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Severe hypercholesterolaemia is a major cardiovascular risk factor. Early detection and treatment can reduce the incidence of cardiovascular disease. Given the high prevalence of hypercholesterolaemia in Andalusia, the development of a screening strategy for its detection in Primary Care may be an efficient measure. Objective To identify patients in Primary Care with severe hypercholesterolaemia that may increase their cardiovascular risk by reviewing LDL-cholesterol results in computerised laboratory systems. Material and methods Observational, retrospective, multi-centre study in 16 hospitals in Andalusia and Ceuta. Anonymous analytical data were acquired from the different laboratory computer systems for the year 2018, and exclusively from Macarena Hospital for the year 2019. Results From a total of 1,969,035 determinations on ≥18 years old, 2791 patients (0.14%) were detected with LDL-cholesterol >250 mg/dl and from a total of 2.327.211 determinations studied in children under 18 years old, 3804 patients (0.16%) were detected with LDL-cholesterol >135 mg/dl. The highest incidence of possible genetic hypercholesterolaemia in adults corresponded to the province of Seville with 23.6 cases/1000 determinations, while in minors, the highest incidence corresponded to the province of Cadiz with 75 possible cases/1000 determinations. A geographical triangle of greater prevalence is observed between the provinces of Seville, Huelva and Cadiz. Conclusions The development of a screening strategy using a computerised review of LDL-cholesterol in Primary Care detects a large number of subjects with severe hypercholesterolaemia that could benefit from an early intervention.

Resumen La hipercolesterolemia severa es un importante factor de riesgo cardiovascular. Su deteccion precoz y tratamiento puede reducir la incidencia de las enfermedades cardiovasculares. Dada la alta prevalencia de hipercolesterolemia en Andalucia, el desarrollo de una estrategia oportunista para su deteccion en atencion primaria puede ser una medida eficiente. Objetivo Identificar pacientes en atencion primaria con hipercolesterolemias severas que puedan incrementar su riesgo cardiovascular mediante una consulta del colesterol- LDL al sistema informatico de laboratorio. Material y metodos Estudio observacional, retrospectivo, multicentrico, en 16 hospitales de Andalucia y Ceuta. Se adquirieron datos analiticos anonimizados de los diferentes sistemas informaticos de laboratorio del ano 2018 y exclusivamente del Hospital Virgen Macarena para el ano 2019. Resultados De un total de 1.969.035 determinaciones ≥ 18 anos se detectaron 2.791 pacientes (0,14%) con colesterol-LDL > 250 mg/dl, y en menores de 18 anos, sobre un total de 2.327.211 determinaciones estudiadas, se detectaron 3.804 pacientes (0,16%) con colesterol-LDL > 135 mg/dl. La mayor incidencia de posibles hipercolesterolemias geneticas en adultos correspondio a la provincia Sevilla con 23,6 casos/1.000 determinaciones, mientras que en menores la mayor incidencia correspondio a la provincia de Cadiz, con 75 posibles casos/1.000 determinaciones. Se observa un triangulo geografico de mayor prevalencia entre las provincias de Sevilla, Huelva y Cadiz. Conclusiones El desarrollo de una estrategia oportunista mediante consulta informatica del colesterol-LDL en atencion primaria detecta un gran numero de sujetos con hipercolesterolemias severas que se podrian beneficiar de una intervencion precoz.

Resumen: Paciente varón de 68 años que acude a urgencias por dolor agudo en miembro inferior izquierdo y dolor lumbar crónico asociado.Se realiza una eco-doppler, objetivándose ocupación de la luz de vena iliaca común izquierda con extensión hasta vena femoral ipsilateral que se confirma mediante una tomografía computarizada con contraste, ambas sugestivas de trombosis venosa profunda de miembro inferior izquierdo, sin hallazgos de ningún proceso neoformativo abdominopélvico concomitante.Tanto la tomografía computarizada como la resonancia magnética demostraron herniación disco-osteofitaria lumbar baja, que disminuyó el espacio existente entre la arteria iliaca común izquierda y la pared anterior de los cuerpos vertebrales, condicionando compresión venosa y por tanto un caso de síndrome de May-Turner variante degenerativa. Abstract: A 68-year-old male patient reporting lumbar and acute left lower limb pain.Doppler ultrasound showed left common iliac vein lumen occupation with extension to the ipsilateral femoral vein also confirmed by contrast enhanced computed tomography suggestive of deep vein thrombosis. No evidence of abdominopelvic neoplasia was found.Both computed tomography and magnetic resonance imaging showed multilevel degenerative lumbar disease with a prominent low left anterior extraforaminal hernia, causing compression of the left iliac vein and therefore a degeneration-related May- Thurner Syndrome.

