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Microglia, the resident macrophage-like population in the CNS, plays an important role in the pathogenesis of many neurodegenerative disorders. Nectandra genus is known to produce different metabolites with anti-inflammatory, anti-oxidant and analgesic properties. Although the species Nectandra angustifolia is popularly used for the treatment of different types of inflammatory processes, its biological effects on neuroinflammation have not yet been addressed. In this study, we have investigated the role of a Nectandra angustifolia ethanolic extract (NaE) in lipopolysaccharide (LPS)-induced neuroinflammation in vitro and in vivo. In LPS-activated BV2 microglial cells, NaE significantly reduced the induced proinflammatory mediators TNF-α, IL-1β, IL-6, COX-2 and iNOS, as well as NO accumulation, while it promoted IL-10 secretion and YM-1 expression. Likewise, reduced CD14 expression levels were detected in microglial cells in the NaE+LPS group. NaE also attenuated LPS-induced ROS and lipid peroxidation build-up in BV2 cells. Mechanistically, NaE prevented NF-κB and MAPKs phosphorylation, as well as NLRP3 upregulation when added before LPS stimulation, although it did not affect the level of some proteins related to antioxidant defense such as Keap-1 and HO-1. Additionally, we observed that NaE modulated some activated microglia functions, decreasing cell migration, without affecting their phagocytic capabilities. In LPS-injected mice, NaE pre-treatment markedly suppressed the up-regulated TNF-α, IL-6 and IL-1β mRNA expression induced by LPS in brain. Our findings indicate that NaE is beneficial in preventing the neuroinflammatory response both in vivo and in vitro. NaE may regulate microglia homeostasis, not only restraining activation of LPS towards the M1 phenotype but promoting an M2 phenotype.

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.

Multiple sclerosis (MS) is a CNS inflammatory demyelinating disease. Recent investigations highlight the gut-brain axis as a communication network with crucial implications in neurological diseases. Thus, disrupted intestinal integrity allows the translocation of luminal molecules into systemic circulation, promoting systemic/brain immune-inflammatory responses. In both, MS and its preclinical model, the experimental autoimmune encephalomyelitis (EAE) gastrointestinal symptoms including “leaky gut” have been reported. Oleacein (OLE), a phenolic compound from extra virgin olive oil or olive leaves, harbors a wide range of therapeutic properties. Previously, we showed OLE effectiveness preventing motor defects and inflammatory damage of CNS tissues on EAE mice. The current studies examine its potential protective effects on intestinal barrier dysfunction using MOG35-55-induced EAE in C57BL/6 mice. OLE decreased EAE-induced inflammation and oxidative stress in the intestine, preventing tissue injury and permeability alterations. OLE protected from EAE-induced superoxide anion and accumulation of protein and lipid oxidation products in colon, also enhancing its antioxidant capacity. These effects were accompanied by reduced colonic IL-1β and TNFα levels in OLE-treated EAE mice, whereas the immunoregulatory cytokines IL-25 and IL-33 remained unchanged. Moreover, OLE protected the mucin-containing goblet cells in colon and the serum levels of iFABP and sCD14, markers that reflect loss of intestinal epithelial barrier integrity and low-grade systemic inflammation, were significantly reduced. These effects on intestinal permeability did not draw significant differences on the abundance and diversity of gut microbiota. However, OLE induced an EAE-independent raise in the abundance of Akkermansiaceae family. Consistently, using Caco-2 cells as an in vitro model, we confirmed that OLE protected against intestinal barrier dysfunction induced by harmful mediators present in both EAE and MS. This study proves that the protective effect of OLE in EAE also involves normalizing the gut alterations associated to the disease.

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.

A proteomic approach was used to characterize potential mediators involved in the improvement in cardiac fibrosis observed with the administration of the mitochondrial antioxidant MitoQ in obese rats. Male Wistar rats were fed a standard diet (3.5% fat; CT) or a high-fat diet (35% fat; HFD) and treated with vehicle or MitoQ (200 μM) in drinking water for 7 weeks. Obesity modulated the expression of 33 proteins as compared with controls of the more than 1000 proteins identified. These include proteins related to endoplasmic reticulum (ER) stress and oxidative stress. Proteomic analyses revealed that HFD animals presented with an increase in cardiac transthyretin (TTR) protein levels, an effect that was prevented by MitoQ treatment in obese animals. This was confirmed by plasma levels, which were associated with those of cardiac levels of both binding immunoglobulin protein (BiP), a marker of ER stress, and fibrosis. TTR stimulated collagen I production and BiP in cardiac fibroblasts. This upregulation was prevented by the presence of MitoQ. In summary, the results suggest a role of TTR in cardiac fibrosis development associated with obesity and the beneficial effects of treatment with mitochondrial antioxidants., This research was funded by Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (FEDER) (PI18/00257, PI21/00431, CIBERCV, Madrid, Spain).

