Induction of CD36 and Thrombospondin-1 in Macrophages by Hypoxia-Inducible Factor 1 and Its Relevance in the Inflammatory Process

Inflammation is part of a complex biological response of vascular tissue to pathogens or damaged cells. First inflammatory cells attempt to remove the injurious stimuli and this is followed by a healing process mediated principally by phagocytosis of senescent cells. Hypoxia and p38-MAPK are associated with inflammation, and hypoxia inducible factor 1 (HIF-1) has been detected in inflamed tissues. We aimed to analyse the role of p38-MAPK and HIF-1 in the transcriptional regulation of CD36, a class B scavenger receptor, and its ligand thrombospondin (TSP-1) in macrophages and to evaluate the involvement of this pathway in phagocytosis of apoptotic neutrophils. We have also assessed HIF-1α, p38-MAPK and CD36 immunostaining in the mucosa of patients with inflammatory bowel disease. Results show that hypoxia increases neutrophil phagocytosis by macrophages and induces the expression of CD36 and TSP-1. Addition of a p38-MAPK inhibitor significantly reduced the increase in CD36 and TSP-1 expression provoked by hypoxia and decreased HIF-1α stabilization in macrophages. Transient transfection of macrophages with a miHIF-1α-targeting vector blocked the increase in mRNA expression of CD36 and TSP-1 during hypoxia and reduced phagocytosis, thus highlighting a role for the transcriptional activity of HIF-1. CD36 and TSP-1 were necessary for the phagocytosis of neutrophils induced by hypoxic macrophages, since functional blockade of these proteins undermined this process. Immunohistochemical studies revealed CD36, HIF-1α and p38-MAPK expression in the mucosa of patients with inflammatory bowel disease. A positive and significant correlation between HIF-1α and CD36 expression and CD36 and p38-MAPK expression was observed in cells of the lamina propria of the damaged mucosa. Our results demonstrate a HIF-1-dependent up-regulation of CD36 and TSP-1 that mediates the increased phagocytosis of neutrophils by macrophages during hypoxia. Moreover, they suggest that CD36 expression in the damaged mucosa of patients with inflammatory bowel disease depends on p38-MAPK and HIF-1 activity

Potencialidad de un residuo de frita procedente del sector cerámico como materia prima para la producción de material vitrocerámico

This work consists of studying the devitrification capacity of a residue from sodium-calcium frit, using the vitreous powder sintering method, which follows the traditional ceramic processing route, including a specific heat treatment to generate the appearance of crystals from the original glass phase. Initially the frit residue has been characterized by instrumental techniques such as XRF, XRD and DTA/TG. Furthermore, the chemical analysis (XRF) has allowed the prediction of devitrification potentiality of this residue by theoretical approaches represented by Gingsberg, Raschin-Tschetverikov and Lebedeva ternary diagrams. Then, this residue was subjected to traditional ceramic method, by changing the grinding time, the pressing pressure and prepared samples were obtained at different temperatures. In this part, the techniques for measuring particle size by laser diffraction and XRD and SEM to evaluate the generated crystalline phases, were applied. Finally, it has been found that this frit residue works as glass-ceramic precursor, devitrifying in wollastonite crystals as majority phase and without being subjected to the melting step of the glass-ceramic typical method.Este trabajo ha sido financiado por el Ministerio de Economía y Competitividad Español a través del Proyecto titulado «Desarrollo de nuevos revestimientos fotovoltaicos ecológicos utilizando materiales reciclados para integración arquitectónica, basados en tecnologías de calcogenuros» (ECOART), cuyo número de expediente es RTC-2014-2294-3

Development of a glass-ceramic glaze formulated from industrial residues to improve the mechanical properties of the porcelain stoneware tiles