Background: Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease affecting the CNS. Recent studies have indicated that intestinal alterations play key pathogenic roles in the development of autoimmune diseases, including MS. The triterpene oleanolic acid (OA), due to its anti-inflammatory properties, has shown to beneficially influence the severity of the experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. We herein investigate EAE-associated gut intestinal dysfunction and the effect of OA treatment. Methods: Mice with MOG-induced EAE were treated with OA or vehicle from immunization day and were daily analyzed for clinical deficit. We performed molecular and histological analysis in serum and intestinal tissues to measure oxidative and inflammatory responses. We used Caco-2 and HT29-MTX-E12 cells to elucidate OA in vitro effects. Results: We found that OA protected from EAE-induced changes in intestinal permeability and preserved the mucin-containing goblet cells along the intestinal tract. Serum levels of the markers for intestinal barrier damage iFABP and monocyte activation sCD14 were consistently and significantly reduced in OA-treated EAE mice. Beneficial OA effects also included a decrease of pro-inflammatory mediators both in serum and colonic tissue of treated-EAE mice. Moreover, the levels of some immunoregulatory cytokines, the neurotrophic factor GDNF, and the gastrointestinal hormone motilin were preserved in OA-treated EAE mice. Regarding oxidative stress, OA treatment prevented lipid peroxidation and superoxide anion accumulation in intestinal tissue, while inducing the expression of the ROS scavenger Sestrin-3. Furthermore, short-chain fatty acids (SCFA) quantification in the cecal content showed that OA reduced the high iso-valeric acid concentrations detected in EAE-mice. Lastly, using in vitro cell models which mimic the intestinal epithelium, we verified that OA protected against intestinal barrier dysfunction induced by injurious agents produced in both EAE and MS. Conclusion: These findings reveal that OA ameliorates the gut dysfunction found in EAE mice. OA normalizes the levels of gut mucosal dysfunction markers, as well as the pro- and anti-inflammatory immune bias during EAE, thus reinforcing the idea that OA is a beneficial compound for treating EAE and suggesting that OA may be an interesting candidate to be explored for the treatment of human MS., This work was supported by Ministerio de Economía y Competitividad (SAF2016-81063 and PID2019-111788RB-I00) and Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (FEDER) (PI18/00257), CIBERCV a way to build Europe, and BG and IG were funded by the FPI Program from the Government of Castilla y León (co-funded by FSE).

Introduction There is currently no universally accepted definition of asthma−COPD overlap (ACO). Objective To compare the prevalence of ACO in patients with asthma or COPD, and to assess their clinical characteristics and the capacity of the different definitions to predict the risk of exacerbation. Method Prospective observational study with a 12-month follow-up in an asthma cohort and a COPD cohort. Four diagnostic criteria were compared: A) the Spanish 2012 consensus; B) the 2016 international consensus; C) the 2017 consensus between the Spanish COPD guidelines (GesEPOC) and GEMA asthma guidelines; and D) the single criterion of ≥300 eosinophils/μL, proposed by GOLD 2019. The risk of exacerbations was evaluated in each group. Results A total of 345 patients were included, 233 (67.5%) with COPD and 112 (32.5%) with asthma, aged 63 ± 14 years, 70.4% men. Fifteen (4.3%) patients met the criteria for ACO according to the criteria described under A above; 30 (8.7%) with the criteria of B; 118 (34.2%) with the criteria of C; and 97 (28.1%), with the D criterion. The ACO-COPD subtype were older, had worse lung function, and an increased risk of exacerbation compared with the ACO-asthma group. Of all the definitions evaluated, those which distinguished a higher risk of exacerbations were the GesEPOC-GEMA consensus and the GOLD proposal. Conclusions The prevalence of ACO varies enormously depending on the diagnostic criteria used. The ACO population is heterogeneous, and the ACO-COPD subtype is very different from the ACO-asthma subtype. The definitions that include eosinophilia identify ACO patients with a greater risk of exacerbation.

Resumen Introduccion En la actualidad no disponemos de una definicion de solapamiento asma-EPOC (ACO) universalmente aceptada. Objetivo Comparar la prevalencia del ACO en pacientes con asma o EPOC, valorar sus caracteristicas clinicas y la capacidad predictiva de riesgo de agudizacion de las diferentes definiciones. Metodo Estudio prospectivo observacional con seguimiento de 12 meses sobre una cohorte de asma y otra con EPOC. Se comparan 4 criterios diagnosticos: A) el consenso espanol del 2012; B) el consenso internacional del 2016; C) el consenso entre la guia espanola de la EPOC (GesEPOC) y la del asma (GEMA) del 2017; y D) el criterio unico de ≥ 300 eosinofilos/μl, propuesto por GOLD 2019. En cada grupo se evaluo el riesgo de agudizaciones. Resultados Se incluyeron 345 pacientes, 233 (67,5%) con EPOC y 112 (32,5%) con asma, con una edad de 63 ± 14 anos; el 70,4% eran hombres. Quince (4,3%) pacientes cumplian criterios de ACO con criterios A; 30 (8,7%) con los B; 118 (34,2%) con los C; y 97 (28,1%) con el criterio D. El subtipo ACO-EPOC presento mas edad, peor funcion pulmonar y mayor riesgo de agudizacion que los ACO-asma. De todas las definiciones evaluadas, las que presentaron mayor riesgo de agudizaciones fueron la del consenso GesEPOC-GEMA y la propuesta de GOLD. Conclusiones La prevalencia de ACO varia enormemente en funcion del criterio diagnostico utilizado. La poblacion de ACO es heterogenea, con un subtipo ACO-EPOC muy diferente al ACO-asma. Las definiciones que incluyen la eosinofilia identifican a los ACO de mas riesgo de agudizacion.

