884 research outputs found

    Redox biology in retinal degeneration

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    Retinitis pigmentosa (RP) involves a group of hereditary diseases that cause progressive and severe visual impairment, with a prevalence of about 1 in 4,000 individuals worldwide. Unfortunately, there is currently no cure for RP and most patients become legally blind by age 40 due to the loss of retinal photoreceptors. The difficulty in finding a treatment relies on the complexity of its genetics. Although more than 3,000 mutations have been described to cause it, about 40-50% of RP cases still correspond to unknown patterns. In most cases, mutations affecting rods, which degenerate first, subsequently produce the death of the remaining photoreceptor cells, the cones. Several therapeutic approaches have been studied during the last decades. In 2011, our group discovered the neuroprotective properties of ‘Norgestrel’, a synthetic progestin used in the female oral contraceptive pill, in the retina. Norgestrel was shown to protect against retinal cell death in three different models: in vitro, in vivo and ex vivo, using retinal explants. In fact, two mouse models were used in order to demonstrate such protection, the balb/c induced light damage model and the genetic rd10 (Pde6b rd10– /rd10– ) model of RP. Since then, some components of its mechanism of action have been elucidated, as is the case of the receptor through which it works, the progesterone receptor membrane component 1 (PGRMC1); the neurotrophic factor basic fibroblast growth factor (bFGF) and its ability to reduce inflammation and gliosis in the diseased retina. Reactive oxygen species (ROS), have been traditionally associated with cellular damage, and have been discovered to participate in signalling responses, including cellular responses that are protetective. The number of studies about their protective properties of ROS have increased in the last decades. Nevertheless, the accumulation of ROS and/or their persistance during time within cells have detrimental consequences. Antioxidant machinery is the defense mechanism that cells possess against harmful ROS. However, this system is not infallible. Worsening of several diseases including RP is known to be produced by the disregulation of intracellular ROS levels, which is known as ‘oxidative stress’. In 2016, we demonstrated that Norgestrel effectively reduces the damaging ROS levels in the balb/c light damage mouse model. In the current study, using the 661W cone photoreceptor-like cell line and retinal explants from rd10 mice, we demonstrated that ROS are used by Norgestrel to enhance cell survival. We found that such stimulation of pro-survival ROS levels occurs very rapidly, and is both PGRMC1 and bFGF-dependent (Chapter 3). Interestingly, we demonstrated that treatment with some antioxidants that prevent the up-regulation of ROS molecules, abrogates the Norgestrel-mediated neuroprotection and therefore, indicates that ROS are a crucial part of this survival response. However, little was known about the subsequent downstream mechanism in the Norgestrel-mediated signalling response that prevents cell death and thus, this study aimed to elucidate other processes that could be implicated in such a response (Chapter 4). Using the genetic rd10 mouse model of RP we additionally demonstrated that Norgestrel was able to reduce the levels of damaging ROS due to its antioxidant properties via stimulating the transcription factor nuclear factor erythroid 2 (NF-E2)-related factor-2 (Nrf2) and its effector protein, superoxide dismutase 2 (SOD2) (Chapter 5). Taken together, this study highlights a dual nature of reactive oxygen species and we have demonstrated for the first time the implication of redox biology in the Norgestrel-mediated neuroprotection against retinal degeneration

    Soluble proteins and free amino nitrogen content in must and wine of cv. Viura in La Rioja

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    The protein fraction of white musts and wines obtained from grapes (Vitis vinifera L. cv. Viura) grown in northern Spain (Rioja) was investigated by SDS-PAGE. Under different fermentation conditions, e.g. aeration, must nitrogen content and yeast strain, SDS-PAGE patterns showed several bands with molecular weights ranging from 16 to 200 kDa. Higher weight proteins were glycosylated, whereas lower weight proteins were not. Under the experimental fermentation conditions none of the proteins showed any chemical modification that would alter the electrophoretical mobility or the covalent binding to their glycosylated moiety

    Design and manufacture of functional catalyst-carrier structures for the bioorthogonal activation of anticancer agents

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    Novel palladium (Pd)-loaded titanium (Ti) devices with high biocompatibility and catalytic activity were prepared using a range of fabrication methods such as powder metallurgy (i.e. sintering with and without space-holder), sputtering, pulsed laser deposition and supersonic cluster beam deposition. The surface of the Ti-[Pd] devices were physico-chemically characterised to confirm the non-alloyed state of the Pd coating onto the titanium substrate. The Pd thickness was optimised to achieve maximum surface area (i.e. maximum catalytic effect) using the minimum amount of material in each method for cost effective production. The catalytic response of the different Ti-[Pd] devices was evaluated under biocompatible conditions by employing an off-on Pd-activatable fluorescent probe. The most robust coating of Pd was produced by an optimised magnetron sputtering method. The sputtered Ti-[Pd] devices were selected to induce the bioorthogonal uncaging of the anticancer drug Vorinostat from a pharmacologically-inactive Pd-activatable precursor in cancer cell culture, demonstrating the capacity of these devices to mediate a local anti-tumour effect via in-situ release of a clinically approved drug. This approach is the first step towards surgically implantable devices that could facilitate targeting affected areas with high spatial selectivity, improving pharmacological activity and reducing systemic side effects through localised treatment directly at the cancer site

