Tubulointerstitial injury and proximal tubule albumin transport in early diabetic nephropathy induced by type 1 diabetes mellitus

A decrease in the tubular expression of albumin endocytic transporters megalin and cubilin has been associated with diabetic nephropathy (DN), but there are no comprehensive studies to date relating early tubulointerstitial injury and the effect of the disease on both transporters in type 1 diabetes mellitus (T1DM). We used eight-week-old male C57BL/6 mice divided into two groups; one of them received the vehicle (control group), while the other received the vehicle + 200 mg/kg streptozotocin (T1DM). Ten weeks after the injection, we evaluated plasma insulin, enzymuria, urinary vitamin D-binding protein (VDBP), tubulointerstitial fibrosis and proximal tubule histology, markers of autophagy, and megalin and cubilin levels. We found a reduction in tubular protein reabsorption (albumin and VDBP as specific substances carried by both transporters) with increased tubulointerstitial injury, development of fibrosis, thickening of tubular basement membrane, and an increase in tubular cell metalloproteases. This was associated with a decrease in the renal expression of megalin and cubilin. We also observed an increase in the amount of cellular vesicles of the phagocytic system in the tubules, which could be linked to an alteration of normal intracellular trafficking of both receptors, thus affecting the normal function of transporters in early stages of DN. In diabetic animals, the added effects of tubulointerstitial injury, the decreases in megalin and cubilin expression, and an altered intracellular trafficking of these receptors, seriously affect protein reabsorptionFil: Giraud Billoud, Maximiliano German. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ezquer, Fernando. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; ChileFil: Bahamonde, Javiera. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; ChileFil: Ezquer, Marcelo. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; Chil

Mesenchymal Stem Cell Therapy in Type 1 Diabetes Mellitus and Its Main Complications: From Experimental Findings to Clinical Practice

Type 1 diabetes mellitus (T1DM) is a complex multifactorial disorder which involves a loss of self-tolerance leading to the autoimmune destruction of pancreatic β−cells. Exogenous insulin administration cannot mimic precise pancreatic β-cell regulation of glucose homeostasis, thereby leading to severe long-term complications. Pancreas or islet transplant only provides partial exogenous insulin independence and induces several adverse effects, including increased morbidity and mortality. The scientific community and diabetic patients are thus, still waiting for an effective therapy which could preserve the remaining β-cells, replenish islet mass and protect newly-generated β-cells from autoimmune destruction. Mesenchymal stem cells (MSCs) have been envisioned as a promising tool for T1DM treatment over the past few years, since they could differentiate into glucose-responsive insulin-producing cells. Their immunomodulatory and proangiogenic roles can be used to help arrest β-cell destruction, preserve residual β-cell mass, facilitate endogenous β-cell regeneration and prevent disease recurrence, thereby making them ideal candidates for the comprehensive treatment of diabetic patients. This review focuses on recent pre-clinical data supporting MSC use in regenerating β-cell mass and also in treating several T1DM-associated complications. Clinical trial results and the ongoing obstacles which must be addressed regarding the widespread use of such therapy are also discussed.Fil: Ezquer, Marcelo. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; ChileFil: Arango Rodriguez, Martha. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; ChileFil: Giraud Billoud, Maximiliano German. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ezquer, Fernando. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; Chil

Diabetic nephropathy, autophagy and proximal tubule protein endocytic transport: A potentially harmful relationship

