Strategies to optimize glucose control during exercise in subjects with type 1 diabetes

Regular physical activity is highly recommended in subjects with type 1 diabetes (T1D) because of its beneficial impact on body composition, cardiovascular disease risk profile, glucose control and psychological wellbeing. However, exercise is challenging for many individuals with T1D, particularly due to the fear of hypoglycaemia, loss of glycaemic control and lack of motivation. The aim of this commentary is to briefly summarize the patterns of dysregulation of glucose homeostasis during and after exercise in subjects with T1D. In addition, we focus on carbohydrate intake and adjustment of insulin dosing as the main strategies used in clinical settings to optimize glucose control and prevent hypoglycaemia before, during and after exercise

Polypropylene Blends and Composite: Processing-Morphology-Performance Relationship of Injected Pieces

Polypropylene (PP) is a low-cost plastic commodity, which currently is in a transition zone between massive use and engineering applications due mainly to its limited mechanical properties, such as low tensile and impact resistance. That is the reason why PP is usually modified with additives and particles to improve its mechanical and thermal performance and thus meet the requirements demanded by engineering applications. Besides, PP composites are suitable materials to be processed by a simple, fast, automatic, and massive technique such as injection molding. This makes PP composites attractive for several applications. However, it is important to keep in mind that PP composites’ performance depends not only on their intrinsic properties but also on processing conditions. This chapter will summarize the relationship between processing and performance of several PP composite—micro, nano, and hybrid—injected parts with the aim of generating a bridge between technologic knowledge and scientist knowledge

Role of Prion protein-EGFR multimolecular complex during neuronal differentiation of human dental pulp-derived stem cells

Cellular prion protein (PrPC) is expressed in a wide variety of stem cells in which regulates their self-renewal as well as differentiation potential. In this study we investigated the presence of PrPCin human dental pulp-derived stem cells (hDPSCs) and its role in neuronal differentiation process. We show that hDPSCs expresses early PrPCat low concentration and its expression increases after two weeks of treatment with EGF/bFGF. Then, we analyzed the association of PrPCwith gangliosides and EGF receptor (EGF-R) during neuronal differentiation process. PrPCassociates constitutively with GM2 in control hDPSCs and with GD3 only after neuronal differentiation. Otherwise, EGF-R associates weakly in control hDPSCs and more markedly after neuronal differentiation. To analyze the functional role of PrPCin the signal pathway mediated by EGF/EGF-R, a siRNA PrP was applied to ablate PrPCand its function. The treatment with siRNA PrP significantly prevented Akt and ERK1/2 phosphorylation induced by EGF. Moreover, siRNA PrP treatment significantly prevented neuronal-specific antigens expression induced by EGF/bFGF, indicating that cellular prion protein is essential for EGF/bFGF-induced hDPSCs differentiation. These results suggest that PrPCinteract with EGF-R within lipid rafts, playing a role in the multimolecular signaling complexes involved in hDPSCs neuronal differentiation

Role of Hsp70 within the losartan effect on epithelium-mesénquima transition during the renal damage caused by hypertension