    The potential role of the adipokine HMGB1 in obesity and insulin resistance. Novel effects on adipose tissue biology

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    Discovery of the adipose tissue as a major source of signaling molecules almost three decades ago set a novel physiological paradigm that paved the way for the identification of metabolic organs as endocrine organs. Adipocytes, the main adipose tissue cell type, do not only represent the principal site of energy storage in form of triglycerides, but also produce a variety of molecules for short and long distance intercellular communication, named adipokines, which coordinate systemic responses. Although the best known adipokines identified and characterized hitherto are leptin and adiponectin, novel adipokines are continuously being described, what have significantly helped to elucidate the role of adipocyte biology in obesity and associated comorbidities. One of these novel adipokines is high-mobility group box 1 (HMGB1), a ubiquitous nuclear protein that has been recently reported to be dysregulated in obese dysfunctional adipocytes. Although the classical function of HMGB1 is related to inflammation and immunity, acting as an alarmin, novel advances evidence an active implication of HMGB1 in tissue remodeling and fibrosis. This review summarizes the current evidence on the mechanisms controlling HMGB1 release, as well as its role as a regulator of adipocyte function and extracellular matrix remodeling, with special emphasis on the potential of this novel adipokine as a target in the obesity treatment

    Pro-survival redox signalling in progesterone-mediated retinal neuroprotection

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    Retinitis pigmentosa (RP) is a group of hereditary retinal diseases, characterised by photoreceptor cell loss. Despite a substantial understanding of the mechanisms leading to cell death, an effective therapeutic strategy is sought. Our laboratory has previously demonstrated the neuroprotective properties of Norgestrel, a progesterone analogue, in the degenerating retina, mediated in part by the neurotrophic factor basic fibroblast growth factor (bFGF). In other retinal studies, we have also presented a pro-survival role for reactive oxygen species (ROS), downstream of bFGF. Thus, we hypothesized that Norgestrel utilises bFGF-driven ROS production to promote photoreceptor survival. Using the 661W photoreceptor-like cell line, we now show that Norgestrel, working through progesterone receptor membrane complex 1 (PGRMC1); generates an early burst of pro-survival bFGF-induced ROS. Using the rd10 mouse model of RP, we confirm that Norgestrel induces a similar early pro-survival increase in retinal ROS. Norgestrel-driven protection in the rd10 retina was attenuated in the presence of antioxidants. This study therefore presents an essential role for ROS signalling in Norgestrel-mediated neuroprotection in vitro and demonstrates that Norgestrel employs a similar pro-survival mechanism in the degenerating retina

    Occupational health of immigrant workers in Spain (ITSAL Project): key informants survey

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    Objetivo: Caracterizar colectivos de inmigrantes trabajadores en España y conocer sus condiciones de salud laboral mediante informantes clave. Método: Estudio cualitativo exploratorio-descriptivo con entrevistas en profundidad realizado en 2006. Se identificaron organizaciones, asociaciones y colectivos relacionados con la población inmigrante en Alicante, Barcelona, Huelva, Madrid y Valencia, y se seleccionaron los más accesibles y representativos. Se entrevistó a 43 informantes clave procedentes de 34 asociaciones u organismos. Se realizó un análisis narrativo del contenido. Resultados: Se señalan dificultades para el reconocimiento de los daños a la salud derivados del trabajo por las situaciones de irregularidad y precariedad, por resistencia por parte de los contratadores o las entidades aseguradoras, y por desconocimiento de los inmigrantes. Los informantes coinciden en que los riesgos laborales en los inmigrantes no difieren de los riesgos de los trabajadores autóctonos en similares circunstancias, pero los inmigrantes padecerían exposiciones más frecuentes e intensas por el acceso mayoritario a puestos menos cualificados y por la necesidad de prolongar las jornadas de trabajo. También se destaca su desconocimiento general en relación con los derechos de protección y de salud en el trabajo, aunque algunos informantes detectan un crecimiento de su actividad reivindicativa a través de los sindicatos. Conclusiones: Este primer acercamiento ha permitido definir algunos condicionantes generales que influirán en la salud laboral de los inmigrantes. La información obtenida servirá de base para profundizar, mediante técnicas adicionales de carácter cualitativo y cuantitativo, en los problemas de salud laboral de los inmigrantes trabajadores en España dentro del marco del Proyecto Inmigración, Trabajo y Salud (ITSAL), actualmente en desarrollo.Objective: To describe the characteristics, working conditions, and occupational health situation of immigrant workers in Spain through key informants. Method: We performed a qualitative, exploratory and descriptive study using indepth interviews carried out in 2006. Organizations and associations working with immigrant collectives in Alicante, Barcelona, Huelva, Madrid and Valencia were identified and the most representative and accessible entities in each location were selected. Fortythree interviews were performed with key informants from 34 different organisms. A narrative content analysis was performed. Results: Informants described difficulties in having health problems recognized as workrelated, due to irregular and precarious employment, employers' and insurance companies' reluctance, and immigrants' lack of knowledge. Informants coincided in reporting that the occupational risks for immigrant workers did not differ from those affecting Spanish workers in the same occupations and circumstances. However, exposure to occupational risks was exacerbated in immigrants because of their greater presence in unqualified jobs and their economic need to prolong working hours. Immigrants had little knowledge of their occupational health and safetyrelated rights, although some informants detected an increase in empowerment in this area, mostly through greater participation in trade unions. Conclusions: This first step allowed us to identify some of the general factors influencing the health and safety of immigrant workers in Spain. This information will be used in a longterm, ongoing research project [Project Immigration, Work and Health (Proyecto Inmigración, Trabajo y Salud [ITSAL]), which aims to evaluate occupational health problems in inmigrants working in Spain through both qualitative and quantitative methods