Diabetic nephropathy (DN) is the most frequent cause of chronic renal failure. Until now, the pathophysiological mechanisms that determine its development and progression have not yet been elucidated. In the present study, we evaluate the role of autophagy at early stages of DN, induced in type 2 diabetes mellitus (T2DM) mouse, and its association with proximal tubule membrane endocytic receptors, megalin and cubilin. In T2DM animals we observed a tubule-interstitial injury with significantly increased levels of urinary GGT and ALP, but an absence of tubulointerstitial fibrosis. Kidney proximal tubule cells of T2DM animals showed autophagic vesicles larger than those observed in the control group, and an increase in the number of these vesicles marked with LBPA by immunofluorescence. Furthermore, a significant decrease in the ratio of LC3II/LC3I isoforms and in p62 protein expression in DN affected animals is shown. Finally, we observed a marked increase in urinary albumin and vitamin D binding-protein levels in T2DM animals as well as a significant decrease in expression of megalin in the renal cortex. These results indicate an alteration of the tubular endocytic transporters in DN, which could be related to autophagic dysfunction, which would in turn result in impaired organelle recycling, thus contributing to the progression of this disease.Fil: Giraud Billoud, Maximiliano German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Fader Kaiser, Claudio Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Agüero, Rocio. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Ezquer, Fernando. Universidad del Desarrollo; ChileFil: Ezquer, Marcelo. Universidad del Desarrollo; Chil

F2 region maximum electron density height predictions for South American latitudes

Values of the F2 region maximum electron density height (hmF2) calculated using ground ionosonde data at South American latitudes are used to check the validity of the International Reference Ionosphere (IRI) to predict this variable. With this in mind we compare hmF2 predictions given by the model when measurements of critical frequency of F2 region and propagation parameter M(3000)F2 were used as input parameter in IRI (hmF2IRI-Exp), against those obtained using the standard International Radio Consultative Committee (CCIR) option (hmF2IRI-CCIR)- In this paper we used hmF2 IRI-Exp values because hmF2 measurements were not available for the considered cases. Moreover, a comparison of the measured M(3000)F2 values with the CCIR predictions have been done. The results show that, in general, the standard predictions follow the diurnal tendency observed in the hmF2 IRI-Exp values. At low latitudes the hmF2IRI-Exp values show oscillations not reproduced by the standard option. Cases with disagreements for 24 hours have been observed at high latitudes. Other cases with good agreement have been also obtained. The results suggest that, in general, the standard option of the model gives good hmF2 predictions at South American latitudes. Few cases showed deviation between 15 and 25%. As we expected, the obtained results suggest that the deviation between predicted and measured M(3000)F2 values is the main contribution for the deviation between hmF2IRI-CCIR and hmF2IRI-Exp. The comparison with the results obtained in previous work shows that the IRI performance in predicting M(3000)F2 and hmF2 is better than in predicting foF2.Fil: Ezquer, Rodolfo Gerardo. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; ArgentinaFil: Scidá, Luis. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; ArgentinaFil: Mansilla, Gustavo Adolfo. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; ArgentinaFil: Mosert, Marta Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Instituto de Ciencias Astronómicas, de la Tierra y del Espacio. Universidad Nacional de San Juan. Instituto de Ciencias Astronómicas, de la Tierra y del Espacio; ArgentinaFil: Herrera, Marcelo F.. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentin

Spatial maps and oscillations in the healthy hippocampus of Octodon degus, a natural model of sporadic Alzheimer’s disease

The Octodon degus is a South American rodent that is receiving increased attention as a potential model of aging and sporadic late-onset Alzheimer’s disease (AD). Impairments in spatial memory tasks in Octodon degus have been reported in relation to either advanced AD-like disease or hippocampal lesion, opening the way to investigate how the function of hippocampal networks affects behavior across AD stages. However, no characterization of hippocampal electrophysiology exists in this species. Here we describe in young, healthy specimens the activity of neurons and local field potential rhythms during spatial navigation tasks with and without objects. Our findings show similarities between the Octodon degus and laboratory rodents. First, place cells with characteristics similar to those found in rats and mice exist in the CA1 subfield of the Octodon degus. Second, the introduction of objects elicits novelty-related exploration and an increase in activity of CA1 cells, with location specific and unspecific components. Third, oscillations of the local field potential are organized according to their spectral content into bands similar to those found in laboratory rodents. These results suggest a common framework of underlying mechanisms, opening the way to future studies of hippocampal dysfunction in this species associated to aging and disease.Fil: Mugnaini, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Polania, Diana. Universidad de Chile; ChileFil: Díaz, Yannina Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ezquer, Marcelo. Universidad del Desarrollo; ChileFil: Ezquer, Fernando. Universidad del Desarrollo; ChileFil: Deacon, Robert M. J.. Universidad de Chile; ChileFil: Cogram, Patricia. Universidad de Chile; Chile. University of California at Irvine; Estados UnidosFil: Kropff, Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Comparacion entre Valores de Vtec Predichos por el Modelo Nequick2 y los Obtenidos a Partir de Gps sobre Boulder durante muy baja actividad Solar