In this research a mixture of 90%wt of industrial residues (recycled soda-lime glass and ashes from a coalpower thermal plant) have been vitrified for their use as ‘‘secondary raw material”. Then, a glaze suspen-sion was prepared to be applied on the porcelain stoneware tile. The tested pieces have been fired by aconventional porcelain cycle at 1180 °C of maximum temperature. The XRD, XRF, SEM/EDS and thedilatometric analysis have been the instrumental techniques used to characterize the material. Finally,an ecological glass-ceramic glaze perfectly fitting on porcelain ceramic tile has been produced, exhibitinga unique phase, anorthite, which ensures a high flexural strength (around 96 MPa) and a significantVickers microhardness of 250 GPa, improving the mechanical properties of a conventional the porcelainceramic tile

M1 Macrophages Activate Notch Signalling in Epithelial Cells: Relevance in Crohn's Disease

Background: The Notch signalling pathway plays an essential role in mucosal regeneration, which constitutes a key goal of Crohn's disease (CD) treatment. Macrophages coordinate tissue repair and several phenotypes have been reported which differ in the expression of surface proteins, cytokines and hypoxia-inducible factors (HIFs). We analysed the role of HIFs in the expression of Notch ligands in macrophages and the relevance of this pathway in mucosal regeneration. Methods: Human monocytes and U937-derived macrophages were polarized towards the M1 and M2 phenotypes and the expression levels of HIF-1α, HIF-2α, Jagged 1 (Jag1) and delta-like 4 (Dll4) were evaluated. The effects of macrophages on the expression of hairy and enhancer of split-1 (HES1, the main target of Notch signalling) and intestinal alkaline phosphatase (IAP, enterocyte marker) in epithelial cells in co-culture were also analysed. Phenotype macrophage markers and Notch signalling were evaluated in the mucosa of CD patients. Results: M1 macrophages were associated with HIF-1-dependent induction of Jag1 and Dll4, which increased HES1 protein levels and IAP activity in co-cultured epithelial cells. In the mucosa of CD patients a high percentage of M1 macrophages expressed both HIF-1α and Jag1 while M2 macrophages mainly expressed HIF-2α and we detected a good correlation between the ratio of M1/M2 macrophages and both HES1 and IAP protein levels. Conclusion: M1, but not M2, macrophages are associated with HIF-1-dependent induction of Notch ligands and activation of epithelial Notch signalling pathway. In the mucosa of chronic CD patients, the prevalence of M2 macrophages is associated with diminution of Notch signalling and impaired enterocyte differentiation. Key Words: MacrophagesCrohn's diseasemucosal healingNotch signallin

Probabilistic study of the effect of anti-epileptic drugs under uncertainty: Cost-effectiveness analysis

[EN] Epilepsy is one of the most ancient diseases. Despite the efforts of scientists and doctors to improve the quality of live of epileptic patients, the disease is still a mystery in many senses. Anti-epileptic drugs are fundamental to reduce epileptic seizures but it have some adverse effects, which influence the quality of life outcomes of the patients. In this paper, we study the effectiveness of anti-epileptic drugs taking into account the inherent uncertainty. We establish a model, which allows to represent the natural history of epilepsy, using Markov chains. After randomizing the mathematical model, we compute the first probability density function of the solution stochastic process applying the random variable transformation technique.We also take advantage of this method to determine the distribution of some key quantities in medical decision, such as the time until a certain proportion of the population remains in each state and the incremental cost-effectiveness ratio. The study is completed computing all these quantities using data available in the literature. In addition, regarding the incremental cost-effectiveness ratio, different third generation anti-epileptic treatments are compared with the Brivaracetam, a new third generation anti-epileptic drug.This work has been supported by the Spanish Ministerio de Economia, Industria y Competitividad (MINECO), the Agencia Estatal de Investigacion (AEI) and Fondo Europeo de Desarrollo Regional (FEDER UE) grant MTM2017-89664-P. Computations have been carried thanks to the collaboration of Raul San Julian Garces and Elena Lopez Navarro granted by European Union through the Operational Program of the European Regional Development Fund (ERDF)/European Social Fund (ESF) of the Valencian Community 2014-2020, grants GJIDI/2018/A/009 and GJIDI/2018/A/010, respectively.Barrachina Martínez, I.; Navarro-Quiles, A.; Ramos, M.; Romero, J.; Roselló, M.; Vivas-Consuelo, D. (2020). Probabilistic study of the effect of anti-epileptic drugs under uncertainty: Cost-effectiveness analysis. Mathematics. 8(7):1-19. https://doi.org/10.3390/math8071120S11987García-Ramos, R., García Pastor, A., Masjuan, J., Sánchez, C., & Gil, A. (2011). FEEN report on epilepsy in Spain. Neurología (English Edition), 26(9), 548-555. doi:10.1016/j.nrleng.2011.03.004Epilepsy http://www.who.int/mediacentre/factsheets/fs999/en/Población Estimada en España http://www.ine.es/inebaseDYN/cp30321Duncan, J. S., Sander, J. W., Sisodiya, S. M., & Walker, M. C. (2006). Adult epilepsy. The Lancet, 367(9516), 1087-1100. doi:10.1016/s0140-6736(06)68477-8Brodie, M. J. (2015). Practical Use of Newer Antiepileptic Drugs as Adjunctive Therapy in Focal Epilepsy. CNS Drugs, 29(11), 893-904. doi:10.1007/s40263-015-0285-4EPARs for Authorised Medicinal Products for Human Use Stelara http://www.emea.europa.eu/humandocs/Humans/EPAR/stelara/stelara.htmKristian, B., Wachtmeister, K., Stefan, F., & Forsgren, L. (2013). Retigabine as add-on treatment of refractory epilepsy - a cost-utility study in a Swedish setting. Acta Neurologica Scandinavica, 127(6), 419-426. doi:10.1111/ane.12077Martyn-St James, M., Glanville, J., McCool, R., Duffy, S., Cooper, J., Hugel, P., & Lane, P. W. (2012). The efficacy and safety of retigabine and other adjunctive treatments for refractory partial epilepsy: A systematic review and indirect comparison. Seizure, 21(9), 665-678. doi:10.1016/j.seizure.2012.07.011Cortés, J.-C., Navarro-Quiles, A., Romero, J.-V., & Roselló, M.-D. (2017). Randomizing the parameters of a Markov chain to model the stroke disease: A technical generalization of established computational methodologies towards improving real applications. Journal of Computational and Applied Mathematics, 324, 225-240. doi:10.1016/j.cam.2017.04.040Sonnenberg, F. A., & Beck, J. R. (1993). Markov Models in Medical Decision Making. Medical Decision Making, 13(4), 322-338. doi:10.1177/0272989x9301300409Barrachina-Martínez, I., Vivas-Consuelo, D., & Piera-Balbastre, A. (2017). Budget Impact Analysis of Brivaracetam Adjunctive Therapy for Partial-Onset Epileptic Seizures in Valencia Community, Spain. Clinical Drug Investigation, 38(4), 353-363. doi:10.1007/s40261-017-0615-zSullivan, S. D., Mauskopf, J. A., Augustovski, F., Jaime Caro, J., Lee, K. M., Minchin, M., … Shau, W.-Y. (2014). Budget Impact Analysis—Principles of Good Practice: Report of the ISPOR 2012 Budget Impact Analysis Good Practice II Task Force. Value in Health, 17(1), 5-14. doi:10.1016/j.jval.2013.08.2291Cortés, J.-C., Navarro-Quiles, A., Romero, J.-V., & Roselló, M.-D. (2018). Some results about randomized binary Markov chains: theory, computing and applications. International Journal of Computer Mathematics, 97(1-2), 141-156. doi:10.1080/00207160.2018.1440290Prieto, L., Sacristán, J. A., Antoñanzas, F., Rubio-Terrés, C., Pinto, J. L., & Rovira, J. (2004). Análisis coste-efectividad en la evaluación económica de intervenciones sanitarias. Medicina Clínica, 122(13), 505-510. doi:10.1016/s0025-7753(04)74288-8Karlsson, G., & Johannesson, M. (1996). The Decision Rules of Cost-Effectiveness Analysis. PharmacoEconomics, 9(2), 113-120. doi:10.2165/00019053-199609020-00003Mulhern, B., Rowen, D., Snape, D., Jacoby, A., Marson, T., Hughes, D., … Brazier, J. (2014). Valuations of epilepsy-specific health states: a comparison of patients with epilepsy and the general population. Epilepsy & Behavior, 36, 12-17. doi:10.1016/j.yebeh.2014.04.011BOT Base de Datos del Medicamento https://botplusweb.portalfarma.com/Informe de Posicionamiento Terapéutico de Brivaracetam (Briviact) en Epilepsia https://www.aemps.gob.es/medicamentosUsoHumano/informesPublicos/docs/IPTbrivaracetam-Briviact-epilepsia.pdfSacristán, J. A., Oliva, J., Del Llano, J., Prieto, L., & Pinto, J. L. (2002). ¿Qué es una tecnología sanitaria eficiente en España? Gaceta Sanitaria, 16(4), 334-343. doi:10.1016/s0213-9111(02)71933-xBertram, M. Y., Lauer, J. A., De Joncheere, K., Edejer, T., Hutubessy, R., Kieny, M.-P., & Hill, S. R. (2016). Cost–effectiveness thresholds: pros and cons. Bulletin of the World Health Organization, 94(12), 925-930. doi:10.2471/blt.15.16441