En esta investigación se toma como referencia el concepto de Educación 4.0 y sus características para poner en tensión las experiencias que, en el marco de la situación de pandemia por Coronavirus ocurrida durante el año 2020, han servido como escenario piloto para validar las capacidades y desafíos de las Instituciones de Educación Superior latinoamericanas frente al entorno de transformación digital global que atraviesa la humanidad. Este análisis permite realizar una primera aproximación sobre las urgencias, prioridades y posibles rutas de desarrollo a nivel político, institucional y profesoral en busca de la calidad y pertinencia educativa que demanda el contexto actual. Se evidencia el reduccionismo tecnológico con el que muchas instituciones han afrontado la situación de transición a clases remotas y, en segundo lugar, la necesidad de incorporar la transformación digital en la visión de desarrollo educativo por parte de las universidades.

La apropiación de las competencias digitales y el uso de las herramientas tecnológicas disponibles son factores determinantes en el logro de objetivos y la satisfacción del proceso de enseñanza-aprendizaje remoto, que ha sido protagonista en tiempos de COVID-19. Estos factores tienen impactos diferentes en las distintas áreas de conocimiento; por ejemplo, el desarrollo curricular y metodológico se complejizan de acuerdo con el nivel de uso y experticia previo de estudiantes y docentes. En esta investigación analizamos las percepciones de los docentes y estudiantes de América Latina sobre el proceso de enseñanza-aprendizaje 212 intermediado por medios digitales al que nos hemos visto expuestos tras la pandemia. Nuestro análisis se realiza por áreas de conocimiento, para lograr un dimensionamiento de las afectaciones en el cumplimiento de objetivos de aprendizaje, esfuerzos y retos a los que se han visto expuestos los miembros de la comunidad académica. Como base metodológica se toma el análisis de encuestas aplicadas en Instituciones de Educación Superior públicas y privadas de Bolivia, Ecuador, Colombia, Paraguay, Uruguay y Perú. Los resultados muestran la necesidad de mantener y cultivar una visión más abierta e innovadora frente a las herramientas tecnológicas y competencias digitales que se involucran cada vez más en la educación. Resulta importante fortalecer los procesos de relación entre los estudiantes y los docentes a través de acompañamiento psicológico y programas de bienestar, que generen un sentido de pertenencia a una institución, un programa académico y una comunidad, que motive a continuar desarrollando con calidad sus respectivas funciones en el proceso educativo Primera edición

En esta investigación se expresa una visión en torno a la cualificación de los profesores para afrontar el enfoque de formación que emergió a partir de la situación de emergencia sanitaria declarada en el año 2020 en América Latina. Presentaremos una descripción de variables influyentes y de discursos profesorales relacionados con la cualificación de los docentes universitarios, que va desde la fortaleza que ha representado para algunos profesores hasta las situaciones que deben mejorarse para articularse adecuadamente con las competencias digitales necesarias. Surge la necesidad de incorporar caminos permanentes de cualificación digital como medio que permita contribuir al mejoramiento del proceso de enseñanza-aprendizaje. Nuestro objetivo es profundizar las condiciones sobre las cuales se han desarrollado los procesos de enseñanza-aprendizaje en el marco de la emergencia sanitaria, para identificar los aspectos de contexto de América Latina, así como las principales brechas existentes para coadyuvar a la identificación de caminos de mejoramiento a nivel estratégico, táctico y operativo. Primera edición

Resumen Los pacientes con COVID-19 grave pueden desarrollar restricciones dolorosas del rango de movimiento de las grandes articulaciones debido a osificaciones heterotopicas. Presentamos el caso de un paciente que desarrollo dolor en las caderas despues de un ingreso prolongado por neumonia COVID-19 severa. La radiografia convencional, la tomografia computrarizada y la gammagrafia osea mostraron extensas osificaciones heterotopicas en caderas. Es probable que tanto factores locales como sistemicos contribuyan al desarrollo de osificaciones heterotopicas y es necesario descartar esta entidad cuando estos pacientes refieran dolor articular. El diagnostico precoz es importante para proporcionar intervenciones no farmacologicas como la movilizacion pasiva suave y medicacion antiinflamatoria y en casos refractarios considerar la reseccion quirurgica del hueso ectopico.

We have evaluated the role of mitochondrial oxidative stress and its association with endoplasmic reticulum (ER) stress activation in the progression of obesity-related cardiovascular fibrosis. MitoQ (200 µM) was orally administered for 7 weeks to male Wistar rats that were fed a high-fat diet (HFD, 35% fat) or a control diet (CT, 3.5% fat). Obese animals presented cardiovascular fibrosis accompanied by increased levels of extracellular matrix proteins and profibrotic mediators. These alterations were associated with ER stress activation characterized by enhanced levels (in heart and aorta vs. CT group, respectively) of immunoglobulin binding protein (BiP, 2.1-and 2.6-fold, respectively), protein disulfide-isomerase A6 (PDIA6, 1.9-fold) and CCAAT-enhancer-binding homologous protein (CHOP, 1.5- and 1.8-fold, respectively). MitoQ treatment was able to prevent (p &lt, 0.05) these modifications at cardiac and aortic levels. MitoQ (5 nM) and the ER stress inhibitor, 4-phenyl butyric acid (4 µM), were able to block the prooxidant and profibrotic effects of angiotensin II (Ang II, 10−6 M) in cardiac and vascular cells. Therefore, the data show a crosstalk between mitochondrial oxidative stress and ER stress activation, which mediates the development of cardiovascular fibrosis in the context of obesity and in which Ang II can play a relevant role.

