La fosfatasa mitocondrial PPTC7, punto de encuentro de la regulación del metabolismo bioenergético y la autofagia

Memoria de tesis presentada por Isabel González Mariscal, Licenciado en Ciencias Ambientales para optar al grado de Doctor. Esta Tesis Doctoral ha sido realizada en el Área de Biología Celular del Departamento de Fisiología, Anatomía y Biología Celular de la Universidad Pablo de Olavide y el Centro Andaluz de Biología del Desarrollo, centro mixto CSIC-UPO.El coenzima Q (ubiquinona o CoQ) es un lípido esencial presente en todos los organismos el cual juega un importante papel en el transporte de electrones y protones en el metabolismo bioenergético. La importancia de esta biomolécula radica en su capacidad rédox. Su forma oxidada recibe los electrones del complejo I o del complejo II de la cadena respiratoria de la mitocondria en eucariotas o de la membrana plasmática en procariotas, y su forma reducida (ubiquinol o CoQH2) los transfiere al complejo III (Olson and Rudney 1983; Halliwell and Gutteridge 1989). El CoQ no sólo actúa en la respiración mitocondrial (Trumpower 1990) sino también funciona como aceptor de electrones en numerosas reacciones de oxidación metabólicas, como es la síntesis de uridina (Nagy, Lacroute et al. 1992), la beta oxidación de ácidos grasos (Frerman 1988), la oxidación de sulfuro a tiosulfato (Hildebrandt and Grieshaber 2008) y como cofactor de las proteínas desacoplantes de la bomba de protones mitocondrial (Echtay, Winkler et al. 2000). El ubiquinol es un antioxidante liposoluble con un importante papel en diversas membranas (Ernster and Dallner 1995; Navarro, Navas et al. 1998), e interviene en sistemas rédox asociados a endomembranas, (Crane and Navas 1997) y membrana plasmática (Sun, Sun et al. 1992; Villalba, Navarro et al. 1995; Santos-Ocaña, Villalba et al. 1998). El CoQH2 puede actuar directamente como sumidero de electrones, o de manera indirecta como en el caso de la reducción del radical tocoferilo para regenerar la vitamina E. La estructura del CoQ se basa en un anillo bencénico soluble hidroxilado con un sustituyente isoprenoide en posición 3 que le confiere el carácter hidrofóbico. La cadena de isoprenos mantiene al coenzima Q anclado a las biomembranas, y su longitud es proporcional a la hidrofobicidad de la molécula. La longitud de la cola, determinada por el número de isoprenos, varía en función de la especie. De este modo, Escherichia coli produce una molécula con 8 isoprenos (CoQ8), Saccharomyces cerevisiae tan sólo 6 (CoQ6), Caenorhabditis elegans CoQ9, y Schizosaccharomyces pombe y Homo sapiens poseen la mayor longitud, CoQ10. Algunos organismos sintetizan variedades de coenzima Q conjuntas, como es el caso de roedores (CoQ9 y CoQ10). La adición de coenzima Q exógeno con diferentes longitudes de la cola poliisoprenoide puede aumentar la respiración, pero también puede inducir estrés oxidativo en la mitocondria y afectar a la longevidad al comportarse como un agente pro-oxidante. La adición de coenzima Q exógeno puede aumentar o permitir la respiración (Santos-Ocana, Do et al. 2002) ya que se distribuye por todas las endomembranas celulares (Fernandez-Ayala, Brea-Calvo et al. 2005) mediante un proceso basado en la ruta endocítica (Padilla-Lopez, Jimenez-Hidalgo et al. 2009). Sin embargo, también puede inducir estrés oxidativo en la mitocondria cuando se utiliza una isoforma no natural para el organismo utilizado como por ejemplo CoQ6 a células humanas (Fernandez-Ayala, Lopez-Lluch et al. 2005) y repercute tanto en la capacidad reproductiva (Jonassen, Davis et al. 2003) como en la longevidad de los nematodos alimentados con bacterias que producen diversas isoformas de coenzima Q (Ishii, Senoo-Matsuda et al. 2004; Yang, Gangoiti et al. 2009).El trabajo ha sido financiado por la Universidad Pablo de Olavide mediante la convocatoria del Plan Propio de Investigación.Peer reviewe

