Beneficios de la atención y hospitalización domiciliaria en pacientes geriátricos y crónicos.

Introducción: Los cambios sociodemográficos, marcados por el envejecimiento poblacional, han convertido nuestra comunidad autónoma y España en general, en escenario inevitable de un crecimiento imparable de la dependencia. Nuevas modalidades asistenciales se están implantando en nuestra sociedad como respuesta a “nuevas” patologías prevalentes: la visita domiciliaria y la hospitalización domiciliaria son tipos de prácticas profesionales que están recibiendo cada vez más atención y supone una ampliación de la oferta de servicios sanitarios. De este modo se obtiene un beneficio social y económico, disminuyendo el número de ingresos hospitalarios, y un beneficio para la familia y el propio paciente. Objetivo: Conocer los beneficios que aportan, tanto a los profesionales como a los pacientes, la hospitalización a domicilio y atención a domicilio. Material y métodos: Revisión bibliográfica. Resultados y discusión: Una intervención planificada de enfermería, con una valoración integral individualizada disminuye los reingresos en pacientes geriátricos. La Hospitalización a Domicilio (HaD) ha demostrado que juega un papel muy importante en el suministro de cuidados de rango hospitalario a pacientes crónicos reagudizados en su domicilio, lo que mejora la calidad de vida de estos y evita los reingresos hospitalarios. La Hospitalización Domiciliaria, es pues, una alternativa para aminorar los costos, frente al costo de la hospitalización tradicional. Conclusiones: La Hospitalización Domiciliaria, es una opción asistencial que ha demostrado su utilidad y a pesar de estar definidas sus funciones, indicaciones, organización y rentabilidad, para la mayoría de los profesionales sanitarios, continúa siendo una actividad no bien conocida.Grado en Enfermerí

Transcription factor NRF2 regulates the expression of autophagy genes

Tesis doctoral inédita, leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 19-10-2018Cells control the quality of the proteome through an integrative network of mechanisms that include protein degradation by autophagy. The regulation of this process by signaling pathways has been intensively studied but less is known about its transcriptional control. Because this degradative pathway has an essential cytoprotective role, especially under stress conditions, in this thesis we have analyzed the regulation of autophagy by the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (NRF2), which is considered a master regulator of cellular homeostastis. NRF2 controls the expression of a wide battery of cytoprotective genes that have a tremendous impact on physiological responses such as inflammation, senescence or metabolism. However, its relevance in proteostasis is just starting to be unveiled. Therefore, we focused our study on the transcriptional regulation of two types of autophagy, i.e. macroautophagy and chaperone mediated autophagy (CMA). We have identified NRF2 enhancer sequences, termed antioxidant response elements (AREs), in the promoter region of 9 genes involved in different steps of macroautophagy and CMA. Consequently, we show that genetic and pharmacological manipulation of NRF2 results in the modulation of autophagy gene expression and activity. The role of NRF2 in the regulation of macroautophagy may have a significant relevance upon stressful conditions, including proteotoxic stress. To address the functional relevance of NRF2 in proteinopathy, we have generated a new mouse model of Alzheimer’s disease (AD) that reproduces the amyloid and TAU pathology in the presence or absence of NRF2 expression. NRF2 deficiency worsens some of the main hallmarks of AD, including low-grade chronic oxidative and inflammatory stress as well as exacerbated proteinopathy due, at least in part, to impaired macroautophagy. Moreover, our results reflect a positive correlation between the expression of NRF2 and macroautophagy in AD patients. We have also established the role of NRF2 in the basal and inducible regulation of CMA, based on the transcriptional regulation of the lysosomal receptor LAMP2A. This novel NRF2/LAMP2A axis may have important implications in the physiological response to stress and, consequently, be of interest for human pathology. In fact, data mining of The Cancer Genome Atlas showed a positive correlation between NRF2 an LAMP2 expression in gliomas and glioblastomas. Overall, this thesis describes a novel role of NRF2 in the regulation of macroautophagy and CMA, suggesting a new strategy to combat proteinopathies.Las células controlan la calidad del proteoma mediante una compleja red que integra diversos mecanismos, incluida la degradación de proteínas mediante autofagia. La regulación de este proceso a través de vías de señalización ha sido ampliamente estudiada, pero su control transcripcional es aún poco conocido. Debido a que esta vía de degradación tiene un papel citoprotector fundamental, especialmente en condiciones de estrés, en esta tesis hemos analizado la regulación de la autofagia por el factor de transcripción NRF2 (Nuclear factor (erythroid-derived 2)-like 2), considerado un regulador maestro de la homeostasis celular. NRF2 controla la expresión de una extensa batería de genes citoprotectores con un importante impacto en respuestas fisiológicas como la inflamación, la senescencia o el metabolismo. Sin embargo, su papel en proteostasis está aún comenzando a comprenderse. Por todo ello, hemos centrado nuestro estudio en la regulación transcripcional de dos tipos de autofagia, la macroautofagia y la autofagia mediada por chaperonas (CMA). Hemos identificado elementos de respuesta a NRF2, llamados elementos de respuesta antioxidante (ARE), en la región promotora de 9 genes involucrados en diferentes pasos de la macroautofagia y la CMA. En consecuencia, mostramos que la manipulación genética y farmacológica de NRF2 resulta en la modulación de la expresión génica y la actividad de la autofagia. El papel del factor de transcripción NRF2 en la regulación de la macroautofagia podría ser importante en condiciones de estrés, incluido el estrés proteotóxico. Para analizar la relevancia funcional de NRF2 en proteinopatía, hemos generado un nuevo modelo animal de la Enfermedad de Alzheimer (EA) que reproduce la amiloidopatía y tauopatía en presencia o ausencia de NRF2. La deficiencia en NRF2 agrava algunos eventos característicos de la EA, como el estrés oxidativo e inflamatorio crónico de bajo grado, así como la proteinopatía debido, al menos en parte, a una desregulación de la macroautofagia. Además, nuestros resultados reflejan una correlación positiva entre NRF2 y marcadores de macroautofagia en muestras de EA. Hemos establecido también un papel de NRF2 en la regulación basal e inducible de la CMA, basado en la regulación transcripcional del receptor lisosomal LAMP2A. Este nuevo eje NRF2/LAMP2A podría tener implicaciones relevantes para patologías humanas. De hecho, el análisis de datos obtenidos de The Cancer Genome Atlas mostró una correlación positiva en la expresión de NRF2 y LAMP2 en gliomas y glioblastomas. Con todo ello, esta tesis describe un nuevo papel de NRF2 en la regulación de la macroautofagia y la CMA, sugiriendo una nueva diana para combatir proteinopatías

