Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation

Proteostasis alteration and neuroinflammation are typical features of normal aging. We have previously shown that neuroinflammation alters cellular proteostasis through immunoproteasome induction, leading to a transient decrease of proteasome activity. Here, we further investigated the role of acute lipopolysaccharide (LPS)-induced hippocampal neuroinflammation in cellular proteostasis. In particular, we focused on macroautophagy (hereinafter called autophagy) and endoplasmic reticulum-associated protein degradation (ERAD). We demonstrate that LPS injection induced autophagy activation that was dependent, at least in part, on glycogen synthase kinase (GSK)-3β activity but independent of mammalian target of rapamycin (mTOR) inhibition. Neuroinflammation also produced endoplasmic reticulum (ER) stress leading to canonical unfolded protein response (UPR) activation with a rapid activating transcription factor (ATF) 6α attenuation that resulted in a time-dependent down-regulation of ERAD markers. In this regard, the time-dependent accumulation of unspliced X-box binding protein (XBP) 1, likely because of decreased inositol-requiring enzyme (IRE) 1α-mediated splicing activity, might underlie in vivo ATF6α attenuation. Importantly, lactacystin-induced activation of ERAD was abolished in both the acute neuroinflammation model and in aged rats. Therefore, we provide a cellular pathway through which neuroinflammation might sensitize cells to neurodegeneration under stress situations, being relevant in normal aging and other disorders where neuroinflammation is a characteristic featureUnión Europea PI12/00445Unión Europea ERDF PI12/0044

Aplicação da teoria de restrições à gestão de faturação das empresas sociais do estado: uma contribuição a o sistema de seguridade social na colômbia

Os Hospitais Públicos da Colômbia, denominados Empresas Sociais do Estado Prestadoras de Serviços de Saúde, mantém conflitos com as Entidades Promotoras de Saúde (EPS) e as Administradoras do Regime Subsidiado (ARS), devido às faturas de cobrança que as entidades hospitalárias enviam a estas instituições e que são devolvidas por inconsistências na sua tramitação, acarretando a demora no pagamento pelos serviços médicos prestados. Neste artigo é descrita a situação atual dos hospitais públicos quanto ao tema, é proposta a estratégia de solução ao problema detectado e é formulada uma aplicação prática e sistemática para corrigi-lo.Colombia's public hospitals, called state social health-service-providing companies come into conflict with the health promoting entities (Entidades Promotoras de Salud) and the subsidised regime administrators (Administradoras del Régimen Subsidiado - ARS) as the billing sent to these institutions by hospitals is often returned due to inconsistencies when being filled in, incurring long delays in payment for medical services provided. This article describes the public hospitals' current situation, gives a strategy form resolving the problem so detected and formulates a practical and systematic application for correcting it.Les Hôpitaux Publics de Colombie, appelés Entreprises Sociales de l´État Fournisseuses de Services de Santé, maintiennent des conflits avec les Entité Promotrices de Santé - EPS - et les Administratrices du Régime de Subsides - ARS -, en raison des factures que les hôpitaux envoient à ces institutions et qui leurs sont renvoyées en raison d´inconsistances dans leur formulation, ce qui produit des retards dans le paiement des services de médecine rendus. Cet article décrit la situation actuelle des hôpitaux publics dans cette matière, la stratégie de solution au problème décelé est énoncée et une application pratique et systématique est formulée pour le corriger.Los hospitales públicos de Colombia, denominados Empresas Sociales del Estado, ESE, Prestadoras de Servicios de Salud, mantienen conflictos con las Entidades Promotoras de Salud (EPS) y las Administradoras del Régimen Subsidiado (ARS), debido a las facturas de cobro que las entidades hospitalarias envían a estas instituciones y son devueltas por inconsistencias en su diligenciamiento. Este hecho acarrea demoras en el pago por servicios médicos prestados. En este artículo se describe la situación actual de los hospitales públicos en esta materia, se enuncia la estrategia de solución al problema detectado y se formula una aplicación práctica y sistemática para corregirlo bajo los principios de la teoría de restricciones

The Expression of TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Can Be Controlled by the Antioxidant Orchestrator NRF2 in Human Carcinoma Cells