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.

© 2020 by the authors., The impact of the mitochondria-targeted antioxidant MitoQ was evaluated in the cardiac alterations associated with obesity. Male Wistar rats were fed either a high fat diet (HFD, 35% fat) or a standard diet (CT, 3.5% fat) for 7 weeks and treated with MitoQ (200 µM). The effect of MitoQ (5 nM) in rat cardiac myoblasts treated for 24 h with palmitic acid (PA, 200 µM) was evaluated. MitoQ reduced cardiac oxidative stress and prevented the development of cardiac fibrosis, hypertrophy, myocardial 18-FDG uptake reduction, and mitochondrial lipid remodeling in HFD rats. It also ameliorated cardiac mitochondrial protein level changes observed in HFD: reductions in fumarate hydratase, complex I and II, as well as increases in mitofusin 1 (MFN1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and cyclophilin F (cycloF). In vitro, MitoQ prevented oxidative stress and ameliorated alterations in mitochondrial proteins observed in palmitic acid (PA)-stimulated cardiac myoblasts: increases in carnitine palmitoyltransferase 1A, cycloF, and cytochrome C. PA induced phosphorylation of extracellular signal-regulated kinases and nuclear factor-κB p65. Therefore, the data show the beneficial effects of MitoQ in the cardiac damage induced by obesity and suggests a crosstalk between lipotoxicity and mitochondrial oxidative stress in this damage., This work was supported by Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (FEDER) (PI18/00257; PI15/00742; CIBERCV) a way to build Europe, Ministerio de Economia y Competitividad (SAF2016-81063). EMM was supported by a contract from CAM (Atracción de talento).

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.)

This is an open-access article distributed under the terms of the Creative Commons Attribution License., Pollen is the most common aeroallergen to cause seasonal conjunctivitis. The result of allergen exposure is a strong Th2-mediated response along with conjunctival mast cell degranulation and eosinophilic infiltration. Oleanolic acid (OA) is natural a triterpene that displays strong anti-inflammatory and immunomodulatory properties being an active anti-allergic molecule on hypersensitivity reaction models. However, its effect on inflammatory ocular disorders including conjunctivits, has not yet been addressed. Hence, using a Ragweed pollen (RWP)-specific allergic conjunctivitis (EAC) mouse model we study here whether OA could modify responses associated to allergic processes. We found that OA treatment restricted mast cell degranulation and infiltration of eosinophils in conjunctival tissue and decreased allergen-specific Igs levels in EAC mice. Th2-type cytokines, secreted phospholipase A2 type-IIA (sPLA2-IIA), and chemokines levels were also significantly diminished in the conjunctiva and serum of OA-treated EAC mice. Moreover, OA treatment also suppressed RWP-specific T-cell proliferation. In vitro studies, on relevant cells of the allergic process, revealed that OA reduced the proliferative and migratory response, as well as the synthesis of proinflammatory mediators on EoL-1 eosinophils and RBL-2H3 mast cells exposed to allergic and/or crucial inflammatory stimuli such as RWP, sPLA2-IIA or eotaxin. Taken together, these findings demonstrate the beneficial activity of OA in ocular allergic processes and may provide a new intervention strategy and potential therapy for allergic diseases. © 2014 Córdova et al., The study was supported by grants from the Spanish MINECO (reference SAF2009-08407). Patricia Gallego-Muñoz and Claudia Cordova were funded by the FPI Program from the Government of Castilla y León (co-funded by FSE). Rubén Martín was supported by the Sara Borrell Program from the Spanish MINECO.