Inflammation in Parkinson's disease: Mechanisms and therapeutic implications

Parkinson's disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from the substantia nigra pars compacta. Although the molecular bases for PD development are still little defined, extensive evidence from human samples and animal models support the involvement of inflammation in onset or progression. However, the exact trigger for this response remains unclear. Here, we provide a systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells. We also discuss the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species. Finally, we summarize the preclinical and clinical approaches targeting neuroinflammation in PD.This work was supported by PID2019-110061RB-I00 and SAF2017-82436R of the Spanish Ministry of Economy and Competiveness; P-024-FTPGB 2018 from the Spanish “Tatiana de Guzman el Bueno Foundation” and by the P_37_732/2016 grant (REDBRAIN) financed by the European Regional Development Fund, Competitiveness Operational Program 2014–2020. Comunidad Autónoma de Madrid (grants B2017/BMD-3827, S2017-BMD-3686). MP is recipient of a contract Juan de la Cierva (MICINN)

Repurposing zileuton as a depression drug using an AI and in vitro approach

Repurposing drugs to target M1 macrophages inflammatory response in depression constitutes a bright alternative for commonly used antidepressants. Depression is a significant type of mood disorder, where patients suffer from pathological disturbances associated with a proinflammatory M1 macrophage phenotype. Presently, the most commonly used antidepressants such as Zoloft and Citalopram can reduce inflammation, but suffer from dangerous side effects without offering specificity toward macrophages. We employed a new strategy for drug repurposing based on the integration of RNA-seq analysis and text mining using deep neural networks. Our system employs a Google semantic AI universal encoder to compute sentences embedding. Sentences similarity is calculated using a sorting function to identify drug compounds. Then sentence relevance is computed using a custom-built convolution differential network. Our system highlighted the NRF2 pathway as a critical drug target to reprogram M1 macrophage response toward an anti-inflammatory profile (M2). Using our approach, we were also able to predict that lipoxygenase inhibitor drug zileuton could modulate NRF2 pathway in vitro. Taken together, our results indicate that reorienting zileuton usage to modulate M1 macrophages could be a novel and safer therapeutic option for treating depression.This research was done under the P_37_732/2016 grant (REDBRAIN) financed by the European Regional Development Fund, Competitiveness Operational Program 2014-2020the