Hyperactivation of the KEAP1-NRF2 axis is a common molecular trait in carcinomas from different origin. The transcriptional program induced by NRF2 involves antioxidant and metabolic genes that render cancer cells more capable of dealing with oxidative stress. The TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) is an important regulator of glycolysis and the pentose phosphate pathway that was described as a p53 response gene, yet TIGAR expression is detected in p53-null tumors. In this study we investigated the role of NRF2 in the regulation of TIGAR in human carcinoma cell lines. Exposure of carcinoma cells to electrophilic molecules or overexpression of NRF2 significantly increased expression of TIGAR, in parallel to the known NRF2 target genes NQO1 and G6PD. The same was observed in TP53KO cells, indicating that NRF2-mediated regulation of TIGAR is p53-independent. Accordingly, downregulation of NRF2 decreased the expression of TIGAR in carcinoma cell lines from different origin. As NRF2 is essential in the bone, we used mouse primary osteoblasts to corroborate our findings. The antioxidant response elements for NRF2 binding to the promoter of human and mouse TIGAR were described. This study provides the first evidence that NRF2 controls the expression of TIGAR at the transcriptional level

Dysfunction of the unfolded protein response increases neurodegeneration in aged rat hippocampus following proteasome inhibition

Dysfunctions of the ubiquitin proteasome system (UPS) have been proposed to be involved in the aetiology and/or progression of several age-related neurodegenerative disorders. However, the mechanisms linking proteasome dysfunction to cell degeneration are poorly understood. We examined in young and aged rat hippocampus the activation of the unfolded protein response (UPR) under cellular stress induced by proteasome inhibition. Lactacystin injection blocked proteasome activity in young and aged animals in a similar extent and increased the amount of ubiquitinated proteins. Young animals activated the three UPR arms, IRE1α, ATF6α and PERK, whereas aged rats failed to induce the IRE1α and ATF6α pathways. In consequence, aged animals did not induce the expression of pro-survival factors (chaperones, Bcl-XL and Bcl-2), displayed a more sustained expression of proapoptotic markers (CHOP, Bax, Bak and JKN), an increased caspase-3 processing. At the cellular level, proteasome inhibition induced neuronal damage in young and aged animals as assayed using Fluorojade-B staining. However, degenerating neurons were evident as soon as 24 h postinjection in aged rats, but it was delayed up to 3 days in young animals. Our findings show evidence supporting age-related dysfunctions in the UPR activation as a potential mechanism linking protein accumulation to cell degeneration. An imbalance between pro-survival and pro-apoptotic proteins, because of noncanonical activation of the UPR in aged rats, would increase the susceptibility to cell degeneration. These findings add a new molecular vision that might be relevant in the aetiology of several age-related neurodegenerative disorders

Respuesta a la frecuencia de defoliación de plantas de festuca alta de una población naturalizada infectada con endófito silvestre y un cultivar comercial libre