La injuria renal relacionada con la hipertensión se caracteriza por atrofia tubular, fibrosis intersticial y fibrosis periglomerular. Entre los factores implicados en la progresión de estas lesiones se destacan la Angiotensina II y el estrés oxidativo, que, a nivel de las células tubulares, inducen una amplia gama de respuestas que incluyen: desorganización del citoesqueleto, pérdida de la polaridad y acumulación de miofibroblastos a través de la transición epitelio mesénquima (EMT) lo que contribuye de forma importante a la fibrosis renal. La EMT implica cuatro eventos fundamentales: Pérdida de la adhesión epitelial; expresión de novo de marcadores mesenquimales y reorganización de los filamentos de actina; disrupción de la membrana basal tubular; y migración e invasión. La regulación de este proceso es compleja e implica la activación de varios sistemas de señalización intracelular (como MAPK y RhoA/ROCK), y la síntesis de mediadores profibróticos, como TGF-B. Una de las respuestas celulares contra los efectos adversos de la acción de ROS es la producción proteínas de choque térmico, las cuales. ayudan a mantener y restaurar la función normal de las células frente a un estrés. En este contexto, nosotros observamos en células de túbulos proximales de ratas SHR, que Losartan induce una reducción del estrés oxidativo a través de la disminución de los niveles Nox4. Este descenso de Nox4 se debe a interacción de Hsp70 con su cochaperona CHIP, que regulan negativamente los niveles de Nox4 mediante degradación proteosómica. Resultados preliminares de nuestro laboratorio mostraron que el bloqueo del receptor AT1 con Losartan incrementa los niveles Hsp70. induciendo estabilización del citoesqueleto de actina, de las uniones intercelulares y disminución de la migración de las células de túbulos proximales renales de ratas espontáneamente hipertensas. En base a esto, en este proyecto investigaremos la relevancia de Hsp70 en la EMT y los mecanismos implicados en la regulación de dicho proceso. Los resultados obtenidos a partir de este trabajo nos brindarán una visión más integrada del rol de Hsp70 y los mecanismos moleculares que operan durante la EMT patológica. En conjunto, los datos aportarán sustento para el diseño racional de nuevas estrategias combinadas con el fin prevenir la nefropatía hipertensiva. Es importante destacar que este proyecto es continuación del proyecto anterior (convocatoria 2016), en el cual pretendemos completar los objetivos propuestos.Renal injury related to hypertension is characterized by tubular atrophy, interstitial fibrosis and periglomerular fibrosis. Angiotensin II and oxidative stress are the main factors involved in the progression of these lesions, which in the tubular cells, induce a range of responses that include cytoskeleton disorganization, polarity loss and myofibroblasts accumulation through the epithelial mesenchymal transition (EMT) contributing significantly to the renal fibrosis. EMT involves four major events: epithelial adhesion Loss; mesenchymal markers de novo expression and actin filaments reorganization; tubular basement membrane disruption; and migration and invasion. The regulation of this process is complex and involves the several intracellular signaling pathways activation (such as MAPK and RhoA/ROCK), and profibrotic mediators synthesis, TGF-B like. A cellular response against the adverse effects of ROS action, is the heat shock protein production. They help maintain and restore the normal function of cells subjected to stress. In this context, we observed in proximal tubule cells of SHR rats that Losartan induces Nox4 levels decrease leading to a reduction of oxidative stress. The Nox4 decrease is due to the interaction of Hsp70 with its cochaperone CHIP, this complex negatively regulates Nox4 levels through proteosomal degradation. Preliminary results from our laboratory showed that AT1 receptor blockade with Losartan increases the heat shock protein Hsp70 levels. The increase in this chaperone induces actin cytoskeleton stabilization, formation of stress fibers preventing, intercellular junctions maintaining and migration decreasing of proximal renal tubule cells (PTC) from spontaneously hypertensive rats. We also showed that these effects are mediated by Hsp70, since when the expression of this chaperone was silenced, these effects were not observed after blockade of receptor. Based on this, in this project we will study the relevance of Hsp70/CHIP in the EMT and the mechanisms involved in the regulation of this process. The results obtained from this work will provide us with a more integrated view of the role of Hsp70 and molecular mechanisms operating during pathological EMT. Taken together, the data provide support for the rational design of new strategies combined to prevent hypertensive nephropathy. Importantly, this project is a continuation of the previous project (2016 convocatory), in which we pretend to complete the proposed objectives

Two cases of Wolfram syndrome who were initially diagnosed with type 1 diabetes

OBJECTIVE: Early diagnosis of syndromic monogenic diabetes allows for proper management and can lead to improved quality of life in the long term. This report aimed to describe 2 genetically confirmed cases of Wolfram syndrome, a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. CASE REPORT: A 16-year-old Caucasian male patient and a 25-year-old Caucasian female patient with a history of diabetes mellitus and optic nerve atrophy presented at our medical center. Both patients were initially diagnosed with type 1 diabetes but negative for islet autoantibodies. Their body mass indexes were under 25 at the diagnosis. Their history and presentation were highly suspicious for Wolfram syndrome. DISCUSSION: The genetic tests revealed a known Wolfram syndrome 1 (WFS1) pathogenic variant (homozygous) in the 16-year-old male patient and 2 known WFS1 pathogenic variants (compound heterozygous) in the 25-year-old female patient with diabetes mellitus and optic nerve atrophy, confirming the diagnosis of Wolfram syndrome. The first patient had a moderate form, and the second patient had a milder form of Wolfram syndrome. CONCLUSION: Providers should consider monogenic diabetes genetic testing, including WFS1 gene, for patients with early-onset diabetes who are negative for islet autoantibodies and lean. Two patients described in this article could have been diagnosed with Wolfram syndrome before they developed optic nerve atrophy. Genetic testing is a valuable tool for the early detection of Wolfram syndrome, which leads to proper management and improved quality of life in patients with this rare medical condition