Detrimental Effect of Cannabidiol on the Early Onset of Diabetic Nephropathy in Male Mice

Anti-inflammatory and antidiabetogenic properties have been ascribed to cannabidiol (CBD). CBD-based medicinal drugs have been approved for over a lustrum, and a boom in the commercialization of CBD products started in parallel. Herein, we explored the efficacy of CBD in streptozotocin (STZ)-induced diabetic mice to prevent diabetic nephropathy at onset. Eight-to-ten-week-old C57BL6J male mice were treated daily intraperitoneally with 10 mg/kg of CBD or vehicle for 14 days. After 8 days of treatment, mice were challenged with STZ or vehicle (healthy-control). At the end of the study, non-fasting blood glucose (FBG) level was 276 ± 42 mg/dL in vehicle-STZ-treated compared to 147 ± 9 mg/dL (p ≤ 0.01) in healthy-control mice. FBG was 114 ± 8 mg/dL in vehicle-STZ-treated compared to 89 ± 4 mg/dL in healthy-control mice (p ≤ 0.05). CBD treatment did not prevent STZ-induced hyperglycemia, and non-FBG and FBG levels were 341 ± 40 and 133 ± 26 mg/dL, respectively. Additionally, treatment with CBD did not avert STZ-induced glucose intolerance or pancreatic beta cell mass loss compared to vehicle-STZ-treated mice. Anatomopathological examination showed that kidneys from vehicle-STZ-treated mice had a 35% increase of glomerular size compared to healthy-control mice (p ≤ 0.001) and presented lesions with a 43% increase in fibrosis and T cell infiltration (p ≤ 0.001). Although treatment with CBD prevented glomerular hypertrophy and reduced T cell infiltration, it significantly worsened overall renal damage (p ≤ 0.05 compared to vehicle-STZ mice), leading to a more severe renal dysfunction than STZ alone. In conclusion, we showed that CBD could be detrimental for patients with type 1 diabetes, particularly those undergoing complications such as diabetic nephropathy

Inglês no grau de enfermagem: um assunto pendente

OBJECTIVE: The new competence profile of nursing professionals, scientific and medical development, the free circulation of health professionals worldwide, and the increasing social and cultural diversity requires that nurses have specific abilities in spoken and written English. The objective of this research is to describe the characteristics of the English language training required for a Bachelors of Nursing in Spain. METHOD: A descriptive cross-sectional observational study has been performed in forty-six Spanish universities that offer the Bachelor in nursing degree. RESULTS: In line with the directives of the European Higher Education Area, all universities contemplate the mandatory credit of a second language emphasizing English, although there is considerable variability in the emphasis: 39.4% do not include any English subject, and of the remaining 60.6% who do include it, 60% considered it an elective subject, 32.5% basic education, and 7.5% mandatory. CONCLUSIONS: The English training has different characteristics in each university, which implies a different commitment from each center for this learning. This fact questions the adequacy of the education in relation to the new competence profile required by the European Higher Education Area, which may adversely affect future professional development.OBJETIVO: El nuevo perfil competencial de los profesionales de Enfermería, el desarrollo científico-sanitario, la libre circulación de profesionales sanitarios a nivel internacional y la creciente diversidad socio-cultural exige que las enfermeras posean competencias específicas en inglés hablado y escrito. El objetivo del presente estudio es describir las características de la formación en lengua inglesa en el Grado en Enfermería en España. MÉTODO: Se ha realizado un estudio observacional descriptivo y transversal en cuarenta y seis universidades españolas que imparten el Grado en Enfermería. RESULTADO: En línea con las directrices del Espacio Europeo de Educación Superior, todas las universidades contemplan la obligatoriedad de acreditar una segunda lengua, destacando el inglés, aunque existe una notable variabilidad en la importancia otorgada: el 39.4% no incluye ninguna asignatura de inglés, y del 60.6% restante que sí la incluye, el 60% la consideran asignatura optativa, el 32.5% formación básica y el 7.5% obligatoria. CONCLUSIONES: La formación en inglés presenta características diferentes en cada universidad, lo que implica una apuesta diferente de cada centro por su aprendizaje. Este hecho cuestiona la adecuación de la oferta formativa en relación al nuevo perfil competencial exigido por el Espacio Europeo de Educación Superior, pudiendo afectar negativamente al futuro desarrollo profesional.OBJETIVO: O perfil de nova competência dos profissionais de enfermagem, o desenvolvimento científico e médico, a livre circulação de profissionais de saúde em todo o mundo, e a crescente diversidade social e cultural requer que os enfermeiros têm habilidades específicas em Inglês falado e escrito. O objetivo desta pesquisa é descrever as características da formação idioma Inglês necessárias para um Bacharelado em Enfermagem, na Espanha. MÉTODO: Um estudo descritivo transversal observacional foi realizado em 46 universidades espanholas que oferecem o grau de Bacharel em enfermagem. RESULTADOS: Em conformidade com as diretivas do Espaço Europeu do Ensino Superior, todas as universidades contemplam o crédito obrigatório de uma segunda língua enfatizando Inglês, embora exista uma grande variabilidade na ênfase: 39,4% não incluem qualquer assunto Inglês, e do restante 60,6 % que o inclua, 60% considerou um assunto eletivo, 32,5% um ensino básico e 7,5% obrigatórios. CONCLUSÕES: O treinamento em Inglês tem características diferentes em cada universidade, o que implica em um compromisso diferente de cada centro para esse aprendizado. Este fato questiona a adequação da educação em relação ao perfil de competências exigidas pelo novo Espaço Europeu do Ensino Superior, o que pode prejudicar o desenvolvimento futuro profissional