Una especificación confiable del estado de la ionósfera dada por modelos empíricos es importante para mitigar los efectos que esta zona atmosférica produce sobre las operaciones de los sistemas de posicionamiento y navegación basadas en satélites. Este estudio evalúa la capacidad del modelo NeQuick2 para predecir el contenido electrónico vertical total (VTEC), hasta la altura de los satélites GPS, sobre Boulder (40,00°N, 254,75°E), durante una época de muy baja actividad solar. Para ello se comparan las predicciones del modelo con valores de VTEC obtenidos a partir de señales de satélites GPS, publicados por el National Geophysical Data Center (NGDC) de EEUU. Teniendo en cuenta las incertezas de los valores de GPS VTEC publicados por el NGDC, los resultados muestran que el modelo estudiado, en general, se comporta como un buen predictor del contenido electrónico total en las condiciones solares consideradas

Densidad Electronica a 600 Km de Altitud. Comparacion de las Mediciones del Satelite Hinotori y las Predicciones del Modelo Nequick2.

En el presente trabajo se analizó el desempeño del modelo ionosférico NeQuick2 para predecir los valores de densidad de electrones libres (Ne) a 600 Km de altura, en un periodo de alta actividad solar y para las latitudes geomagnéticas -15°, 0° y +15°, las cuales corresponden a la franja de la anomalía ecuatorial. Las predicciones del modelo, fueron comparadas con datos de mediciones de Ne, obtenidas por el satélite japonés Hinotori; que realizó mediciones desde Febrero de 1981 hasta Junio de 1982. Solo se consideraron los registros con valores de F10.7 entre 63 y 193 para seguir recomendaciones de la ITU incluidas en Modelo NeQuick2, lo cual dejo un total de más de 450 mil registros a analizar. Los resultados obtenidos en este trabajo sugieren la necesidad de realizar estudios adicionales que lleven a una mejor representación del perfil de tope de Ne dada por el modelo

Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice

Background: Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. Methods: Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. Results: Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. Conclusions: Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.Fil: De Gregorio, Cristian. Universidad del Desarrollo; ChileFil: Contador, David. Universidad del Desarrollo; ChileFil: Díaz, Diego. Universidad del Desarrollo; ChileFil: Cárcamo, Constanza. Universidad del Desarrollo; ChileFil: Santapau, Daniela. Universidad del Desarrollo; ChileFil: Lobos Gonzalez, Lorena. Universidad del Desarrollo; ChileFil: Acosta, Cristian Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Campero, Mario. Universidad de Chile; ChileFil: Carpio, Daniel. Universidad Austral de Chile; ChileFil: Gabriele, Caterina. University Of Catanzaro; ItaliaFil: Gaspari, Marco. University Of Catanzaro; ItaliaFil: Aliaga Tobar, Victor. Universidad de Chile; ChileFil: Maracaja Coutinho, Vinicius. Universidad de Chile; ChileFil: Ezquer, Marcelo. Universidad del Desarrollo; ChileFil: Ezquer, Fernando. Universidad del Desarrollo; Chil

The Antidiabetic Effect of MSCs Is Not Impaired by Insulin Prophylaxis and Is Not Improved by a Second Dose of Cells