Physiological Functions and Regulation of the Na+/H+ Exchanger [NHE1] in Renal Tubule Epithelial Cells

The sodium-hydrogen exchanger isoform-1 [NHE1] is a ubiquitously expressed plasma membrane protein that plays a central role in intracellular pH and cell volume homeostasis by catalyzing an electroneutral exchange of extracellular sodium and intracellular hydrogen. Outside of this important physiological function, the NHE1 cytosolic tail domain acts as a molecular scaffold regulating cell survival and actin cytoskeleton organization through NHE1-dependent signaling proteins. NHE1 plays main roles in response to physiological stress conditions which in addition to cell shrinkage and acidification, include hypoxia and mechanical stimuli, such as cell stretch. NHE1-mediated modulation of programmed cell death results from the exchanger-mediated changes in pHi, cell volume, and/or [Na+]I; and, it has recently become known that regulation of cellular signaling pathways are involved as well. This review focuses on NHE1 functions and regulations. We describe evidence showing how these structural actions integrate with ion translocation in regulating renal tubule epithelial cell survival.Fil: Garramuño, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Bocanegra, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Gil Lorenzo, Andrea Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Costantino, Valeria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Efecto de las variables del proceso de inyección sobre la resistencia al impacto de PP

En este trabajo se estudió la influencia de las variables del proceso de inyección, sobre la respuesta en impacto biaxial de piezas de Polipropileno homopolímero (PPH). Con este fin, se fabricaron probetas con geometría de disco variando sistemáticamente las temperaturas de molde (Tm) y de inyección (Ti). Como resultado, se encontró que en las ventanas de procesamiento empleadas, a menores Tm y a mayores Ti las probetas muestran una mayor energía de perforación, y el tipo de fractura tiende a ser dúctil. Sin embargo, se observó que el PPH estudiado se encuentra en la zona de transición dúctil-frágil, por lo tanto, existe una dispersión asociada al porcentaje de ductilidad (energía absorbida) de una pieza dada.The present work studies the influence of injection molding process conditions over the impact response of Polypropylene Homopolymer (PPH) parts. For this, disc shaped samples were injection-molded for a wide range of mold (Tm) and injection (Ti) temperatures values. Impact response was assessed through the falling weight force-displacement curves. As a result, it was found that by decreasing Tm and increasing Ti , test samples show higher impact energies and ductile failure modes. However, it was observed that the studied PPH is under the ductile-fragile transition regime and therefore there is an associated statistical dispersion in the absorbed impact energy values obtained for a given set of processing parameters.Fil: Gonzalez, Daysi. Universidad Simon Bolivar; VenezuelaFil: Costantino, María Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación En Ciencia y Tecnología de Materiales (i); Argentina. Universidad Nacional de Mar del Plata. Facultad de Ingeniería; ArgentinaFil: Pettarin, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación En Ciencia y Tecnología de Materiales (i); Argentina. Universidad Nacional de Mar del Plata. Facultad de Ingeniería; ArgentinaFil: Frontini, Patricia Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación En Ciencia y Tecnología de Materiales (i); Argentina. Universidad Nacional de Mar del Plata. Facultad de Ingeniería; ArgentinaFil: Candal, María Virginia. Universidad Simon Bolivar; Venezuel

Molecular mechanisms of hypertensive nephropathy: Renoprotective effect of losartan through hsp70

Hypertensive nephrosclerosis is the second most common cause of end-stage renal disease after diabetes. For years, hypertensive kidney disease has been focused on the afferent arterioles and glomeruli damage and the involvement of the renin angiotensin system (RAS). Nonetheless, in recent years, novel evidence has demonstrated that persistent high blood pressure injures tubular cells, leading to epithelial–mesenchymal transition (EMT) and tubulointerstitial fibrosis. Injury primarily determined at the glomerular level by hypertension causes changes in post-glomerular peritubular capillaries that in turn induce endothelial damage and hypoxia. Microvasculature dysfunction, by inducing hypoxic environment, triggers inflammation, EMT with epithelial cells dedifferentiation and fibrosis. Hypertensive kidney disease also includes podocyte effacement and loss, leading to disruption of the filtration barrier. This review highlights the molecular mechanisms and histologic aspects involved in the pathophysiology of hypertensive kidney disease incorporating knowledge about EMT and tubulointerstitial fibrosis. The role of the Hsp70 chaperone on the angiotensin II–induced EMT after angiotensin II type 1 receptor (AT1R) blockage, as a possible molecular target for therapeutic strategy against hypertensive renal damage is discussed.Fil: Costantino, Valeria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Fisiología; ArgentinaFil: Gil Lorenzo, Andrea Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Fisiología; ArgentinaFil: Bocanegra, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Vallés, Patricia G.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Fisiología; Argentin