El estudio revisa las condiciones en términos de políticas, capacidades, resultados y nuevas tecnologías que marcan la ruta de desarrollo de la ciencia, la tecnología y la innovación (CTeI), desde una perspectiva global, para la construcción de un escenario con tendencias regionales, fundamentado en la gestión del conocimiento. El marco de política a nivel mundial, nacional y regional presenta un enfoque de desarrollo sostenible en que la CTeI es soporte para la solución de problemas ambientales, sociales y económicos. Las capacidades científicas y tecnológicas a nivel regional se encuentran en desarrollo con importantes apuestas hacia la formación de talento humano, la publicación científica de alto impacto y la gestión de la innovación, especialmente empresarial; dando como resultado un comportamiento creciente de los indicadores de CTeI con importantes retos de cara a su consolidación, entre ellos la articulación efectiva con el sector empresarial y social, la disminución de brechas digitales, así como el fortalecimiento de la infraestructura y la especialización para el uso de nuevas tecnologías que son clave en el desarrollo de CTeI de alto nivel como la inteligencia artificial, la computación cuántica, las realidades extendidas y el registro distribuido. Este escenario marca una tendencia favorable para la construcción de bases científicas y tecnológicas a nivel regional, que orienten el desarrollo de estructuras sociales y económicas basadas en el conocimiento.

Este estudio realiza contribuciones a la medición de la calidad en la educación superior. Mediante revisión documental y análisis del discurso, se revisan los factores relevantes en los modelos de gestión de la investigación de las universidades confesionales acreditadas de alta calidad en Colombia, contrastando aspectos propios de la identidad humanista cristiana con los estándares de medición formalmente establecidos por el Ministerio de Educación. Se concluye que estos aspectos que soportan la filosofía institucional aparentemente comienzan a ocupar un segundo plano en las prioridades de estas universidades, lo que da paso a la estandarización educativa medida por indicadores de resultado.

This article belongs to the Special Issue Cells in Cardiovascular Disease., Secreted phospholipase A2-IIA (sPLA2-IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA2-IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA2-IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA2-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA2-IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA2-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA2-IIA. In conclusion, sPLA2-IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects., This work was supported by grants from Plan Estatal I+D+i: MINECO SAF2012-34460 and SAF2016-81063; ISCII PI18/010257729; and CIBERCV. The study was co-funded by Fondo Europeo de Desarrollo Regional (FEDER), a way to make Europe. RM was supported by the Sara Borrell Program from ISCIII; BG and CC were funded by the FPI Program from the Government of Castilla y León (all co-funded by FSE).

To explore the impact of obesity on the cardiac lipid profile in rats with diet-induced obesity, as well as to evaluate whether or not the specific changes in lipid species are associated with cardiac fibrosis. Methods: Male Wistar rats were fed either a high-fat diet (HFD, 35% fat) or standard diet (3.5% fat) for 6 weeks. Cardiac lipids were analyzed using by liquid chromatography-tandem mass spectrometry. Results: HFD rats showed cardiac fibrosis and enhanced levels of cardiac superoxide anion (O 2 ), HOMA index, adiposity, and plasma leptin, as well as a reduction in those of cardiac glucose transporter (GLUT 4), compared with control animals. Cardiac lipid profile analysis showed a significant increase in triglycerides, especially those enriched with palmitic, stearic, and arachidonic acid. An increase in levels of diacylglycerol (DAG) was also observed. No changes in cardiac levels of diacyl phosphatidylcholine, or even a reduction in total levels of diacyl phosphatidylethanolamine, diacyl phosphatidylinositol, and sphingomyelins (SM) was observed in HFD, as compared with control animals. After adjustment for other variables (oxidative stress, HOMA, cardiac hypertrophy), total levels of DAG were independent predictors of cardiac fibrosis while the levels of total SM were independent predictors of the cardiac levels of GLUT 4. Conclusions: These data suggest that obesity has a significant impact on cardiac lipid composition, although it does not modulate the different species in a similar manner. Nonetheless, these changes are likely to participate in the cardiac damage in the context of obesity, since total DAG levels can facilitate the development of cardiac fibrosis, and SM levels predict GLUT4 levels, This work was supported by funds from the Sociedad Española de Arteriosclerosis (Basic Research Award 2015), from Plan Estatal I+D+I 2013-2016: PI15/01060 and SAF2016-81063. The study was cofunded by Fondo Europeo de Desarrollo Regional (FEDER), a way to build Europe