Serosurvey for selected pathogens in Iberian roe deer

<p>Abstract</p> <p>Background</p> <p>The roe deer is the most abundant and widespread wild Eurasian cervid. Its populations are expanding and increasingly in contact with livestock. This may affect the distribution of infectious diseases shared with other wild and domestic ungulates.</p> <p>Methods</p> <p>We investigated the antibody seroprevalence against Pestivirus, Herpesvirus, Bluetongue (BT) virus, <it>M. avium paratuberculosis </it>(MAP), and <it>Brucella </it>sp. in 519 roe deer from different regions in Spain, south-western Europe.</p> <p>Results</p> <p>No antibodies were detected against BT and <it>Brucella </it>sp. However, antibodies were detected against Pestivirus (1.5%), Herpesvirus (0.2%) and MAP (9.2%). MAP antibodies were detected in seven of the eight populations (range 5-16.4%).</p> <p>Conclusions</p> <p>The detection of MAP antibodies in samples from most roe deer populations suggests that contact with MAP is widespread in this wildlife species. The highest prevalence was detected in sites with abundant dairy cattle and frequent use of liquid manure on pastures. Considering the results obtained regarding exposure to different pathogens, we suggest that antibody prevalences in this non-gregarious browser are largely determined by environmental factors, potentially modulating vector populations or pathogen survival in the environment.</p

Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A

Chaperone-mediated autophagy (CMA) is a selective degradative process for cytosolic proteins that contributes to the maintenance of proteostasis. The signaling mechanisms that control CMA are not fully understood but might involve response to stress conditions including oxidative stress. Considering the role of CMA in redoxtasis and proteostasis, we sought to determine if the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) has an impact on CMA modulation. In this work, we identified and validated 2 NFE2L2 binding sequences in the LAMP2 gene and demonstrated in several human and mouse cell types that NFE2L2 deficiency and overexpression was linked to reduced and increased LAMP2A levels, respectively. Accordingly, lysosomal LAMP2A levels were drastically reduced in nfe2l2-knockout hepatocytes, which also displayed a marked decrease in CMA activity. Oxidant challenge with paraquat or hydrogen peroxide, or pharmacological activation of NFE2L2 with sulforaphane or dimethyl fumarate also increased LAMP2A levels and CMA activity. Overall, our study identifies for the first time basal and inducible regulation of LAMP2A, and consequently CMA activity, by NFE2L2. Abbreviations: ACTB: actin, beta, ARE: antioxidant response element; ATG5: autophagy related 5; BACH1: BTB domain and CNC homolog 1; ChIP: chromatin immunoprecipitation; CMA: chaperone-mediated autophagy; DHE: dihydroethidium; DMF: dimethyl fumarate; ENCODE: Encyclopedia of DNA elements at the University of California, Santa Cruz; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA: glucosylceramidase beta; GFP: green fluorescent protein; HMOX1: heme oxygenase 1; H2O2: hydrogen peroxide; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KEAP1: kelch like ECH associated protein 1; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; LAMP1: lysosomal associated membrane protein 1; MAFF: MAF bZIP transcription factor F; MAFK: MAF bZIP transcription factor K; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PQ: paraquat; PI: protease inhibitors; qRT-PCR: quantitative real-time polymerase chain reaction; RNASE: ribonuclease A family member; SFN: sulforaphane; SQSTM1/p62: sequestosome 1; TBP: TATA-box binding proteinThis paper was funded by the Spanish Ministry of Economy and Competitiveness under the grant SAF2016-76520-R and by grants from the National Institute of Health/National Institute on Aging P01 AG031782. M.P. is recipient of a FPU fellowship of Autonomous University of Madrid. E.A. was supported by NIH/NIA AG038072 P&

Contrasting responses of non-small cell lung cancer to antiangiogenic therapies depend on histological subtype