Myocarditis and dilated cardiomyopathy (DCM) are inflammatory diseases of the myocardium, for which appropriate treatment remains a major clinical challenge. Oleanolic acid (OA), a natural triterpene widely distributed in food and medicinal plants, possesses a large range of biological effects with beneficial properties for health and disease prevention. Several experimental approaches have shown its cardioprotective actions, and OA has recently been proven effective for treating Th1 cell-mediated inflammatory diseases; however, its effect on inflammatory heart disorders, including myocarditis, has not yet been addressed. Therefore, the present study was undertaken to determine the effectiveness of OA in prevention and treatment of experimental autoimmune myocarditis (EAM). The utility of OA was evaluated in vivo through their administration to cardiac α-myosin (MyHc-α614-629)-immunized BALB/c mice from day 0 or day 21 post-immunization to the end of the experiment, and in vitro through their addition to stimulated-cardiac cells. Prophylactic and therapeutic administration of OA dramatically decreased disease severity: the heart weight/body weight ratio as well as plasma levels of brain natriuretic peptide and myosin-specific autoantibodies production were significantly reduced in OA-treated EAM animals, compared with untreated ones. Histological heart analysis showed that OA-treatment diminished cell infiltration, fibrosis and dystrophic calcifications. OA also decreased proliferation of cardiac fibroblast in vitro and attenuated calcium and collagen deposition induced by relevant cytokines of active myocarditis. Furthermore, in OA-treated EAM mice the number of Treg cells and the production of IL-10 and IL-35 were markedly increased, while proinflammatory and profibrotic cytokines were significantly reduced. We demonstrate that OA ameliorates both developing and established EAM by promoting an antiinflammatory cytokine profile and by interfering with the generation of cardiac-specific autoantibodies, as well as through direct protective effects on cardiac cells. Therefore, we envision this natural product as novel helpful tool for intervention in inflammatory cardiomyopathies including myocarditis. © 2014 Elsevier Ltd., This work was supported by Ministerio de Economía y Competitividad (SAF2012-34460), Consejería de la Junta de Castilla y León (BIO 103/VA11/11), Fondo de Investigaciones Sanitarias (PI12/01729), Sara Borrell Programa (to RM) and Junta de Castilla y León FPI Programa (to CC) co-funded by FSE. The authors are members of the Red de Investigación Cardiovascular (RIC; RD12/0042/0033 and RD12/0042/0026).

Human brucellosis is characterized by the presence of both acute inflammatory episodes and chronic inflammation with granuloma formation. On this basis, the proinflammatory effects of smooth lipopolysaccharide of Brucella (S-LPS) were addressed and compared to those of LPS from Escherichia coli. For this purpose, the induction of cyclooxygenase-2 (COX-2), the production of the chemokine monocyte chemoattractant protein-1 (MCP-1), and the activation of the nuclear factor kappa B (NF-kappa B) were studied. S-LPS was found to induce both COX-2 expression and MCP-1 production; however, the potency of E. coli LPS exceeded that of Brucella S-LPS by some orders of magnitude. However, at concentrations above 1 microg/ml, all of the LPS produced comparable effects, including their ability to activate the NF-kappa B system. These observations help explain the inflammatory events associated with Brucella infection and the ability of Brucella to produce monocyte recruitment and granuloma formation.

1. The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the expression of several proteins displaying pro-inflammatory activities the regulation of which is associated to the transcription factor NF-kappaB, was assayed in the human astrocytoma cell line 1321N1. 2. Tumour necrosis factor-alpha (TNF-alpha) activated NF-kappaB as judged from both the appearance of kappaB-binding activity in the nuclear extracts, the degradation of IkappaB proteins in the cell lysates, and the activation of IkappaB kinases using an immunocomplex kinase assay with glutathione S-transferase (GST)-IkappaB proteins as substrates. 3. HTB up to 3 mM did not inhibit the nuclear translocation of NK-kappaB/Rel proteins as judged from electrophoretic mobility-shift assays; however, HTB inhibited the degradation of IkappaBbeta without significantly affecting the degradation of both IkappaBalpha and IkappaBepsilon. 4. In keeping with their inhibitory effect on IkappaBbeta degradation in the cell lysates, both HTB and triflusal inhibited the phosphorylation of GST-IkappaBbeta elicited by TNF-alpha, without affecting the phosphorylation of GST-IkappaBalpha. 5. The effect of both HTB and triflusal on kappaB-dependent trans-activation was studied by assaying the expression of both cyclo-oxygenase-2 (COX-2) and vascular cell adhesion molecule-1 (VCAM-1). HTB and triflusal inhibited in a dose-dependent manner the expression of COX-2 and VCAM-1 mRNA and the induction of COX-2 protein at therapeutically relevant concentrations. 6. These findings show the complexity of the biochemical mechanisms underlying the activation of NF-kappaB in the different cell types and extend the anti-inflammatory effects of HTB and triflusal to neural cells.