El objetivo del presente trabajo fue evaluar el efecto de dos frecuencias de defoliación sobre el crecimiento vegetativo y reproductivo de plantas de festuca alta provenientes de semilla cosechada en una población naturalizada e infectada con Epichloë coenophiala (FNE+) y de un cultivar comercial libre de endófito (FCE-, cv. Continental Taita). Además, en las plantas de FNE+ se analizó el efecto de la frecuencia de defoliación sobre la transmisión vertical del endófito a las semillas. La siembra se realizó el 02/05/2016 y la densidad de plantas para todos los tratamientos fue de 200 plantas m-2. Los factores experimentales fueron: tipo de micropastura de festuca alta (FNE+ y FCE-) y frecuencia de defoliación (AF: alta y BF: baja, defoliaciones cada 450±100°Cd y cada 850±100°Cd, respectivamente, en el período comprendido entre el 20/10/2016 y el 16/08/2017). Se realizaron 8 cortes para el tratamiento AF y 4 cortes para el BF. Se empleó un diseño experimental completamente aleatorizado con arreglo factorial y 5 repeticiones. Se halló que con AF las plantas de FNE+ presentaron mayor acumulación de biomasa total que las FCE- (168,19±8,84 y 149,12±3,74 g MS m-2 respectivamente, p=0,009), mientras que con BF la situación fue inversa (FNE+: 104,13±7,07 y FCE-: 120,13±5,79 g MS m-2, p=0,009). El número de macollos en las plantas de ambos tipos de micropastura fue mayor con AF que con BF (p<0,0001); el promedio fue 2346±302 y 1940±250 macollos m-2 respectivamente. El número de panojas por planta fue mayor en FNE+ que en FCE- (2,85±0,20 y 1,55±0,34, respectivamente, p=0,002) y no fue afectado por la frecuencia de defoliación (p=0,065). Las plantas de FNE+ tendieron a mostrar mayor esfuerzo reproductivo que las FCE-, aunque la diferencia solo fue significativa en BF. La producción de semillas fue mayor en las plantas de FNE+ que en las de FCE- (316,44±35,03 y 183,53±18,19 semillas/planta, respectivamente, p=0,0033) y no fue afectada por la frecuencia de defoliación (p=0,2581), aunque el aumento de la frecuencia de defoliación tendió a disminuir la producción de semillas en las plantas FNE+. Todas las semillas analizadas producidas por las plantas FNE+ resultaron positivas al diagnóstico de endófito, por lo que no hubo efecto de la frecuencia de defoliación sobre la transmisión de este. En conclusión, a pesar de que la frecuencia de defoliación afectó en forma diferencial la producción de biomasa total por planta en ambos tipos de micropasturas, las plantas de FNE+ siempre mostraron una mejor performance reproductiva. Esta última respuesta y la perfecta transmisión del endófito a las semillas observadas en ambas frecuencias de defoliación contribuirían a explicar el avance de los porcentajes de plantas infectadas comúnmente observado a campo.The objective of the present work was to evaluate the effect of two defoliation frequencies on the vegetative and reproductive growth of tall fescue plants originated from seed harvested in a naturalized population infected with Epichloë coenophiala (FNE+) and from a commercial endophyte-free cultivar (FCE-, cv Continental Taita). In addition, the effect of the defoliation frequencies applied on the vertical transmission of the endophyte to the seeds produced by FNE+ plants was analyzed. On 2 May 2016 seeds were sown in micropastures at a density of 200 plants m-2. The experimental factors were: type of tall fescue micropasture (FNE+ and FCE-) and frequency of defoliation (AF: high and BF: low, defoliated every 450±100°Cd and every 850±100°Cd, respectively, during the period between 20 October 2016 and 16 August 2017). Eight cuts were carried out in AF and 4 cuts in BF. A completely randomized experimental design with a factorial arrangement and five replicates was used. Under AF, FNE+ plants presented higher accumulation of total biomass than FCE- (168.19±8.84 and 149.12±3.74 g DM m-2 respectively, p=0.009), while the opposite occurred under BF (FNE+: 104.13±7.07 and FCE-: 120.13±5.79 g DM m-2, p=0.009). Independently of micropasture type, the number of tillers per plant was higher under AF than under BF (2346±302 and 1940±250 tillers m-2 respectively, p<0.0001). The number of panicles per plant was higher in FNE+ than in FCE- (2.85±0.20 and 1.55±0.34, respectively, p=0.002) and was not affected by the frequency of defoliation (p=0.065). The FNE+ plants tended to show a greater reproductive effort than FCE-, although the difference was only significant under BF. Seed production was higher in FNE+ than in FCE- plants (316.44±35.03 and 183.53±18.19 seeds/plant, respectively, p=0.0033) and it was not affected by the defoliation frequency (p=0.2581), although the highest frequency of defoliation tended to decrease the seed production of FNE+ plants. All the analyzed seeds produced by FNE+ plants were positive to the endophyte diagnosis, so endophyte transmission was not affected by the frequency of defoliation. In conclusion, despite the fact that the defoliation frequency affected differentially total plant biomass of both types of micropastures, FNE+ plants always showed a better reproductive performance than FCE- plants. The last finding together with the fact that the transmission of the endophyte to the seeds was perfect and not affected by the defoliation frequency, would help to explain the progress of the percentages of infected plants commonly observed in the field.EEA BalcarceFil: Petigrosso, Lucas R. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; ArgentinaFil: Navarro, Diego. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; ArgentinaFil: Assuero, Silvia Graciela. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; ArgentinaFil: Vignolio, Osvaldo. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; Argentina.Fil: Castaño, Jorge Alberto. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; Argentina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; Argentina.Fil: Colabelli, Mabel Noemí. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; Argentin

Lipopolysacharide-induced neuroinflammation leads to the accumulation of ubiquitinated proteins and increases susceptibility to neurodegeneration induced by proteasome inhibition in rat hippocampus

