glucose metabolism measured with [(18)F]FDG autoradiography 2 h after cardiac arrest and resuscitation was lower in the frontal, parietal, occipital, and temporal cortices of cardiac arrest animals, showing, respectively, a 36% (p = 0.006), 32% (p = 0.016), 36% (p = 0.009), and 32% (p = 0.013) decrease compared to sham group. Striatum, hippocampus, thalamus, brainstem, and cerebellum showed no significant changes. Relative regional metabolism indicated a redistribution of metabolism from cortical area to brainstem and cerebellum. CONCLUSIONS Our data suggest that cerebral regions have different susceptibility to moderate global ischemia in terms of glucose metabolism. The neocortex showed a higher sensibility to hypoxia-ischemia than other regions. Other subcortical regions, in particular brainstem and cerebellum, showed no significant change compared to non-ischemic rats

Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics

Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time-and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy

Metformin and temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor survival. Cytoreduction in association with radiotherapy and temozolomide (TMZ) is the standard therapy, but response is heterogeneous and life expectancy is limited. The combined use of chemotherapeutic agents with drugs targeting cell metabolism is becoming an interesting therapeutic option for cancer treatment. Here, we found that metformin (MET) enhances TMZ effect on TMZ-sensitive cell line (U251) and overcomes TMZ-resistance in T98G GBM cell line. In particular, combined-treatment modulated apoptosis by increasing Bax/Bcl-2 ratio, and reduced Reactive Oxygen Species (ROS) production. We also observed that MET associated with TMZ was able to reduce the expression of glioma stem cells (GSC) marker CD90 particularly in T98G cells but not that of CD133. In vivo experiments showed that combined treatment with TMZ and MET significantly slowed down growth of TMZ-resistant tumors but did not affect overall survival of TMZ-sensitive tumor bearing mice. In conclusion, our results showed that metformin is able to enhance TMZ effect in TMZ-resistant cell line suggesting its potential use in TMZ refractory GBM patients. However, the lack of effect on a GBM malignancy marker like CD133 requires further evaluation since it might influence response duration