L-arginine ameliorates defective autophagy in GM2 gangliosidoses by mTOR modulation

Aims: Tay–Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by β-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay–Sachs and Sandhoff diseases. Results: Pathological autophagosomes with impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities. Innovation: Our data provide a novel molecular mechanism underlying GM2 gangliosidosis. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for these diseases. Conclusions: We contend that the expression of autophagy/lysosome/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy

“Covid-19 y su repercusión en el sistema musculoesquelético”

Covid-19 in the worldwide caused one of the pandemics with a great impact and the repercussions it caused at a systemic level have not only in a respiratory system, so, they have been identified in other parts of the organism systems  and even the musculoskeletal. For this reason, the main objective of this research was to analyze scientific evidence on covid-19 and its impact on the musculoskeletal system. The systematic review methodology was used, conducting an exhaustive search in international and national databases, considering inclusion and exclusion criteria. Among the results identified, it can be mentioned that the global prevalence of musculoskeletal disorders was determined during the covid-19 pandemic, which maintains figures from 20% to 81%, which in turn varies according to the disorder, in this case pain back, cervical, lumbar dorsal, muscle pain, arthralgia and myalgia were the most predominant. And among the risk factors, overweight, sedentary lifestyle, forced postures and prolonged bed rest due to the disease stood out. Persistent symptoms in this system were also described in infected patients, where joint pain, myalgia, muscle and spinal pain (low back pain, thoracolumbar pain) were the most identified and those may persist from one month to 6 months after infection. Therefore, covid-19 did have musculoskeletal repercussions in the general population, both due to confinement and the disease itself, and it is necessary that patients be provided comprehensive control and care in the face of these persistent disorders.El Covid-19 a nivel mundial causó una de las pandemias de mucho impacto y las repercusiones que ocasionó a nivel sistémico no solo han sido respiratorias, de hecho, se han identificado en otros sistemas del organismo e incluso el musculoesquelético. Es por ello, que la presente investigación tuvo como objetivo principal analizar evidencias científicas sobre covid-19 y su repercusión en el sistema musculoesquelético. Se empleó la metodología de revisión sistemática, realizando una búsqueda exhaustiva en bases de datos internacionales y nacionales, considerando criterios de inclusión y exclusión. Entre los resultados identificados, se puede mencionar que se determinó la prevalencia mundial de trastornos musculoesqueléticos durante la pandemia del covid-19, la cual mantiene cifras de 20% hasta 81%, a su vez varía de acuerdo al trastorno, en este caso los dolores de espalda, cervical, dorsal lumbar, dolores musculares, artralgia y mialgia fueron los más predominantes. Entre los factores de riesgo destacaron el sobrepeso, sedentarismo, posturas forzadas y el reposo prolongado en cama por la enfermedad. También se describieron síntomas persistentes en este sistema en los pacientes infectados, en donde el dolor articular, mialgias, dolores musculares y a la columna (lumbalgia, dorsolumbar) fueron los más identificados y aquellos pueden persistir un mes hasta 6 meses después de la infección. Por lo cual, el covid-19 si tuvo repercusiones musculoesqueléticas en la población en general, tanto por el confinamiento como por la misma enfermedad y es necesario que en los pacientes se les brinde un control y atención integral ante estos trastornos persistentes

Síndrome de abstinencia neonatal: una problemática actual en la unidad de neonatología