The effect of secretory phospholipase A2 (sPLA2) on intracellular Ca2+ signaling in human astrocytoma cells was studied. sPLA2 increased cytosolic [Ca2+] ([Ca2+]c) in both Ca2+-containing and Ca2+-free medium, thus suggesting Ca2+ release from intracellular stores. The activation by sPLA2 of arachidonate release via cytosolic PLA2 (cPLA2) was also independent of extracellular Ca2+. As sPLA2 requires Ca2+ for activity, these results indicate that both Ca2+ mobilization and cPLA2 activation induced by sPLA2 are unrelated to phospholipase activity but dependent on signaling mechanisms. The sPLA2-induced [Ca2+]c peak was sensitive to Bordetella pertussis toxin and inhibited by caffeine, suggesting its mediation by inositol 1,4,5-trisphosphate (IP3). sPLA2 induced tyrosine phosphorylation and membrane targeting of phospholipase Cgamma-1 (PLCgamma-1). Moreover, the Ca2+ peak was sensitive to protein tyrosine kinase inhibitors. sPLA2 activates two signaling pathways: one leading to the activation of the MAP kinase/cPLA2 cascade and another leading to PLCgamma activation and Ca2+ release.

The biological effects of type IIA 14-kDa phospholipase A2 (sPLA2) on 1321N1 astrocytoma cells were studied. sPLA2 induced a release of [3H]arachidonic acid ([3H]AA) similar to that elicited by lysophosphatidic acid (LPA), a messenger acting via a G-protein-coupled receptor and a product of sPLA2 on lipid microvesicles. In contrast, no release of [1-14C]oleate could be detected in cells labeled with this fatty acid. As these findings pointed to a selective mechanism of [3H]AA release, it was hypothesized that sPLA2 could act by a signaling mechanism involving the activation of cytosolic PLA2 (cPLA2), i.e. the type of PLA2 involved in the release of [3H]AA elicited by agonists. In keeping with this view, stimulation of 1321N1 cells with sPLA2 elicited the decrease in electrophoretic mobility that is characteristic of the phosphorylation of cPLA2, as well as activation of p42 mitogen-activated protein (MAP) kinase, c-Jun kinase, and p38 MAP kinase. Incubation with sPLA2 of quiescent 1321N1 cells elicited a mitogenic response as judged from an increased incorporation of [3H]thymidine. Attempts to correlate the effect of extracellular PLA2 with the generation of LPA were negative. Incubation with pertussis toxin prior to the addition of either sPLA2 or LPA only showed abrogation of the response to LPA, thus suggesting the involvement of pertussis-sensitive Gi-proteins in the case of LPA. Treatments with inhibitors of the catalytic effect of sPLA2 such as p-bromophenacyl bromide and dithiothreitol did not prevent the effect on cPLA2 activation. In contrast, preincubation of 1321N1 cells with the antagonist of the sPLA2 receptor p-aminophenyl-alpha-D-mannopyranoside-bovine serum albumin, blocked cPLA2 activation with a EC50 similar to that described for the inhibition of binding of sPLA2 to its receptor. Moreover, treatment of 1321N1 cells with the MAP kinase kinase inhibitor PD-98059 inhibited the activation of both cPLA2 and p42 MAP kinase produced by sPLA2. In summary, these data indicate the existence in astrocytoma cells of a signaling pathway triggered by engagement of a sPLA2-binding structure, that produces the release of [3H]AA by activating the MAP kinase cascade and cPLA2, and leads to a mitogenic response after longer periods of incubation.