Motivation, needs and expectations of nursing degree students towards English language learning

Los nuevos estudios de Grado, Máster y Doctorado consideran que el manejo de la lengua inglesa es una competencia transversal fundamental. Este trabajo tiene como objetivo conocer la motivación, necesidades y expectativas del alumnado del Grado en Enfermería de la Universidad de Huelva en el aprendizaje del inglés como segunda lengua. Se ha realizado un estudio observacional descriptivo de corte transversal. El alumnado otorga una gran importancia a la formación en inglés para su futuro desempeño con diferencias significativas en cuanto a su aplicabilidad en los diferentes ámbitos profesionales. A pesar de su alta motivación, un alto porcentaje considera que la oferta académica universitaria no cubre sus necesidades formativas. Se cuestiona por tanto la necesidad de ampliar y reorientar la formación de manera que se cumplan las expectativas del alumnado, las demandas profesionales y conseguir potenciar el aprendizaje de otras lenguas como vehículo de desarrollo académico y profesional.The new Degree, Master and Doctorate studies considers English language use as an essential competency. This paper aims to get a better knowledge of first and second year students Nursing Degree students within the University of Huelva in terms of motivation, needs and expectations regarding learning English as second language. An observational descriptive study from a cross-sectional approach has been performed. Students consider highly important English language learning for their future professional development while showing important significant differences about its applicability on the different professional settings. Despite their high motivation, a high percentage consider than the academic catalogue do not cover their learning needs. These results justify the need for further research and for a potential reorientation of the English language educative programs to match students' expectations, their professional needs and to enhance other language learning as a vehicle for academic and professional development

Au@16-pH-16/miR-21 mimic nanosystem: An efficient treatment for obesity through browning and thermogenesis induction