Introduction: Drug use during pregnancy causes chronic exposure and passive addiction of the fetus to these substances, leading to negative effects and affections, the interruption of drug supply at birth, causes deprivation which triggers neonatal abstinence syndrome. Objective: Determine the frequency and related factors with the abstinence syndrome in the neonatal intensive care unit of the Children’s Hospital Dr. Francisco the Icaza Bustamante. Materials and methods: Is investigated to the neonates admitted, with a maternal history of drug use, with Finnegan scale score equal to or greater than 8 points, during the period from January 2017 to December 2021. Results: It was obtained a sample of 91 neonates (3.47%), predominating the male sex (73.6%), the neonates to term (84.6%), maternal age from 20 to 30 years (63.7%), the most consumed drug heroin (82.4%), the more frequent manifestation was irritability and crying (71.4%), and the syndrome of abstinence mild (72.5%). Conclusions: The neonatal abstinence syndrome is common in the neonatology unit, your diagnosis and comprehensive treatment is vital, and the existence of preventive programmes, detection and comprehensive care for pregnant women with drug addiction.Introducción: El consumo de drogas durante el embarazo provoca la exposición crónica y adicción pasiva del feto a dichas sustancias, llevando a efectos negativos y afecciones, la interrupción del aporte de la droga al nacimiento, provoca deprivación lo cual desencadena el síndrome de abstinencia neonatal. Objetivo: Determinar la frecuencia y factores relacionados con el síndrome de abstinencia en la unidad de cuidados intensivos neonatales del Hospital del Niño Dr. Francisco de Icaza Bustamante. Materiales y métodos: Se investigó a los neonatos ingresados, con antecedente materno de consumo de drogas, con puntuación de escala de Finnegan igual o mayor a 8 puntos, durante el periodo de enero del 2017 a diciembre del 2021. Resultados: Se obtuvo una muestra de 91 neonatos (3.47%), predominando el sexo masculino (73.6%), los neonatos a término (84.6%), edad materna de 20 a 30 años (63.7%), la droga más consumida la heroína (82.4%), la manifestación más frecuente fue irritabilidad y llanto (71.4%) y el síndrome de abstinencia leve (72.5%). Conclusiones: El síndrome de abstinencia neonatal es frecuente en la unidad de neonatología, su diagnóstico y tratamiento integral es vital, y la existencia de programas preventivos, detección y atención integral a la mujer gestante con adicción a drogas

L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation.

AIMS: Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by β-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay-Sachs and Sandhoff diseases. RESULTS: Pathological autophagosomes with impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities. INNOVATION: Our data provide a novel molecular mechanism underlying GM2 gangliosidosis. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for these diseases. CONCLUSIONS: We contend that the expression of autophagy/lysosome/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy

Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson-Gilford Progeria

Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson-Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1. Consistent with these results, the expression of caspase 1 and Nlrp3, but not of the other inflammasome receptors was higher in the heart and liver of Zmpste2

Modelo prolab: Ayllu Pet, plataforma que conecta a dueños y cuidadores de mascotas dentro de un modelo de negocio colaborativo y sostenible

El presente plan de negocio pretende brindar una solución que facilite la interacción de los dueños y cuidadores de mascotas a través de un modelo colaborativo y basado en el modelo de la economía verde. Mediante una plataforma digital, los dueños encontrarán a cuidadores experimentados que brindan su hogar para acoger a las mascotas y cubrir todas sus necesidades dentro de un ambiente de bienestar y responsable con el medioambiente. Las mascotas se han vuelto parte de los hogares y en los productos de la canasta familiar están incluidos los alimentos, servicios y accesorios de ellas. En ese sentido, la industria de mascotas ha tenido un sorprendente crecimiento económico y ello encuentra correspondencia con que la tenencia de animales domésticos siga en aumento. Durante el estudio, se validaron las hipótesis relacionadas a la deseabilidad, factibilidad y viabilidad del negocio. Se aplicaron las pruebas de usabilidad y se obtuvo como resultado que los dueños y cuidadores están dispuestos a pertenecer a la comunidad de Ayllu Pet, se identifican con la propuesta de valor, y tienen disposición a pagar las tarifas del servicio (dueño de mascota) y están conformes con la remuneración fijada (cuidador). Se realizaron las simulaciones bajo diversos escenarios sobre el plan de marketing y publicidad, y atención del servicio, que arrojaron resultados favorables de desempeño y eficiencia. Se validaron los escenarios de crecimiento económico a partir de una inversión inicial de S/520,000.00, lo que generó un VAN de S/3’430.727,56 y una TIR de 65,05 % en un escenario moderado. A partir de este resultado, se puede afirmar que el modelo de negocio es financieramente viable. Finalmente, para la rentabilidad social, se utilizó la tasa social de descuento establecida por el MEF en 8 %, y se obtuvo un VAN social de S/68,231,877.62. A partir de lo señalado, la propuesta de negocio que se presenta plantea la creación de una comunidad colaborativa que brindará un espacio de confianza entre dueños y cuidadores de mascotas en armonía con el medioambiente

Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria

Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson–Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1. Consistent with these results, the expression of caspase 1 and Nlrp3, but not of the other inflammasome receptors was higher in the heart and liver of Zmpste24−/− mice, which phenocopy the human disease. These data were further corroborated in LmnaG609G/G609G mice, another HGPS animal model. We also showed that pharmacological inhibition of the NLRP3 inflammasome by its selective inhibitor, MCC950, improved cellular phenotype, significantly extended the lifespan of progeroid animals, and reduced inflammasome-dependent inflammation. These findings suggest that inhibition of the NLRP3 inflammasome is a potential therapeutic approach for the treatment of HGPS.Junta de Andalucía PI-0036-201

Diseño de actividades de escape room para dinamizar el trabajo en grupo en un contexto de docencia semipresencial

Diseñar actividades de escape room encuadradas como aprendizaje gamificado con el objetivo de incrementar la motivación, participación, interacción así como el desarrollo de habilidades de trabajo en grupo en un contexto de docencia semipresencialDepto. de Organización de EmpresasFac. de Ciencias Económicas y EmpresarialesFALSEsubmitte

Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells

Systemic treatments for hepatocellular carcinoma (HCC) have been largely unsuccessful. This study investigated the antitumoral activity of Amitriptyline, a tricyclic antidepressant, in hepatoma cells. Amitriptyline-induced toxicity involved early mitophagy activation that subsequently switched to apoptosis. Amitriptyline induced mitochondria dysfunction and oxidative stress in HepG2 cells. Amitriptyline specifically inhibited mitochondrial complex III activity that is associated with decreased mitochondrial membrane potential (ΔΨm) and increased reactive oxygen species (ROS) production. Transmission electron microscopy (TEM) studies revealed structurally abnormal mitochondria that were engulfed by double-membrane structures resembling autophagosomes. Consistent with mitophagy activation, fluorescence microscopy analysis showed mitochondrial Parkin recruitment and colocalization of mitochondria with autophagosome protein markers. Pharmacological or genetic inhibition of autophagy exacerbated the deleterious effects of Amitriptyline on hepatoma cells and led to increased apoptosis. These results suggest that mitophagy acts as an initial adaptive mechanism of cell survival. However persistent mitochondrial damage induced extensive and lethal mitophagy, autophagy stress and autophagolysome permeabilization leading eventually to cell death by apoptosis. Amitriptyline also induced cell death in hepatoma cells lines with mutated p53 and non-sense p53 mutation. Our results support the hypothesis that Amitriptyline-induced mitochondrial dysfunction can be a useful therapeutic strategy for HCC treatment, especially in tumors showing p53 mutations and/or resistant to genotoxic treatments.This work was supported by FIS PI13/00129 grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyecto de Investigación de Excelencia de la Junta de Andalucía CTS-5725, AEPMI (Asociación de Enfermos de Patología Mitocondrial) and ENACH (Asociación de Enfermedades Neurodegenerativas por Acumulación Cerebral de Hierro).Peer Reviewe

NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice

While NLRP3‐inflammasome has been implicated in cardiovascular diseases, its role in physiological cardiac aging is largely unknown. During aging, many alterations occur in the organism, which are associated with progressive impairment of metabolic pathways related to insulin resistance, autophagy dysfunction, and inflammation. Here, we investigated the molecular mechanisms through which NLRP3 inhibition may attenuate cardiac aging. Ablation of NLRP3‐inflammasome protected mice from age‐related increased insulin sensitivity, reduced IGF‐1 and leptin/adiponectin ratio levels, and reduced cardiac damage with protection of the prolongation of the agedependent PR interval, which is associated with atrial fibrillation by cardiovascular aging and reduced telomere shortening. Furthermore, old NLRP3 KO mice showed an inhibition of the PI3K/AKT/mTOR pathway and autophagy improvement, compared with old wild mice and preserved Nampt‐mediated NAD+ levels with increased SIRT1 protein expression. These findings suggest that suppression of NLRP3 prevented many age‐associated changes in the heart, preserved cardiac function of aged mice and increased lifespan.Andalusian regional government; Consejería de Salud de la Junta de Andalucia, Grant/ Award Number: PI‐0036‐2014; Ministerio de economía y competitividad, Grant/Award Number: SAF2017‐84494‐C2‐1‐