Transrectal ultrasound (TRUS)-guided prostate biopsy is the technique of choice for the assessment of clinical suspicion of prostate cancer (PC) based on abnormal digital rectal examination (DRE) and/or elevated or rising levels of prostate-specific antigen (PSA).To identify factors involved in TRUS-guided prostate biopsy, which can be modified by radiologists in order to improve Gleason score (GS) accuracy, and to assess the influence of clinical variables.We carried out a retrospective review of the records of 185 patients with PC treated surgically at our hospital between 2005 and 2008. Biopsy schemes were classified according to the number of cores (≤7, 8-9, 10-11, 12-15) and the needle length (11, 16, 20 mm). Clinical characteristics - age, family history of PC, DRE, PSA levels, and sonographic data - and prostatectomy GS (pGS) were collected.Non-random concordance between biopsy Gleason score (bGS) and pGS was obtained for 36% of patients (P0.001). Under- and over-staging were 30% and 4%, respectively. Concordance was correlated with the core number (45% for ≤7, 54% for 8-9, 85% for 10-11, and 80% for 12-15; P0.001), but not with the needle length. The concordance rate showed a seven-fold increase when 10-11 cores were obtained (95% CI, 2-18; P0.001) compared to those cases in which the core number obtained was ≤7. Among clinical variables, only PSA correlated with concordance, showing an inverse relationship.The Gleason correlation values were not improved when 12 or more cores were collected. These values reached a plateau beyond that number of samples. Therefore, when determining treatment strategies, physicians must consider the biopsy scheme used since it has proven to be a predictor of the accuracy of the PC grading system.

Este artículo es resultado de una exploración exhaustiva de las distintas fuentes primarias y secundarias que evidencian el estado actual del problema en torno a la importancia del desarrollo humano desde el sujeto situado, como una apuesta pertinente para la educación, caracterizándose fundamentalmente por la estrategia de búsqueda bibliográfica y criterios de selección de los libros, textos de divulgación y artículos científicos que den cuenta del concepto de desarrollo humano en su visión tradicional hasta la re-significación del mismo a la luz de los referentes teóricos, conceptuales y metodológicos esbozados por Martha Nussbaum.

Producción Científica, We have investigated mechanisms that contribute to reinforce the relationship between inflammation and cancer. Secreted phospholipase A2 group IIA (sPLA2-IIA) is a molecule relevant in inflammatory events and has been proposed as a marker for some of these. Previously, we reported the mitogenic properties of this sPLA2 in the human astrocytoma cell line 1321N1. Here, we go deeper into the mechanisms that link this inflammatory protein with proliferation in one of the most aggressive types of tumors. We found that phosphorylation of the extracellular regulated kinase (ERK) was preceded by the activation of the small GTPase Ras, and both failed to be activated by inhibiting protein kinase C (PKC). Fractionation and immunofluorescence studies revealed translocation of PKC alpha, delta, and epsilon to the membrane fraction upon stimulation with sPLA2-IIA. Immunoprecipitation analysis showed that sPLA2-IIA induces phosphorylation of the epidermal growth factor receptor (EGFR) through a PKC-dependent pathway. We found that phosphorylation of this receptor contributed to Ras and ERK activation and that inhibition of ERK, PKC, and EGFR blocked the mitogenic response induced by sPLA2-IIA. This study showed that sPLA2-IIA is able to bring into play EGFR to trigger its signaling and that PKC leads the distribution of resources. Interestingly, we found that this is not a cell-specific response, because sPLA2-IIA was also able to transactivate EGFR in MCF7 human breast cancer cells. Therefore, this mechanism could contribute to worsen the prognosis of a tumor in an inflammatory microenvironment. We also present more links of the tumor chain possibly susceptible to targeting., Anexo: Erratum: Secreted PLA 2 induces proliferation in astrocytoma through the EGF receptor: another inflammation-cancer, Ministerio de Ciencia, Innovación y Universidades (grants SAF2005-01242 and SAF2009-08407), Junta de Castilla y León (grant CSI11A08)

11 páginas, 8 figuras., Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease for which there exist no therapies without undesired side effects. Thus, the establishment of less toxic treatments is an ongoing challenge. Nowadays, research on medicinal plants has been attracting much attention, since screening of its active principles could prove useful in identification of safe and innovative pharmaceutical molecules. In this study we investigated the therapeutic effect of oleanolic acid (OA) a plant-derived triterpene with potent anti-inflammatory and immunomodulatory activities, whose actions on CNS diseases remain far from completely characterized. We focussed on the potential therapeutic effect of oleanolic acid (OA) on an accepted experimental model of MS, the experimental autoimmune encephalomyelitis (EAE). We have found that OA treatment, before or at the early onset of EAE, ameliorates neurological signs of EAE-mice. These beneficial effects of OA seem to be associated with a reduction of blood–brain barrier leakage and lower infiltration of inflammatory cells within the CNS, as well as with its modulatory role in Th1/Th2 polarization: inhibition of proinflammatory cytokines and chemokines, and stimulation of anti-inflammatory ones. Moreover, EAE-animals that were treated with OA had lower levels of anti-MOG antibodies than untreated EAE-mice. Our findings show that the administration of the natural triterpenoid OA reduces and limits the severity and development of EAE. Therefore, OA therapy might be of clinical interest for human MS and other Th1 cell-mediated inflammatory diseases., This work was supported by the Ramon y Cajal Program (to M.H.), F.P.I. Program from the Autonomous Government of Castilla y Leon (to R.M.) both co-funded by F.S.E., Grants SAF2005-01242 and SAF2008-00245 from the Spanish Ministry of Science and Technology, and Grant CSI11A08 from the Autonomous Government of Castilla y Leon.