The impact of the mitochondria-targeted antioxidant MitoQ was evaluated in the metabolic alterations and the adipose tissue remodeling associated with obesity. Male Wistar rats were fed either a high-fat diet (HFD; 35% fat) or a standard diet (3.5% fat) for 7 wk and treated with MitoQ (200 µM). A proteomic analysis of visceral adipose tissue from patients with obesity and patients without obesity was performed. MitoQ partially prevented the increase in body weight, adiposity, homeostasis model assessment index, and adipose tissue remodeling in HFD rats. It also ameliorated protein level changes of factors involved in insulin signaling observed in adipose tissue of obese rats: reductions in adiponectin and glucose transporter 4 (GLUT 4) and increases in dipeptidylpeptidase 4, suppressor of cytokine signaling 3 (SOCS3), and insulin receptor substrate 1 phosphorylation. MitoQ prevented down-regulation of adiponectin and GLUT 4 and increases in SOCS3 levels in a TNF-α-induced insulin-resistant 3T3-L1 adipocyte model. MitoQ also ameliorated alterations in mitochondrial proteins observed in obese rats: increases in cyclophylin F and carnitine palmitoyl transferase 1A and reductions in mitofusin1, peroxiredoxin 4, and fumarate hydratase. The proteomic analysis of the visceral adipose tissue from patients with obesity show alterations in mitochondrial proteins similar to those observed in obese rats. Therefore, the data show the beneficial effect of MitoQ in the metabolic dysfunction induced by obesity.-Marín-Royo, G., Rodríguez, C., Le Pape, A., Jurado-López, R., Luaces, M., Antequera, A., Martínez-González, J., Souza-Neto, F. V., Nieto, M. L., Martínez-Martínez, E., Cachofeiro, V. The role of mitochondrial oxidative stress in the metabolic alterations in diet-induced obesity in rats., This work was supported by Instituto de Salud Carlos III–Fondo Europeo de Desarrollo Regional (FEDER) [PI15/01060, PI18/00257, PI18/0919, and Ciber de Enfermedades Cardiovasculares (CIBERCV)], a Way to Build Europe, Ministerio de Economia y Competitividad (SAF2016-81063), and Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR; Program of Support to Research Groups, 2017-SGR-00333). E.M.-M. was supported by a contract from Complementary and Alternative Medicine (Comunidad Autónoma de Madrid) (Atracción de Talento).

Cardiac lipotoxicity is involved in the cardiac functional consequences associated with obesity. Therefore, the aim of this study was to explore whether changes in the mitochondrial lipid cardiac profile could reflect differences in cardiac function and structure in obese and non-obese rats with myocardial infarction (MI). Whether these changes can also be reflected in a specific plasma miRNA signature as markers of cardiac damage was also evaluated. Rats were fed with either standard (3.5% fat) or high fat diet (35% fat) for 6 weeks before the induction of MI and sacrificed 4 weeks later. MI showed cardiac lipotoxicity independently of the presence of obesity, although obese and non-obese rats did not present the same cardiac lipid profile at mitochondrial level. Several cardiac lipid species in mitochondria, including cardiolipins and triglycerides, were associated with myocardial fibrosis, with mitochondrial triglyceride levels being independently associated with it; this supports that lipotoxicity can affect cardiac function. MI down-regulated plasma levels of miRNA 15b-5p and 194-5p in obese and non-obese animals, which were associated with cardiac function, mitochondrial lipids and myocardial fibrosis, with miRNA 15b-5p levels being independently associated with cardiac fibrosis. This could support that lipotoxicity could affect heart function by modulating plasma miRNAs., This work was supported by Instituto de Salud Carlos III-FondoEuropeo de Desarrollo Regional (FEDER) (PI15/01060; CIBERCV) a way to build Europe, Ministerio de Economia y Competitividad (SAF2016-81063) and from the Sociedad Española de Cardiología (Basic Research in Cardiology 2016). EMM was supported by a contract from CAM (Atracción de talento).

Obesity is accompanied by metabolic alterations characterized by insulin resistance and cardiac lipotoxicity. Galectin-3 (Gal-3) induces cardiac inflammation and fibrosis in the context of obesity; however, its role in the metabolic consequences of obesity is not totally established. We have investigated the potential role of Gal-3 in the cardiac metabolic disturbances associated with obesity. In addition, we have explored whether this participation is, at least partially, acting on mitochondrial damage. Gal-3 inhibition in rats that were fed a high-fat diet (HFD) for 6 weeks with modified citrus pectin (MCP; 100 mg/kg/day) attenuated the increase in cardiac levels of total triglyceride (TG). MCP treatment also prevented the increase in cardiac protein levels of carnitine palmitoyl transferase IA, mitofusin 1, and mitochondrial complexes I and II, reactive oxygen species accumulation and decrease in those of complex V but did not affect the reduction in 18F-fluorodeoxyglucose uptake observed in HFD rats. The exposure of cardiac myoblasts (H9c2) to palmitic acid increased the rate of respiration, mainly due to an increase in the proton leak, glycolysis, oxidative stress, β-oxidation and reduced mitochondrial membrane potential. Inhibition of Gal-3 activity was unable to affect these changes. Our findings indicate that Gal-3 inhibition attenuates some of the consequences of cardiac lipotoxicity induced by a HFD since it reduced TG and lysophosphatidyl choline (LPC) levels. These reductions were accompanied by amelioration of the mitochondrial damage observed in HFD rats, although no improvement was observed regarding insulin resistance. These findings increase the interest for Gal-3 as a potential new target for therapeutic intervention to prevent obesity-associated cardiac lipotoxicity and subsequent mitochondrial dysfunction., This work was supported by Instituto de Salud Carlos III – European Regional Development Fund (Fondo Europeo de Desarrollo Regional) [grant number: PI15/01060; CIBERCV] a way to build Europe. Ministerio de Economía y Competitividad [grant numbers: SAF2012-34460 and SAF2016-81063], the FPI Program del Gobierno de Castilla y León (co-funded by FSE). NL-A was supported by a Miguel Servet grant CP13/00221 from the Instituto de Salud Carlos III – European Regional Development Fund (Fondo Europeo de Desarrollo Regional), a way to build Europe, Fondo de Investigaciones Sanitarias [PI15/02160].