    Molecular evolutionary characterization of the mussel "Mytilus" histone multigene family: first record of a tandemly repeated unit of five histone genes containing an H1 subtype with orphon features

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    [Abstract] The present work represents the first characterization of a clustered histone repetitive unit containing an H1 gene in a bivalve mollusk. To complete the knowledge on the evolutionary history of the histone multigene family in invertebrates, we undertake its characterization in five mussel Mytilus species, as an extension of our previous work on the H1 gene family. We report the quintet H4–H2B–H2A–H3–H1 as the major organization unit in the genome of Mytilus galloprovincialis with two 5S rRNA genes with interspersed nontranscribed spacer segments linked to the unit, which is not justified by their cotranscription with histone genes. Surprisingly, 3′ UTR regions of histone genes show two different mRNA termination signals, a stem-loop and a polyadenylation signal, both related to the evolution of histone gene expression patterns throughout the cell cycle. The clustered H1 histones characterized share essential features with “orphon” H1 genes, suggesting a common evolutionary origin for both histone subtypes which is supported by the reconstructed phylogeny for H1 genes. The characterization of histone genes in four additional Mytilus species revealed the presence of strong purifying selection acting among the members of the family. The chromosomal location of most of the core histone genes studied was identified by FISH close to telomeric regions in M. galloprovincialis. Further analysis on nucleotide variation would be necessary to assess if H1 proteins evolve according to the birth-and-death model of evolution and if the effect of the strong purifying selection maintaining protein homogeneity could account for the homologies detected between clustered and “orphon” variants.Xunta de Galicia; 10PX110304P

    Assessment of nitrification process in a sequencing batch reactor: Modelling and genomic approach

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    Nitrification of ammoniacal nitrogen (N–NH4+) to nitrate (N–NO3-) was investigated in a lab-scale sequencing batch reactor (SBR) to evaluate its efficiency. During the nitrification process the removal of N–NH4+ reached 96%, resulting in 73% formation of N–NO3-. A lineal correlation (r2 = 0.9978) was obtained between the concentration of volatile suspended solids (VSS) and the maximal N–NO3- concentration at the end of each batch cycle under stationary state. The bacterial taxons in the initial inoculum were identified, revealing a complex diverse community mainly in the two major bacterial phyla Proteobacteria and Actinobacteria. The FAPROTAX algorithm predicted the presence in the inoculum of taxa involved in relevant processes of the nitrogen metabolism, highlighting the bacterial genera Nitrospira and Nitrosomonas that are both involved in the nitrification process. A kinetic model was formulated for predicting and validating the transformation of N–NH4+, N–NO2- and N–NO3- and the removal of organic and inorganic carbon (TOC and IC, respectively). The results showed how the increase in biomass concentration slowed down the transformation to oxidised forms of nitrogen and increased denitrification in the settling and filling stages under free aeration conditions

    A radiobiological study of the schemes with a low number of fractions in high-dose-rate brachytherapy as monotherapy for prostate cancer

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    Purpose Schemes with high doses per fraction and small number of fractions are commonly used in high-dose-rate brachytherapy (HDR-BT) for prostate cancer. Our aim was to analyze the differences between published clinical results and the predictions of radiobiological models for absorbed dose required in a single fraction monotherapy HDR-BT. Material and methods Published HDR-BT clinical results for low- and intermediate-risk patients with prostate cancer were revised. For 13 clinical studies with 16 fractionation schedules between 1 and 9 fractions, a dose-response relation in terms of the biochemical control probability (BC) was established using Monte Carlo-based statistical methods. Results We obtained a value of α/β = 22.8 Gy (15.1-60.2 Gy) (95% CI) much larger than the values in the range 1.5-3.0 Gy that are usually considered to compare the results of different fractionation schemes in prostate cancer radiotherapy using doses per fraction below 6 Gy. The doses in a single fraction producing BC = 90% and 95% were 22.3 Gy (21.5-24.2 Gy) and 24.3 Gy (23.0-27.9 Gy), respectively. Conclusions The α/β obtained in our analysis of 22.8 Gy for a range of dose per fraction between 6 and 20.5 Gy was much greater than the one currently estimated for prostate cancer using low doses per fraction. This high value of α/β explains reasonably well the data available in the region of high doses per fraction considered.Spanish Ministerio de Ciencia y Competitividad FPA2015-67694-PEuropean Union (EU)Junta de Andalucía FQM038
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