Despite the abundance of registered clinical trials worldwide, the availability of effective drugs for obesity treatment is limited due to their associated side effects. Thus, there is growing interest in therapies that stimulate energy expenditure in white adipose tissue. Recently, we demonstrated that the delivery of a miR-21 mimic using JetPEI effectively inhibits weight gain in an obese mouse model by promoting metabolism, browning, and thermogenesis, suggesting the potential of miR-21 mimic as a treatment for obesity. Despite these promising results, the implementation of more advanced delivery system techniques for miR-21 mimic would greatly enhance the advancement of safe and efficient treatment approaches for individuals with obesity in the future. Our objective is to explore whether a new delivery system based on gold nanoparticles and Gemini surfactants (Au@16-ph-16) can replicate the favorable effects of the miR-21 mimic on weight gain, browning, and thermogenesis. We found that dosages as low as 0.2 μg miR-21 mimic /animal significantly inhibited weight gain and induced browning and thermogenic parameters. This was evidenced by the upregulation of specific genes and proteins associated with these processes, as well as the biogenesis of beige adipocytes and mitochondria. Significant increases in miR-21 levels were observed in adipose tissue but not in other tissue types. Our data indicates that Au@16-ph-16 could serve as an effective delivery system for miRNA mimics, suggesting its potential suitability for the development of future clinical treatments against obesity.This research was supported by the following grants: This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI21/01924 and PI18/00785 and co-funded by the European Union, by the Consejería de Transformación Económica, Industria, Conocimiento y Universidades-Junta de Andalucía and ERDF-EU (PI20-01274) and by University of Sevilla VI PP USO SSGG (2021/00001297). PI-0092–2017 and PI-0235–2021 from Consejeria de Salud (Junta de Andalucia), Spain. S.L. is a recipient of a Plan Andaluz de Investigación, Desarrollo e Innovación post-doctoral grant from the Consejería de Economía, Conocimiento, Empresas y Universidades (DOC-01138). A.M.G. was a recipient of a Plan Propio de Investigación, Transferencia y Divulgación Científica postdoctoral grant from University of Málaga. FJBS, and REBAV-R are under contract with the ‘Nicolas Monardes’ program from the Servicio Andaluz de Salud, Consejería de Salud y Consumo-Junta de Andalucía (RC-0001-2021, RC-0006-2020 and C-0060-2018, respectively. A.V-R. was supported by a grant from the Ministerio de Economía y Competitividad (Proyectos I+D+i para Jóvenes Investigadores, SAF2014-60649-JIN).Peer reviewe

Fostering English-taught higher education programs in a Spanish university: the "TechEnglish" innovative project

In recent years, coinciding with adjustments to the Bologna process, many European universities have attempted to improve their international profile by increasing course offerings in English. According to the Institute of International Education (IIE), Spain has notably increased its English-taught higher education programs, ranking fifth in the list of European countries by number of English-taught Master's programs in 2013. This article presents the goals and preliminary results of an on-going innovative education project (TechEnglish) that aims to promote course offerings in English at the Technical University of Madrid (Universidad Politécnica de Madrid, UPM). The UPM is the oldest and largest of all Technical Universities in Spain. It offers graduate and postgraduate programs that cover all the engineering disciplines as well as architecture. Currently, the UPM has no specific bilingual/multilingual program to promote teaching in English, although there is an Educational Model Whitepaper (with a focus on undergraduate degrees) that promotes the development of activities like an International Semester or a unique shared curriculum. The TechEnglish project is an attempt to foster courses taught in English at 7 UPM Technical Schools, including students and 80 faculty members. Four tasks were identified: (1) to design a university wide framework to increase course offerings, (2) to identify administrative difficulties, (3) to increase visibility of courses offered, and (4) to disseminate the results of the project. First, to design a program we analyzed existing programs at other Spanish universities, and other projects and efforts already under way at the UPM. A total of 13 plans were analyzed and classified according to their relation with students (learning), professors (teaching), administration, course offerings, other actors/institutions within the university (e.g., language departments), funds and projects, dissemination activities, mobility plans and quality control. Second, to begin to identify administrative and organizational difficulties in the implementation of teaching in English, we first estimated the current and potential course offerings at the undergraduate level at the UPM using a survey (student, teacher and administrative demand, level of English and willingness to work in English). Third, to make the course offerings more attractive for both Spanish and international students we examined the way the most prestigious universities in Spain and in Europe try to improve the visibility of their academic offerings in English. Finally, to disseminate the results of the project we created a web page and a workspace on the Moodle education platform and prepared conferences and workshops within the UPM. Preliminary results show that increasing course offerings in English is an important step to promote the internationalization of the University. The main difficulties identified at the UPM were related to how to acknowledge/certify the departments, teachers or students involved in English courses, how students should register for the courses, how departments should split and schedule the courses (Spanish and English), and the lack of qualified personnel. A concerted effort could be made to increase the visibility of English-taught programs offered on-line

Informe final del escaneo de horizonte sobre futuras especies exóticas invasoras en España

73 p.La introducción de especies exóticas invasoras (EEI) es una de las principales causas de la pérdida de biodiversidad a nivel global, que provoca grandes costes socioeconómicos. Sin embargo, el número de nuevas introducciones continúa creciendo año tras año. Por lo tanto, urge identificar posibles futuras EEI con el objetivo de diseñar e implementar medidas que prevengan y mitiguen los efectos negativos de su introducción. Así, el objetivo de este estudio es prospectar qué especies exóticas no establecidas en España podrían llegar fácilmente en los próximos 10 años, establecerse y causar importantes impactos ecológicos. Para ello, se ha realizado un escaneo de horizonte, siguiendo la metodología establecida en trabajos previos, siendo el primero para el conjunto de las especies exóticas invasoras en España. Se añadieron en el análisis especies que no son autóctonas de España, incluyendo los archipiélagos de Canarias y Baleares, y que no están establecidas en España. Un total de 39 científicos, expertos en distintos grupos taxonómicos y ecosistemas, ha evaluado 933 especies. Con el objetivo de analizar el acuerdo entre las evaluaciones individuales de los expertos y su consistencia, se llevaron a cabo dos análisis de fiabilidad complementarios, cuyos resultados se discuten en este informe. Como resultado del escaneo, se obtuvo una lista priorizada de 105 especies (46 con riesgo muy alto y 59 con riesgo alto). La mayoría de estas especies (84,8%), sin embargo, no están incluidas actualmente en el Catálogo Español de Especies Exóticas Invasoras. Por lo tanto, se recomienda la realización de un análisis de riesgo más detallado de estas especies y, si se confirma el riesgo alto, la solicitud de su incorporación en dicho catálogo o en el Listado de especies alóctonas susceptibles de competir con las especies silvestres autóctonas, alterar su pureza genética o los equilibrios ecológicos. Del mismo modo, se propone la realización de escaneos de horizonte específicos para los archipiélagos de Canarias y Baleares, ya que muchas de las especies autóctonas de la Península no lo son de las islas y podrían tener un gran impacto si allí se introdujeran. Este informe también analiza la afinidad taxonómica (i.e. filo) y funcional (i.e. productor primario, depredador, omnívoro, herbívoro o filtrador) de las especies de la lista priorizada, su origen geográfico y las principales vías de introducción. Por último, discute los mecanismos de impacto de dichas especies.Ministerio de Ciencia e Innovació

(+)-trans-Cannabidiol-2-hydroxy pentyl is a dual CB1R antagonist/CB2R agonist that prevents diabetic nephropathy in mice

Natural cannabidiol ((-)-CBD) and its derivatives have increased interest for medicinal applications due to their broad biological activity spectrum, including targeting of the cannabinoid receptors type 1 (CB1R) and type 2 (CB2R). Herein, we synthesized the (+)-enantiomer of CBD and its derivative (+)-CBD hydroxypentylester ((+)-CBD-HPE) that showed enhanced CB1R and CB2R binding and functional activities compared to their respective (-) enantiomers. (+)-CBD-HPE Ki values for CB1R and CB2R were 3.1 ± 1.1 and 0.8 ± 0.1 nM respectively acting as CB1R antagonist and CB2R agonist. We further tested the capacity of (+)-CBD-HPE to prevent hyperglycemia and its complications in a mouse model. (+)-CBD-HPE significantly reduced streptozo tocin (STZ)-induced hyperglycemia and glucose intolerance by preserving pancreatic beta cell mass. (+)-CBD HPE significantly reduced activation of NF-κB by phosphorylation by 15% compared to STZ-vehicle mice, and CD3+ T cell infiltration into the islets was avoided. Consequently, (+)-CBD-HPE prevented STZ-induced apoptosis in islets. STZ induced inflammation and kidney damage, visualized by a significant increase in plasma proinflammatory cytokines, creatinine, and BUN. Treatment with (+)-CBD-HPE significantly reduced 2.5- fold plasma IFN-γ and increased 3-fold IL-5 levels compared to STZ-treated mice, without altering IL-18. (+)-CBD-HPE also significantly reduced creatinine and BUN levels to those comparable to healthy controls. At the macroscopy level, (+)-CBD-HPE prevented STZ-induced lesions in the kidney and voided renal fibrosis and CD3+ T cell infiltration. Thus, (+)-enantiomers of CBD, particularly (+)-CBD-HPE, have a promising potential due to their pharmacological profile and synthesis, potentially to be used for metabolic and immune-related disorders.Depto. de Bioquímica y Biología MolecularFac. de MedicinaTRUEpu