We have investigated whether mineralocorticoid receptor activation can participate in the profibrotic effects of leptin in cardiac myofibroblasts, as well as the potential mechanisms involved. The presence of eplerenone reduced the leptin-induced increase in protein levels of collagen I, transforming growth factor β, connective tissue growth factor and galectin-3 and the levels of both total and mitochondrial of superoxide anion (O2 . −) in cardiac myofibroblasts. Likewise, the MEK/ERK inhibitor, PD98059, and the PI3/Akt inhibitor, LY294002, showed a similar pattern. Mitochondrial reactive oxygen species (ROS) scavenger (MitoTempo) attenuated the increase in body weight observed in rats fed a high fat diet (HFD). No differences were found in cardiac function or blood pressure among any group. However, the cardiac fibrosis and enhanced O2 .-levels observed in HFD rats were attenuated by MitoTempo, which also prevented the increased circulating leptin and aldosterone levels in HFD fed animals. This study supports a role of mineralocorticoid receptor in the cardiac fibrosis induced by leptin in the context of obesity and highlights the role of the mitochondrial ROS in this process., This work was supported by Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (FEDER) (PI15/01060; RD12/0042/0024, RD12/0042/0026 and RD12/0042/0033, CIBERCV; Miguel Servet contract CP13/00221) a way to build Europe. Ministerio de Economia y Competitividad (SAF2012-34460 and SAF2016-81063), the FPI Program del Gobierno de Castilla y León (co-funded by FSE) and COST ADMIRE network (BM1301).

[Background] Atherosclerotic plaque formation is characterized by recruitment of monocytes/macrophages, which contributes to its calcification by releasing pro-osteogenic cytokines. Chemotaxis-related proteins, including netrin-1, gremlin-1 and macrophage inflammatory protein-1β (MIP-1β), regulate immune cell migration. However, their relation with the presence of subclinical atherosclerosis, assessed by measures of coronary artery calcifications (CAC) in patients without known coronary artery disease (CAD), remains unclear., [Aims] To examine whether these chemoattractant-related proteins are associated with the presence of CAC in patients without known CAD., [Methods] A retrospective case-control observational study was conducted in 120 outpatients without CAD, undergoing a CAC evaluation by computed tomography with the Agatston Calcium score, categorized as CAC− (none) and CAC+ (≥ 1). Serum biomarkers were quantified by ELISA., [Results] Lpa, dyslipidaemia and smoking were significantly higher (p = 0.006, p ≤ 0.0001 and p = 0.001, respectively) in CAC+ patients. Serum netrin-1 levels were lower in CAC+ than in CAC− patients (196.8 ± 127.8 pg/ml versus 748.3 ± 103.2 pg/ml, p ≤ 0.0001), and a similar pattern was found for gremlin-1 (1.14 ± 0.39 ng/ml versus 4.33 ± 1.20 ng/ml, p ≤ 0.0001). However, TNFα and MIP-1β were strongly upregulated in CAC+ patients (447.56 ± 74 pg/ml versus 1104 ± 144 pg/ml and 402.00 ± 94 pg/ml versus 905.0 ± 101.6 pg/ml, respectively, p ≤ 0.001). Multivariate analyses revealed that low netrin-1 and gremlin-1 levels and high TNFα and MIP-1β amounts were associated with CAC presence, after adjustment for clinical and biochemical variables., [Conclusions] We found a netrin-1 and gremlin-1 deficiency and a TNFα and MIP-1β overproduction in CAC+ patients' serum. These proteins may be used to identify individuals with subclinical atherosclerosis. Further research is warranted in a larger cohort of patients to establish these chemotactic-related proteins as biomarkers that improve CAD risk stratification., This work was supported by MINECO: grant SAF2016-81063 to MLN; and by the Government of Castilla y León: grants GRS923/A/14, BIO/VA35/15 and BIO/VA45/14 to JCM and MLN, and the FPI Program co-funded by FSE to BG.

Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications., This work was supported by the FPI Program from the Autonomous Government of Castilla y Leon (to RM and CC) co-funded by FSE, and by the Spanish Ministry of Science and Innovation (grant SAF2009-08407 and SAF2016-81063).