An evaluation of morphological and functional multi-parametric MRI sequences in classifying non-muscle and muscle invasive bladder cancer

Objectives: Our goal is to determine the ability of multi-parametric magnetic resonance imaging (mpMRI) to differentiate muscle invasive bladder cancer (MIBC) from non-muscle invasive bladder cancer (NMIBC). Methods: Patients underwent mpMRI before tumour resection. Four MRI sets, i.e. T2-weighted (T2W) + perfusion-weighted imaging (PWI), T2W plus diffusion-weighted imaging (DWI), T2W + DWI + PWI, and T2W + DWI + PWI + dif-fusion tensor imaging (DTI) were interpreted qualitatively by two radiologists, blinded to histology results. PWI, DWI and DTI were also analysed quantitatively. Accuracy was determined using histopathology as the reference standard. Results: A total of 82 tumours were analysed. Ninety-six percent of T1-labeled tumours by the T2W + DWI + PWI image set were confirmed to be NMIBC at histopathology. Overall accuracy of the complete mpMRI protocol was 94% in differentiating NMIBC from MIBC. PWI, DWI and DTI quantitative parameters were shown to be significantly different in cancerous versus non-cancerous areas within the bladder wall in T2-labelled lesions. Conclusions: MpMRI with DWI and DTI appears a reliable staging tool for bladder cancer. If our data are validated, then mpMRI could precede cystoscopic resection to allow a faster recognition of MIBC and accelerated treatment pathways. Key Points: • A critical step in BCa staging is to differentiate NMIBC from MIBC. • Morphological and functional sequences are reliable techniques in differentiating NMIBC from MIBC. • Diffusion tensor imaging could be an additional tool in BCa staging

Heat shock protein 70 and CHIP promote Nox4 ubiquitination and degradation within the losartan antioxidative effect in proximal tubule cells

Background: Angiotensin II/Angiotensin II type 1 receptor (AT1R) effects are dependent on ROS production stimulated by NADPH oxidase activation. Hsp70 regulates a diverse set of signaling pathways through their interactions with proteins. CHIP is a E3 ubiquitin ligase that targets proteins for polyubiquitination and degradation. Aim: We study whether Hsp70/CHIP contribute to the negative regulation of Nox4 after AT1R blockage. Methods/Results: Primary culture of proximal tubule epithelial cells (PTCs) from SHR and WKY were stimulated with Angiotensin II (AII) or treated with Losartan (L) or Losartan plus Angiotensin II (L+AII). Losartan decreased AT1R and Nox4 while enhancing caveolin-1 and Hsp70 protein expression in SHR PTCs. Immunoprecipitation and immunofluorescence proved interaction and colocalization of increased Hsp70/CHIP with decreased Nox4 in SHR PTCs (L) vs (All). Hsp72 knockdown resulted in enhanced Nox4 protein levels, NADPH oxidase activity and ROS generation in (L+AII) revealing that Losartan was unable to abrogate AII effects on Nox4 expression and oxidative activity. Moreover, MG132 exposed PTCs (L) demostrated blocked ubiquitinated Nox4 degradation and increased colocalization of Nox4/Ubiquitin by inmunofluorescence. Conversely, Hsp72 depletion reduced Nox4/Ubiquitin colocalization causing Nox4 upregulation due to proteosomal degradation inhibition, although Losartan treatment. Conclusion: Our study demonstrates that Hsp70 and CHIP mediates the ubiquitination and proteasomal degradation of Nox4 as part ofthe antioxidative effect of Losartan in SHR.Fil: Costantino, Valeria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Gil Lorenzo, Andrea Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Lopez Appiolaza, Carlos Martìn. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Cacciamani, Valeria. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Cátedra de Fisiología Patológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Benardon, María Eugenia. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Cátedra de Fisiología Patológica; ArgentinaFil: Bocanegra, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Garramuño, Patricia. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Cátedra de Fisiología Patológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin