Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: lessons from Gaucher, GM1-gangliosidosis and Fabry diseases

Lysosomal storage disorders (LSDs) are often caused by mutations that destabilize native folding and impair the trafficking of enzymes, leading to premature endoplasmic reticulum (ER)-associated degradation, deficiencies of specific hydrolytic functions and aberrant storage of metabolites in the lysosomes. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) are available for a few of these conditions, but most remain orphan. A main difficulty is that virtually all LSDs involve neurological decline and neither proteins nor the current SRT drugs can cross the blood–brain barrier. Twenty years ago a new therapeutic paradigm better suited for neuropathic LSDs was launched, namely pharmacological chaperone (PC) therapy. PCs are small molecules capable of binding to the mutant protein at the ER, inducing proper folding, restoring trafficking and increasing enzyme activity and substrate processing in the lysosome. In many LSDs the mutated protein is a glycosidase and the accumulated substrate is an oligo- or polysaccharide or a glycoconjugate, e.g. a glycosphingolipid. Although it might appear counterintuitive, substrate analogues (glycomimetics) behaving as competitive glycosidase inhibitors are good candidates to perform PC tasks. The advancements in the knowledge of the molecular basis of LSDs, including enzyme structures, binding modes, trafficking pathways and substrate processing mechanisms, have been put forward to optimize PC selectivity and efficacy. Moreover, the chemical versatility of glycomimetics and the variety of structures at hand allow simultaneous optimization of chaperone and pharmacokinetic properties. In this Feature Article we review the advancements made in this field in the last few years and the future outlook through the lessons taught by three archetypical LSDs: Gaucher disease, GM1-gangliosidosis and Fabry disease.The Spanish Ministerio de Economía y Competitividad (MINECO, contract numbers SAF2013-44021-R and CTQ2015-64425-C2-1-R), the Junta de Andalucía (contract number FQM-1467), and the European Union Seventh Framework Programme (FP7-People-2012-CIG), grant agreement number 333594 (to E. M. S. F., Marie Curie Reintegration Grant) are acknowledged. Cofinancing from the European Regional Development Funds (FEDER and FSE) is also thanked.We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Stereoselective Synthesis of Iminosugar 2-Deoxy(thio)glycosides from Bicyclic Iminoglycal Carbamates Promoted by Cerium(IV) Ammonium Nitrate and Cooperative Brønsted Acid-Type Organocatalysis

The first examples of iminosugar-type 2-deoxy(thio)glycoside mimetics are reported. The key step is the activation of a bicyclic iminoglycal carbamate to generate a highly reactive acyliminium cation. Cerium(IV) ammonium nitrate efficiently promoted the formation of 2-deoxy S-glycosides in the presence of thiols, probably by in situ generation of catalytic HNO3, with complete α-stereoselectivity. Cooperative phosphoric acid/Schreiner's thiourea organocatalysis proved better suited for generating 2-deoxy O-glycosides, significantly broadening the scope of the approach.Ministerio de Economía y Competitividad SAF201676083-RMinisterio de Ciencia, Innovación y Universidades RTI2018-097609-B-C21European Cooperation in Science and Technology CA18132Consejo Europeo de Investigación ERC-COG: 64823

Medida de espesores faciales por ecografía y tomografía axial computarizada

La reconstrucción facial a partir de un cráneo es una de las líneas de investigación en Antropología Forense a nivel internacional. Hasta el momento se han llevado a cabo una serie de técnicas encaminadas a tratar de reconstruir a partir del cráneo el rostro del individuo en vida. Estos estudios se han realizado en su mayoría sobre cadáveres. En la actualidad se están tratando de establecer diferentes modelos faciales y para ello se han ampliado tanto las medidas clásicamente tomadas y se han incorporado otras nuevas, todas ellas realizadas en sujetos vivos. En nuestro estudio proponemos tomar estas medidas de partes blandas a partir de las imágenes obtenidas mediante ecografía y mediante TAC y comparar los resultados entre estas dos técnicas así como con los que han obtenidos otros autores. El material utilizado en este estudio han sido las imágenes tomadas mediante ecografía sobre 20 individuos y TAC sobre 5 de ellos, de población española actual. Los resultados obtenidos confirman la fiabilidad de ambos métodos en la medida de espesores de tejidos blandos faciales.The facial reconstruction from a skull is a line of research in forensic anthropology at international level. So far we have carried out different techniques to reconstruct the face from the skull of an individual from soft-tissue studies, conducted mostly over corpses. At the moment it is being tried to establish different models for the face and have expanded both the measures conventionally taken as other new, all made __in living subjects. In our study we propose to take these measurements of soft-tissue parts from the images obtained by ultrasound and by CT and compare the results between these two techniques and the results obtained by other authors. The materials used in this study were the images taken by ultrasound on 20 subjects and CT on 5 of them, current Spanish population. The results confirm the reliability of both methods in the measurement of facial soft tissue thickness

New Castanospermine Glycoside Analogues Inhibit Breast Cancer Cell Proliferation and Induce Apoptosis without Affecting Normal Cells

sp2-Iminosugar-type castanospermine analogues have been shown to exhibit anti-tumor activity. However, their effects on cell proliferation and apoptosis and the molecular mechanism at play are not fully understood. Here, we investigated the effect of two representatives, namely the pseudo-S- and C-octyl glycoside 2-oxa-3-oxocastanospermine derivatives SO-OCS and CO-OCS, on MCF-7 and MDA-MB-231 breast cancer and MCF-10A mammary normal cell lines. We found that SO-OCS and CO-OCS inhibited breast cancer cell viability in a concentration- and time-dependent manner. This effect is specific to breast cancer cells as both molecules had no impact on normal MCF-10A cell proliferation. Both drugs induced a cell cycle arrest. CO-OCS arrested cell cycle at G1 and G2/M in MCF-7 and MDA-MB-231cells respectively. In MCF-7 cells, the G1 arrest is associated with a reduction of CDK4 (cyclin-dependent kinase 4), cyclin D1 and cyclin E expression, pRb phosphorylation, and an overexpression of p21Waf1/Cip1. In MDA-MB-231 cells, CO-OCS reduced CDK1 but not cyclin B1 expression. SO-OCS accumulated cells in G2/M in both cell lines and this blockade was accompanied by a decrease of CDK1, but not cyclin B1 expression. Furthermore, both drugs induced apoptosis as demonstrated by the increased percentage of annexin V positive cells and Bax/Bcl-2 ratio. Interestingly, in normal MCF-10A cells the two drugs failed to modify cell proliferation, cell cycle progression, cyclins, or CDKs expression. These results demonstrate that the effect of CO-OCS and SO-OCS is triggered by both cell cycle arrest and apoptosis, suggesting that these castanospermine analogues may constitute potential anti-cancer agents against breast cancer. © 2013 Allan et al.Peer Reviewe

Tendencias, brecha y evolución de la investigación sobre responsabilidad social empresarial en las instituciones de educación superior cmo apoyo de los SGDs en la literatura científica

La Responsabilidad Social Corporativa (RSC) ha consolidado como línea de investigación. Sin embargo, a pesar de la prolífica producción bibliográfica, todavía existen gaps en el análisis de la implementación y las implicaciones de la RSC en los programas educativos de las instituciones de educación superior (IES). La RSC debe ser tenida en cuenta por su relevancia para los profesores y para los graduados. Este estudio va más allá del análisis de las estrategias y prácticas de RSC de la institución. Para ello, se ha realizado una revisión de la literatura con apoyo bibliométrico utilizando VOSviewer para ver la estructua conceptual del campo de investigación a través del análisis de co-palabras bajo un marco longitudinal desde 2004 hasta 2022 con 96 registros. A partir de las redes bibliométricas se proporcionan las tendencias, gaps y evolución de la RSC en las IES. Además se hacen contribuciones prácticas a los responsables de las políticas y, específicamente, a las universidades para incluir la RSC en los planes de estudio para contribuir mejor a la empleabilidad de los graduados e, incluso, al cumplimiento de los Objetivos de Desarrollo Sostenible (ODS).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Die Wettbewerbsfähigkeit der arabischen Mittelmeerländer im internationalen Vergleich