BACKGROUND: Neuroinflammation and protein accumulation are characteristic hallmarks of both normal aging and age-related neurodegenerative diseases. However, the relationship between these factors in neurodegenerative processes is poorly understood. We have previously shown that proteasome inhibition produced higher neurodegeneration in aged than in young rats, suggesting that other additional age-related events could be involved in neurodegeneration. We evaluated the role of lipopolysaccharide (LPS)-induced neuroinflammation as a potential synergic risk factor for hippocampal neurodegeneration induced by proteasome inhibition. METHODS: Young male Wistar rats were injected with 1 μL of saline or LPS (5 mg/mL) into the hippocampus to evaluate the effect of LPS-induced neuroinflammation on protein homeostasis. The synergic effect of LPS and proteasome inhibition was analyzed in young rats that first received 1 μL of LPS and 24 h later 1 μL (5 mg/mL) of the proteasome inhibitor lactacystin. Animals were sacrificed at different times post-injection and hippocampi isolated and processed for gene expression analysis by real-time polymerase chain reaction; protein expression analysis by western blots; proteasome activity by fluorescence spectroscopy; immunofluorescence analysis by confocal microscopy; and degeneration assay by Fluoro-Jade B staining. RESULTS: LPS injection produced the accumulation of ubiquitinated proteins in hippocampal neurons, increased expression of the E2 ubiquitin-conjugating enzyme UB2L6, decreased proteasome activity and increased immunoproteasome content. However, LPS injection was not sufficient to produce neurodegeneration. The combination of neuroinflammation and proteasome inhibition leads to higher neuronal accumulation of ubiquitinated proteins, predominant expression of pro-apoptotic markers and increased neurodegeneration, when compared with LPS or lactacystin (LT) injection alone. CONCLUSIONS: Our results identify neuroinflammation as a risk factor that increases susceptibility to neurodegeneration induced by proteasome inhibition. These results highlight the modulation of neuroinflammation as a mechanism for neuronal protection that could be relevant in situations where both factors are present, such as aging and neurodegenerative diseases

Regional difference in inflammatory response to LPS-injection in the brain: Role of microglia cell density

To elucidate whether density of cells could contribute to the extent of microglial activation, we performed in vitro assays using three different densities of N13 microglia stimulated with LPS. Our results showed that induction of pro-inflammatory factors as TNF-α and iNOS was directly related to cell density, meanwhile the induction of the anti-inflammatory IL-10 was inversely related to cell density. Accordingly, in vivo assays showed that after LPS-injection, iNOS expression was more intense in substantia nigra, a brain area showing specific susceptibility to neurodegeneration after microglia activation, whereas IL-10 expression was more sustained in striatum, an area resistant to damage. These results support that microglia density is pivotal to control the balance between pro- and anti-inflammatory factors release.Instituto de Salud Carlos III PI060781, PI060567Junta de Andalucía CVI-90

INFOTIC. Infografías académicas y herramientas de visualización de datos científicos con herramientas TIC: formación docente, diseño de recursos multimedia y experiencias didácticas para la enseñanza semipresencial

El proyecto ha gravitado en torno al uso didáctico de las infografías científicas como una herramienta destinada a la enseñanza semipresencial y telemática, aportando nuevos recursos para estudiantes y docentes y permitiendo implementar dinámicas adaptadas a las nuevas tecnologías. En este sentido, una infografía se puede definir como un conjunto de ideas complejas representadas mediante palabras, imágenes, gráficos, etc., que les confieren un aspecto visualmente atractivo. Las infografías conforman un hilo comunicativo de transmisión de estas ideas gracias al uso de textos informativos, que refuerzan su carácter pedagógico, e imágenes ilustrativas para potenciar la claridad y el dinamismo del mensaje. La visualidad de los datos integrados en las infografías es la característica más destacable de estos recursos, haciéndolas interesantes para su aplicación en la enseñanza y divulgación académica. En el marco de este proyecto, poseen una finalidad eminentemente didáctica, ayudando a que temas complejos puedan ser entendidos por un público no especializado

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Aplicación de la Teoría de Restricciones (TOC) a la gestión de facturación de las Empresas Sociales del Estado, ESE Una contribución al Sistema de Seguridad Social en Colombia

Los hospitales públicos de Colombia, denominados Empresas Sociales del Estado, ESE, Prestadoras de Servicios de Salud, mantienen conflictos con las Entidades Promotoras de Salud (EPS) y las Administradoras del Régimen Subsidiado (ARS), debido a las facturas de cobro que las entidades hospitalarias envían a estas instituciones y son devueltas por inconsistencias en su diligenciamiento. Este hecho acarrea demoras en el pago por servicios médicos prestados. En este artículo se describe la situación actual de los hospitales públicos en esta materia, se enuncia la estrategia de solución al problema detectado y se formula una aplicación práctica y sistemática para corregirlo bajo los principios de la teoría de restricciones