Producción Científica, Background: Triterpene alcohols and acids are multifunctional compounds widely distributed throughout the plant kingdom that exhibit a variety of beneficial health properties, being synthetic analogs of oleanolic acid under clinical evaluation as anti-tumoral therapeutic agents. However, the antineoplastic activity of two natural occuring triterpenoid alcohols extracted from olive oil, erythrodiol (an intermediate from oleanolic acid), and its isomer, uvaol, has barely been reported, particularly on brain cancer cells. Astrocytomas are among the most common and aggressive type of primary malignant tumors in the neurological system lacking effective treatments, and in this study, we addressed the effect of these two triterpenic diols on the human 1321N1 astrocytoma cell line. Principal Findings: Erythrodiol and uvaol effectively affected cell proliferation, as well as cell cycle phases and induced 1321N1 cell death. Both triterpenes successfully modulated the apoptotic response, promoting nuclear condensation and fragmentation. They caused retraction and rounding of cultured cells, which lost adherence from their supports, while F-actin and vimentin filaments disappeared as an organized cytoplasmic network. At molecular level, changes in the expression of surface proteins associated with adhesion or death processes were also observed. Moreover, triterpene exposure resulted in the production of reactive oxygen species (ROS) with loss of mitochondrial transmembrane potential, and correlated with the activation of c-Jun N-terminal kinases (JNK). The presence of catalase reversed the triterpenic diols-induced mitochondrial depolarization, JNK activation, and apoptotic death, indicating the critical role of ROS in the action of these compounds. Conclusions: Overall, we provide a significant insight into the anticarcinogenic action of erythrodiol and uvaol that may have a potential in prevention and treatment of brain tumors and other cancers., Ministerio de Ciencia e Innovación (grants SAF2005-01242, SAF2008-00245 and AGL2008-022845), Junta de Castilla y León (grant CSI11A08)

Brain injury induces the expression of well-known cytokines, such as tumor necrosis factor-alpha (TNFα), and other, which functions are less understood, as secreted phospholipase A2 group IIA (sPLA2-IIA). Since in pathological processes, cytokines function coordinately in networks, to further explore the actions of sPLA2-IIA in tumorigenesis, we investigated the effect of sPLA2-IIA in the presence of TNFα in human 1321N1 astrocytoma cells. In these cells, TNFα activates the apoptotic programme that is accompanied of cytoskeleton changes; however, simultaneous treatment with sPLA2-IIA prevents TNFα-mediated apoptosis and reverses the modification of the markers associated to this response. In fact, the mitogenic activity elicited by the phospholipase alone is preserved. This inhibitory effect is not found in other TNFα-mediated responses, even a functional cooperation is observed on COX-2 protein induction. The cross-talk between TNFα and sPLA2-IIA is associated with ERK activity since its pharmacological inhibition attenuates both synergistic and inhibitory responses. We have also observed that upon sPLA2-IIA stimulation, endogenous ERK has the capacity to bind and phosphorylate sequences present within the cytoplasmic domain of TNFR1/CD120a. These findings thus indicate that sPLA2-IIA and TNFα transduction pathways interact to modulate inflammatory responses and provide additional insights about the capacity of sPLA2-IIA to promote apoptosis resistance in astrocytoma cells. © 2009., Supported by the Red de Centros RECAVA, C03/01. M.H. is under the Ramón y Cajal Program (Co-funded by F.S.E.). E.I. and R.M. are recipients of a Spanish Research Ministry fellowship. This study was funded by the Plan Nacional de Salud y Farmacia Grant SAF2005-01242 and SAF2008-00245.