Type 1 diabetes mellitus (T1D) is due to autoimmune destruction of pancreatic beta-cells. Previously, we have shown that intravenously administered bone marrow-derived multipotent mesenchymal stromal cells (MSCs) allows pancreatic islet recovery, improves insulin secretion and reverts hyperglycemia in low doses streptozotocin (STZ)-induced diabetic mice. Here we evaluate whether insulin prophylaxis and the administration of a second dose of cells affect the antidiabetic therapeutic effect of MSC transplantation. Insulitis and subsequent elimination of pancreatic beta-cells was promoted in C57BL/6 mice by the injection of 40 mg/kg/day STZ for five days. Twenty-four days later, diabetic mice were distributed into experimental groups according to if they received or not insulin and/or one or two doses of healthy donor-derived MSCs. Three and half months later: glycemia, pancreatic islets number, insulinemia, glycated hemoglobin level and glucose tolerance were determined in animals that did not received exogenous insulin for the last 1.5 months. Also, we characterized MSCs isolated from mice healthy or diabetic. The therapeutic effect of MSC transplantation was observed in diabetic mice that received or not insulin prophylaxis. Improvements were similar irrespective if they received one or two doses of cells. Compared to MSCs from healthy mice, MSCs from diabetic mice had the same proliferation and adipogenic potentials, but were less abundant, with altered immunophenotype and no osteogenic potential

SPINK7 expression changes accompanied by HER2, P53 and RB1 can be relevant in predicting oral squamous cell carcinoma at a molecular level

The oral squamous cell carcinoma (OSCC), which has a high morbidity rate, affects patients worldwide. Changes in SPINK7 in precancerous lesions could promote oncogenesis. Our aim was to evaluate SPINK7 as a potential molecular biomarker which predicts OSCC stages, compared to: HER2, TP53, RB1, NFKB and CYP4B1. This study used oral biopsies from three patient groups: dysplasia (n = 33), less invasive (n = 28) and highly invasive OSCC (n = 18). The control group consisted of clinically suspicious cases later to be confirmed as normal mucosa (n = 20). Gene levels of SPINK7, P53, RB, NFKB and CYP4B1 were quantified by qPCR. SPINK7 levels were correlated with a cohort of 330 patients from the TCGA. Also, SPINK7, HER2, TP53, and RB1, were evaluated by immunohistofluorescence. One-way Kruskal–Wallis test and Dunn's post-hoc with a p < 0.05 significance was used to analyze data. In OSCC, the SPINK7 expression had down regulated while P53, RB, NFKB and CYP4B1 had up regulated (p < 0.001). SPINK7 had also diminished in TCGA patients (p = 2.10e-6). In less invasive OSCC, SPINK7 and HER2 proteins had decreased while TP53 and RB1 had increased with respect to the other groups (p < 0.05). The changes of SPINK7 accompanied by HER2, P53 and RB1 can be used to classify the molecular stage of OSCC lesions allowing a diagnosis at molecular and histopathological levels.Fil: Pennacchiotti, Graciela Laura. Universidad de Chile; ChileFil: Valdes Garrido, Fabio. Instituto Nacional del Cáncer; ChileFil: González Arriaga, Wilfredo Alejandro. Universidad de Valparaíso; ChileFil: Montes, Héctor Federico. Universidad Nacional de Cuyo. Facultad de Odontologia; ArgentinaFil: Parra, Judith Maria Roxana. Universidad Nacional de Cuyo. Facultad de Odontologia; ArgentinaFil: Guida, Valeria Andrea. Universidad Nacional de Cuyo. Facultad de Odontologia; ArgentinaFil: Gomez, Silvina Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Guerrero Gimenez, Martin Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fernandez Muñoz, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Zoppino, Felipe Carlos Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Caron, Ruben Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Ezquer, Marcelo Eduardo. Universidad del Desarrollo; ChileFil: Ramires Fernández, Ricardo. Universidad Mayor; ChileFil: Bruna, Flavia Alejandra. 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 Odontologia; Argentin