[Background and purpose] Netrin‐1, an axon guidance protein, reduces serum levels of pro‐inflammatory mediators and stabilizes the blood−brain barrier limiting the entrance of immune cells into the central nervous system. The aim was to investigate its presence in the experimental autoimmune encephalomyelitis (EAE) model and in multiple sclerosis (MS) patients with and without clinical activity., [Methods] Netrin‐1 levels were evaluated in EAE mouse tissues. Afterwards, serum netrin‐1 was cross‐sectionally quantified in 90 patients with different MS phenotypes and 30 control subjects. An additional group of 10 relapsing−remitting MS (RRMS) patients was longitudinally evaluated throughout a relapse (RRMSr) with an interval of 60 days. Tumour necrosis factor α (TNFα), a reference inflammatory cytokine, and netrin‐1 were quantified by enzyme‐linked immunosorbent assay., [Results] Experimental autoimmune encephalomyelitis mice showed significantly lower netrin‐1 levels and higher TNFα amounts in sera, spinal cord and cerebella than healthy control mice. MS patients showed significantly lower serum netrin‐1 levels than controls (511.62 ± 209.30 and 748.32 ± 103.24 pg/ml, respectively; P ≤ 0.005). The lowest protein levels were found in RRMSr, remaining significantly lower throughout the relapse. TNFα serum concentrations were higher in MS patients compared to controls, and negatively correlated with netrin‐1 levels (r = −0.3734, P ≤ 0.0001)., [Conclusions] Netrin‐1 decreased in EAE and in MS patients, mainly during relapse, suggesting an anti‐inflammatory role of netrin‐1. Further research should be performed in a larger cohort of patients to validate netrin‐1 as a biomarker of MS inflammatory activity., This study was supported by MINECO (grants SAF2012‐34460 and ISCIII‐PI080441). CC, BG and IG were supported by the FPI‐Junta de Castilla y León Program, Spain (FSE co‐funded).

BACKGROUND AND PURPOSE Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating diseases that develop as a result of deregulated immune responses causing glial activation and destruction of CNS tissues. Oleanolic acid and erythrodiol are natural triterpenes that display strong anti-inflammatory and immunomodulatory activities. Oleanolic acid beneficially influences the course of established EAE. We now extend our previous observations to erythrodiol and address the efficacy of both compounds to protect against EAE, given under different regimens.

et al., [Introduction]: Different alcoholic beverages exert different effects on inflammation and oxidative stress but these results are controversial and scanty in some aspects. We analyze the effect of different alcoholic beverages after a fat-enriched diet on lipid profile, inflammatory factors and oxidative stress in healthy people in a controlled environment. [Methods]: We have performed a cross-over design in five different weeks. Sixteen healthy volunteers have received the same oral fat-enriched diet (1486 kcal/m) and a daily total amount of 16 g/m of alcohol, of different beverages (red wine, vodka, brandy or rum) and equivalent caloric intakes as sugar with water in the control group. We have measured the levels of serum lipids, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNFα), interleukin 6 (IL-6), soluble phospholipase A2 (sPLA2), lipid peroxidation (LPO) and total antioxidant capacity (TAC). [Results]: Red wine intake was associated with decreased of mean concentrations of hsCRP, TNFα and IL-6 induced by fat-enriched diet (p < 0.05); nevertheless, sPLA2 concentrations were not significantly modified. After a fat-enriched diet added with red wine, TAC increased as compared to the same diet supplemented with rum, brandy, vodka or the control (water with sugar) (p < 0.05). [Conclusions]: Moderate red wine intake, but not other alcoholic beverages, decreased pro-inflammatory factors and increased total antioxidant capacity despite a fat-enriched diet intake in healthy young volunteers., [Introducción]: El efecto de las bebidas alcohólicas sobre la inflamación y el estrés oxidativo es variable y solo parcialmente conocido. [Objetivo]: Analizar el efecto de diferentes bebidas alcohólicas sobre el perfil lipídico, factores de inflamación y estrés oxidativo en personas sanas con ingesta de una dieta enriquecida en grasas. [Métodos]: Se diseñó un estudio cruzado durante cinco semanas. Dieciséis voluntarios sanos recibieron la misma dieta enriquecida con grasa oral (1.486 kcal/m2) más 16 g/m2 de alcohol diarios, consumido como vino tinto, vodka, brandy o ron, o un equivalente calórico en el grupo control (azúcar y agua). Se midieron lípidos en suero, proteína C reactiva de alta sensibilidad (PCR-as), factor de necrosis tumoral (TNF) α, interleucina 6 (IL-6), fosfolipasa A2 soluble (sPLA2), la peroxidación lipídica (LPO) y la capacidad antioxidante total (TAC). [Resultados]: La ingesta de vino tinto se asoció con una disminución significativa de las concentraciones de PCR-as, TNFα e IL-6, inducida por una dieta rica en grasas (p

License Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0)., Stroke is considered the most common and severely disabling neurological disease. It is one of the leading causes of death after heart disease and cancer, causing 10% deaths worldwide and involving risk factors such as smoking, obesity and nutritional disbalance. Disability affects 75% of stroke survivors through severe mental and/or physical impairment depending on the affected brain area (Go et al., 2014)., This work was supported by UBACYT 20020130100258BA (A.B.), PIP CONICET 00269 (A.B.) and UBACYT 20020130300033BA (L.C.).