6 p.- Papers presented at the International Workshop "The Conservation of Subterranean Cultural Heritage", held 25-27 March 2014, in Seville, Spain.Paranhos constitutes one of the main water galleries excavated in the granite substratum of Porto City (Portugal) to gather the groundwater for public use during the past five centuries. This gallery is a Subterranean Cultural Heritage site with a potential use for underground geotourism under safe conditions. An environmental monitoring programme has been conducte in the site comprising rapid multi-parameters. This programme has allowed the identification of urban-induced causes of contamination of the aquifer and internal tunnel atmosphere (waste-water and gas leakage). This study has also comprised the determination of effective radioactive dose in different sectors of the tunnel for potential visitors based on 222Rn studies.Financiado con el Proyecto (HAR-2010-11432-E) Red de Ciencia y Tecnología para la Conservación del Patrimonio CulturalPeer reviewe

Anti-Inflammatory (M2) Response Is Induced by a sp(2)-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy

Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of (S (S),1R)-1-docecylsulfiny-5N,6O-oxomethylidenenojirimycin ((Ss)-DS-ONJ), a member of the sp(2)-iminosugar glycolipid (sp(2)-IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with (Ss)-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of (S (S))-DS-ONJ in microglia. (S (S))-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR

Efficacy of short-course colchicine treatment in hospitalized patients with moderate to severe COVID-19 pneumonia and hyperinflammation: a randomized clinical trial

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si lo hubiere, y los autores pertenecientes a la UAMSome patients with COVID-19 pneumonia develop an associated cytokine storm syndrome that aggravates the pulmonary disease. These patients may benefit of anti-inflammatory treatment. The role of colchicine in hospitalized patients with COVID-19 pneumonia and established hyperinflammation remains unexplored. In a prospective, randomized controlled, observer-blinded endpoint, investigator-initiated trial, 240 hospitalized patients with COVID-19 pneumonia and established hyperinflammation were randomly allocated to receive oral colchicine or not. The primary efficacy outcome measure was a composite of non-invasive mechanical ventilation (CPAP or BiPAP), admission to the intensive care unit, invasive mechanical ventilation requirement or death. The composite primary outcome occurred in 19.3% of the total study population. The composite primary outcome was similar in the two arms (17% in colchicine group vs. 20.8% in the control group; p = 0.533) and the same applied to each of its individual components. Most patients received steroids (98%) and heparin (99%), with similar doses in both groups. In this trial, including adult patients with COVID-19 pneumonia and associated hyperinflammation, no clinical benefit was observed with short-course colchicine treatment beyond standard care regarding the combined outcome measurement of CPAP/BiPAP use, ICU admission, invasive mechanical ventilation or deat

Patrimonio académico como herramienta para el desarrollo de futuras carreras científicas

Desde hace tiempo la Unión Europea busca y fomenta la cooperación entre la Universidad y los Institutos de Educación Secundaria para el desarrollo de futuras carreras científicas. Después de varios proyectos de investigación competitivos desarrollados por separado, hemos encontrado importantes confluencias entre el patrimonio custodiado por la Universidad Complutense y el IES San Isidro; ambas instituciones cuentan con una larga historia y atesoran un patrimonio científico, artístico y educativo de gran interés que es necesario conectar y poner en valor. La universidad ha desarrollado varios programas de cooperación en varios niveles y muchas de ellos planteaban mostrar y experimentar con el fin de descubrir, propuesta en la que queremos ahondar y avanzar a través del patrimonio educativo