The Ceramic Industry in Spain: Challenges and Opportunities in Times of Crisis

In the last few years, the Spanish ceramic industry has gone through a severe crisis, which has led to great market loss and reduction in profi ts. Nevertheless, the ceramic industries in Spain have always characterised themselves as an innovative sector, highly predisposed to changes. It is precisely in times of crisis that the industries most seek to break new ground in their quest for new innovations that will give them an edge over competitors. This study provides an overview of the advances that have recently materialised in the ceramic tile industry. Various technological issues are thus highlighted, such as tile decoration by inkjet printing, laser technology, physical vapour deposition (PVD) technology, fi ring using laser technology (laser­fi ring project), etc. These techniques are being used to develop innovative products, thus obtaining tiles with bactericidal capability, conductive glazes, anti­electrostatic tiles, etc

Role of the epithelial barrier in intestinal fibrosis associated with inflammatory bowel disease: relevance of the epithelial-to mesenchymal transition

In inflammatory bowel disease (IBD), chronic inflammation in the gastrointestinal tract can lead to tissue damage and remodelling, which can ultimately result in fibrosis. Prolonged injury and inflammation can trigger the activation of fibroblasts and extracellular matrix (ECM) components. As fibrosis progresses, the tissue becomes increasingly stiff and less functional, which can lead to complications such as intestinal strictures, obstructive symptoms, and eventually, organ dysfunction. Epithelial cells play a key role in fibrosis, as they secrete cytokines and growth factors that promote fibroblast activation and ECM deposition. Additionally, epithelial cells can undergo a process called epithelial-mesenchymal transition, in which they acquire a more mesenchymal-like phenotype and contribute directly to fibroblast activation and ECM deposition. Overall, the interactions between epithelial cells, immune cells, and fibroblasts play a critical role in the development and progression of fibrosis in IBD. Understanding these complex interactions may provide new targets for therapeutic interventions to prevent or treat fibrosis in IBD. In this review, we have collected and discussed the recent literature highlighting the contribution of epithelial cells to the pathogenesis of the fibrotic complications of IBD, including evidence of EMT, the epigenetic control of the EMT, the potential influence of the intestinal microbiome in EMT, and the possible therapeutic strategies to target EMT. Finally we discuss the pro-fibrotic interactions epithelial-immune cells and epithelial-fibroblasts cells

Firms’ distance to the European productivity frontier

In this article we explore the factors contributing to reduce the distance of laggard frms to the European frontier, focusing on institutional factors. To characterize Total Factor Productivity frontier frms within industries for the European Union we use frm level data from AMADEUS for the period 2003–2014. Our fndings provide evidence on the importance of governance quality and easiness in getting credit in explaining the distance of laggard frms to the European productivity frontier. We also fnd that other factors at the country level -tertiary education, R&D stock, and trade openness- and at the frm level -size, age, and capital-intensity- infuence the distance of laggards to the frontier. In addition, we examine the role of the Great Recession in moderating the contribution of all these factors to reduce firms’ distance to the European productivity frontier