Group IIA secreted phospholipase A2 (sPLA2-IIA) is the most abundant element in human tissues of a large family of low molecular weight phospholipases A2, which shows properties different from those displayed by the cytosolic phospholipase A2 involved in the release of arachidonic acid. sPLA2-IIA behaves as a ligand for a group of receptors inside the C-type multilectin mannose receptor family and also interacts with heparan sulfate proteoglycans such as glypican, the dermatan/chondroitin sulfate-rich decorin, and the chondroitin sulfate-rich versican, thus being able to internalize to specific compartments within the cell and producing biological responses. This review provides a short summary of the biological actions of sPLA2-IIA on intracellular signaling pathways. © 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved., L.F. was supported by a grant from Sociedad Española de Cardiología. This work was supported by grants from Plan Nacional de Salud y Farmacia (Grant SAF98-0176), FIS (Grant 00/0393) and CICYT and European Commission (Grant 1FD-2325).

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that elicits cell responses by activating the mitogen-activated protein kinase (MAP kinase) cascade and transcription factors such as nuclear factor-kappaB (NF-kappaB). As these elements play a central role in the mechanisms of signaling involved in the activation of cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), the effect of TNF-alpha on arachidonate (AA) metabolism in 1321N1 astrocytoma cells was assayed. TNF-alpha produced a phosphorylation of cPLA2, which was preceded by an activation of both c-Jun N-terminal kinase (JNK) and p38-MAP kinase, and this was associated with the release of [3H]AA. In contrast, TNF-alpha did not activate the extracellular signal-regulated kinase (MAP kinase) p42, nor did it elicit a mitogenic response. Analysis of [3H]AA metabolites by reverse-phase HPLC showed that all of the [3H]AA released during the first hour after TNF-alpha addition eluted as authentic AA, whereas in samples obtained at 24 h after addition of TNF-alpha, 25% of the [3H]AA had been converted into COX products as compared with only 9% in control cells. In keeping with these findings, TNF-alpha produced an increase of COX-2 expression, as judged from both RT-PCR studies and immunoblot of COX-2 protein, and a long-lasting activation of NF-kappaB. These data show that TNF-alpha produces in astrocytoma cells an early activation of both p38-MAP kinase and JNK, which is followed by the phosphorylation of cPLA2 and the release of AA. On the other hand, the activation of NF-kappaB may explain the induction of the expression of COX-2 and the delayed generation of prostanoids.

Producción Científica, Type IIA secretory phospholipase A2 (sPLA2) is an acute-phase reactant that plays a role in atherogenesis and is expressed in atherosclerotic arterial walls displaying inflammatory features. This generates a relevant question addressing the biological effects of this enzyme on monocytic cells, in view of the role of these cells in the inflammatory process associated with atherosclerosis. sPLA2 produced a mild activation of the p42 mitogen-activated protein module of the mitogen-activated protein kinase (MAPK) cascade and a prominent activation of c-Jun N-terminal kinase in THP-1 monocytes. This activation showed both an early and a late peak, different from that elicited by tumor necrosis factor-α (TNF-α), which only showed the first peak. This was accompanied by activation of arachidonate metabolism, as judged from both the activation of the cytosolic phospholipase A2 (cPLA2) and the induction of cyclooxygenase-2 (COX-2) expression. sPLA2 also elicited the production of monocyte chemoattractant protein-1 (MCP-1) and showed a synergistic effect with TNF-α on both COX-2 induction and MCP-1 production. sPLA2 upregulated the expression of Fas ligand at the cell surface, but it did not influence Fas expression nor cell survival of monocytes. In summary, these data indicate that some of the atherogenic effects of sPLA2 can be exerted by engagement of an sPLA2-binding structure on monocytic cells, most probably the M-type receptor for sPLA2, which produces the activation of the MAPK cascade, induces a proinflammatory phenotype, and upregulates the cell surface expression of Fas ligand., Plan Nacional de Salud y Farmacia (grant SAF98/0176), Comisión Interministerial de Ciencia y Tecnología - Comisión Europea (grant 1FD97-0590), Fondo de Investigación Sanitaria (grant FIS00/0393)

Ischemic brain injury is a dynamic process involving oxidative stress, inflammation, cell death and the activation of endogenous adaptive and regenerative mechanisms depending on the activation of transcription factors such as hypoxia-inducible factor 1-alpha. Accordingly, we have previously described a new focal hypoxia model by direct intracerebral cobalt chloride injection. In turn, oleanolic acid, a plantderived triterpenoid, has been extensively used in Asian countries for its anti-inflammatory and antitumor properties. A variety of novel pharmacological effects have been attributed to this triterpenoid, including beneficial effects on neurodegenerative disorders - including experimental autoimmune encephalomyelitis - due to its immunomodulatory activities at systemic level, as well as within the central nervous system. In this context, we hypothesize that this triterpenoid may be capable of exerting neuroprotective effects in ischemic brain, suppressing glial activities that contribute to neurotoxicity while promoting those that support neuronal survival. In order to test this hypothesis, we used the intraperitoneal administration of oleanoic acid in adult rats for seven days previous to focal cortical hypoxia induced by cobalt chloride brain injection. We analyzed the neuroprotective effect of oleanoic acid from a morphological point of view, focusing on neuronal survival and glial reaction., This study is supported by grants UBACYT000093 (A.B.)