The vascular endothelial growth factor (VEGF) pathway is a clinically validated antiangiogenic target for non-small cell lung cancer (NSCLC). However, some contradictory results have been reported on the biological effects of antiangiogenic drugs. In order to evaluate the efficacy of these drugs in NSCLC histological subtypes, we analyzed the anticancer effect of two anti-VEGFR2 therapies (sunitinib and DC101) in chemically induced mouse models and tumorgrafts of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Antiangiogenic treatments induced vascular trimming in both histological subtypes. In ADC tumors, vascular trimming was accompanied by tumor stabilization. In contrast, in SCC tumors, antiangiogenic therapy was associated with disease progression and induction of tumor proliferation. Moreover, in SCC, anti-VEGFR2 therapies increased the expression of stem cell markers such as aldehyde dehydrogenase 1A1, CD133, and CD15, independently of intratumoral hypoxia. In vitro studies with ADC cell lines revealed that antiangiogenic treatments reduced pAKT and pERK signaling and inhibited proliferation, while in SCC-derived cell lines the same treatments increased pAKT and pERK, and induced survival. In conclusion, this study evaluates for the first time the effect of antiangiogenic drugs in lung SCC murine models in vivo and sheds light on the contradictory results of antiangiogenic therapies in NSCLC

Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas

Transcription factor NRF2 orchestrates a cellular defense against oxidative stress and, so far, has been involved in tumor progression by providing a metabolic adaptation to tumorigenic demands and resistance to chemotherapeutics. In this study, we discover that NRF2 also propels tumorigenesis in gliomas and glioblastomas by inducing the expression of the transcriptional co-activator TAZ, a protein of the Hippo signaling pathway that promotes tumor growth. The expression of the genes encoding NRF2 (NFE2L2) and TAZ (WWTR1) showed a positive correlation in 721 gliomas from The Cancer Genome Atlas database. Moreover, NRF2 and TAZ protein levels also correlated in immunohistochemical tissue arrays of glioblastomas. Genetic knock-down of NRF2 decreased, while NRF2 overexpression or chemical activation with sulforaphane, increased TAZ transcript and protein levels. Mechanistically, we identified several NRF2-regulated functional enhancers in the regulatory region of WWTR1. The relevance of the new NRF2/TAZ axis in tumorigenesis was demonstrated in subcutaneous and intracranial grafts. Thus, intracranial inoculation of NRF2-depleted glioma stem cells did not develop tumors as determined by magnetic resonance imaging. Forced TAZ overexpression partly rescued both stem cell growth in neurospheres and tumorigenicity. Hence, NRF2 not only enables tumor cells to be competent to proliferate but it also propels tumorigenesis by activating the TAZ-mediated Hippo transcriptional program.This study was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) under the grant SAF2016-76520-R. ME is recipient of a postdoctoral contract Juan de la Cierva; DL and NRA of a FPU contract of MINECO; MP and RFG of a FPI contracts of Autonomous University of Madrid. RG has been funded by the AECC Scientific Foundation

TGFBI expression is associated with a better response to chemotherapy in NSCLC

<p>Abstract</p> <p>Background</p> <p>Lung cancer is one of the most prevalent neoplasias in developed countries. Advances in patient survival have been limited and the identification of prognostic molecules is needed. Resistance to treatment is strongly related to tumor cell adhesion to the extracellular matrix and alterations in the quantity and nature of molecules constituting the tumor cell niche. Recently, transforming growth factor beta-induced protein (TGFBI), an extracellular matrix adaptor protein, has been reported to be differentially expressed in transformed tissues. Loss of TGFBI expression has been described in several cancers including lung carcinoma, and it has been suggested to act as a tumor suppressor gene.</p> <p>Results</p> <p>To address the importance of TGFBI expression in cancer progression, we determined its expression in NSCLC clinical samples using immunohistochemistry. We identified a strong association between elevated TGFBI expression and the response to chemotherapy. Furthermore, we transiently over-expressed and silenced TGFBI in human NSCLC cell lines. Cells over-expressing TGFBI displayed increased sensitivity to etoposide, paclitaxel, cisplatin and gemcitabine. We observed that TGFBI-mediated induction of apoptosis occurred through its binding to αvβ3 integrin. We also determined that full-length TGFBI did not induce caspase 3/7 activation but its proteolytic fragments that were < 3 kDa in size, were able to activate caspase 3, 7 and 8. This pro-apoptotic effect was blocked by anti-αvβ3 integrin antibodies.</p> <p>Conclusions</p> <p>The results shown here indicate that TGFBI is a predictive factor of the response to chemotherapy, and suggest the use of TGFBI-derived peptides as possible therapeutic adjuvants for the enhancement of responses to chemotherapy.</p