HIF-Overexpression and Pro-Inflammatory Priming in Human Mesenchymal Stromal Cells Improves the Healing Properties of Extracellular Vesicles in Experimental Crohn’s Disease

Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have therapeutic potential in the treatment of several immune disorders, including ulcerative colitis, owing to their regenerative and immunosuppressive properties. We recently showed that MSCs engineered to overexpress hypoxia-inducible factor 1-alpha and telomerase (MSC-T-HIF) and conditioned with pro-inflammatory stimuli release EVs (EVMSC-T-HIFC) with potent immunomodulatory activity. We tested the efficacy of EVMSC-T-HIFC to repolarize M1 macrophages (Mφ1) to M2-like macrophages (Mφ2-like) by analyzing surface markers and cytokines and performing functional assays in co-culture, including efferocytosis and T-cell proliferation. We also studied the capacity of EVMSC-T-HIFC to dampen the inflammatory response of activated endothelium and modulate fibrosis. Finally, we tested the therapeutic capacity of EVMSC-T-HIFC in an acute colitis model. EVMSC-T-HIFc induced the repolarization of monocytes from Mφ1 to an Mφ2-like phenotype, which was accompanied by reduced inflammatory cytokine release. EVMSC-T-HIFc-treated Mφ1 had similar effects of immunosuppression on activated peripheral blood mononuclear cells (PBMC) as Mφ2, and reduced the adhesion of PBMCs to activated endothelium. EVMSC-T-HIFc also prevented myofibroblast differentiation of TGF-β-treated fibroblasts. Finally, administration of EVMSC-T-HIFc promoted healing in a TNBS-induced mouse colitis model in terms of preserving colon length and intestinal mucosa architecture and altering the ratio of Mφ1/ Mφ2 infiltration. In conclusion, EVMSC-T-HIFC have effective anti-inflammatory properties, making them potential therapeutic agents in cell free-based therapies for the treatment of Crohn’s disease and likely other immune-mediated inflammatory diseases

Progastrin Represses the Alternative Activation of Human Macrophages and Modulates Their Influence on Colon Cancer Epithelial Cells

Macrophage infiltration is a negative prognostic factor for most cancers but gastrointestinal tumors seem to be an exception. The effect of macrophages on cancer progression depends on their phenotype, which may vary between M1 (pro-inflammatory, defensive) to M2 (tolerogenic, pro-tumoral). Gastrointestinal cancers often become an ectopic source of gastrins and macrophages present receptors for these peptides. The aim of the present study is to analyze whether gastrins can affect the pattern of macrophage infiltration in colorectal tumors. We have evaluated the relationship between gastrin expression and the pattern of macrophage infiltration in samples from colorectal cancer and the influence of these peptides on the phenotype of macrophages differentiated from human peripheral monocytes in vitro. The total number of macrophages (CD68+ cells) was similar in tumoral and normal surrounding tissue, but the number of M2 macrophages (CD206+ cells) was significantly higher in the tumor. However, the number of these tumor-associated M2 macrophages correlated negatively with the immunoreactivity for gastrin peptides in tumor epithelial cells. Macrophages differentiated from human peripheral monocytes in the presence of progastrin showed lower levels of M2-markers (CD206, IL10) with normal amounts of M1-markers (CD86, IL12). Progastrin induced similar effects in mature macrophages treated with IL4 to obtain a M2-phenotype or with LPS plus IFNγ to generate M1-macrophages. Macrophages differentiated in the presence of progastrin presented a reduced expression of Wnt ligands and decreased the number and increased cell death of co-cultured colorectal cancer epithelial cells. Our results suggest that progastrin inhibits the acquisition of a M2-phenotype in human macrophages. This effect exerted on tumor associated macrophages may modulate cancer progression and should be taken into account when analyzing the therapeutic value of gastrin immunoneutralization