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Oliveira H.,University of Bordeaux 1 | Oliveira H.,CNRS Organic Polymer Chemistry Laboratory | Perez-Andres E.,CIC bioGUNE | Thevenot J.,University of Bordeaux 1 | And 6 more authors.
Journal of Controlled Release | Year: 2013

Local and temporal control of drug release has for long been a main focus in the development of novel drug carriers. Polymersomes, which can load both hydrophilic and hydrophobic species and, at the same time, be tailored to respond to a desired stimulus, have drawn much attention over the last decade. Here we describe polymersomes able to encapsulate up to 6% (w/w) of doxorubicin (DOX) together with 30% (w/w) of superparamagnetic iron oxide nanoparticles (USPIO; γ-Fe2O3). Upon internalization in HeLa cells and when a high frequency AC magnetic field (14 mT at 750 kHz) was applied, the developed delivery system elicited an 18% increase in cell toxicity, associated with augmented DOX release kinetics. In order to ensure that the observed cytotoxicity arose from the increased doxorubicin release and not from a pure magnetic hy-perthermia effect, polymersomes loaded with magnetic nanoparticles alone were also tested. In this case, no increased toxicity was observed. We hypothesize that the magnetic field is inducing a very local hyperther-mia effect at the level of the polymersome membrane, increasing drug release. This approach opens new perspectives in the development of smart delivery systems able to release drug upon demand and therefore, improving treatment control. © 2013 Elsevier B.V. All rights reserved.

Kurt T.D.,University of California at San Diego | Bett C.,University of California at San Diego | Fernandez-Borges N.,CIC bioGUNE | Joshi-Barr S.,University of California at San Diego | And 11 more authors.
Journal of Neuroscience | Year: 2014

Zoonotic prion transmission was reported after the bovine spongiform encephalopathy (BSE) epidemic, when >200 cases of prion disease in humans were diagnosed as variant Creutzfeldt-Jakob disease. Assessing the risk of cross-species prion transmission remains challenging. We and others have studied how specific amino acid residue differences between species impact prion conversion and have found that the β2-α2 loop region of the mouse prion protein (residues 165-175) markedly influences infection by sheep scrapie, BSE, mouse-adapted scrapie, deer chronic wasting disease, and hamster-adapted scrapie prions. The tyrosine residue at position 169 is strictly conserved among mammals and an aromatic side chain in this position is essential to maintain a 310-helical turn in the β2-α2 loop. Here we examined the impact of the Y169G substitution together with the previously described S170N, N174T "rigid loop" substitutions on cross-species prion transmission in vivo and in vitro. We found that transgenic mice expressing mouse PrP containing the triple-amino acid substitution completely resisted infection with two strains of mouse prions and with deer chronic wasting disease prions. These studies indicate that Y169 is important for prion formation, and they provide a strong indication that variation of the β2-α2 loop structure can modulate interspecies prion transmission. © 2014 the authors.

Fernandez-Borges N.,CIC bioGUNE
Current topics in medicinal chemistry | Year: 2013

Prion diseases belong to a group of fatal infectious diseases with no effective therapies available. Throughout the last 35 years, less than 50 different drugs have been tested in different experimental animal models without hopeful results. An important limitation when searching for new drugs is the existence of appropriate models of the disease. The three different possible origins of prion diseases require the existence of different animal models for testing anti-prion compounds. Wild type, over-expressing transgenic mice and other more sophisticated animal models have been used to evaluate a diversity of compounds which some of them were previously tested in different in vitro experimental models. The complexity of prion diseases will require more pre-screening studies, reliable sporadic (or spontaneous) animal models and accurate chemical modifications of the selected compounds before having an effective therapy against human prion diseases. This review is intended to put on display the more relevant animal models that have been used in the search of new antiprion therapies and describe some possible procedures when handling chemical compounds presumed to have anti-prion activity prior to testing them in animal models.

Alberdi E.,University of the Basque Country | Sanchez-Gomez M.V.,University of the Basque Country | Cavaliere F.,University of the Basque Country | Perez-Samartin A.,University of the Basque Country | And 4 more authors.
Cell Calcium | Year: 2010

Amyloid beta (Aβ) oligomers accumulate in brain tissue of Alzheimer disease patients and are related to pathogenesis. The precise mechanisms by which Aβ oligomers cause neurotoxicity remain unresolved. In this study, we investigated the role of ionotropic glutamate receptors on the intracellular Ca2+ overload caused by Aβ. Using rat cortical neurons in culture and entorhinal-hippocampal organotypic slices, we found that Aβ oligomers significantly induced inward currents, intracellular Ca2+ increases and apoptotic cell death through a mechanism requiring NMDA and AMPA receptor activation. The massive entry of Ca2+ through NMDA and AMPA receptors induced by Aβ oligomers caused mitochondrial dysfunction as indicated by mitochondrial Ca2+ overload, oxidative stress and mitochondrial membrane depolarization. Importantly, chronic treatment with nanomolar concentration of Aβ oligomers also induced NMDA- and AMPA receptor-dependent cell death in entorhinal cortex and hippocampal slice cultures. Together, these results indicate that overactivation of NMDA and AMPA receptor, mitochondrial Ca2+ overload and mitochondrial damage underlie the neurotoxicity induced by Aβ oligomers. Hence, drugs that modulate these events can prevent from Aβ damage to neurons in Alzheimer's disease. © 2009 Elsevier Ltd. All rights reserved.

Carracedo A.,CIC BioGUNE | Carracedo A.,Ikerbasque | Carracedo A.,University of the Basque Country | Cantley L.C.,Beth Israel Deaconess Medical Center | And 3 more authors.
Nature Reviews Cancer | Year: 2013

Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better understanding of the 'metabolic switch' in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a handful of metabolic pathways, while other pathways have remained in the dark. This Progress article brings to light the important contribution of fatty acid oxidation to cancer cell function. © 2013 Macmillan Publishers Limited. All rights reserved.

Kung F.,University of Maryland University College | Anguita J.,CIC bioGUNE | Anguita J.,Ikerbasque | Pal U.,University of Maryland University College
Future Microbiology | Year: 2013

Borrelia burgdorferi, a pathogen transmitted by Ixodes ticks, is responsible for a prevalent illness known as Lyme disease, and a vaccine for human use is unavailable. Recently, genome sequences of several B. burgdorferi strains and Ixodes scapularis ticks have been determined. In addition, remarkable progress has been made in developing molecular genetic tools to study the pathogen and vector, including their intricate relationship. These developments are helping unravel the mechanisms by which Lyme disease pathogens survive in a complex enzootic infection cycle. Notable discoveries have already contributed to understanding the spirochete gene regulation accounting for the temporal and spatial expression of B. burgdorferi genes during distinct phases of the lifecycle. A number of pathogen and vector gene products have also been identified that contribute to microbial virulence and/or persistence. These research directions will enrich our knowledge of vector-borne infections and contribute towards the development of preventative strategies against Lyme disease. © 2013 Future Medicine Ltd.

Min M.,University of Cambridge | Mayor U.,CIC BioGUNE | Mayor U.,Ikerbasque | Lindon C.,University of Cambridge
Open Biology | Year: 2013

Ordered progression of mitosis requires precise control in abundance of mitotic regulators. The anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase plays a key role by directing ubiquitin-mediated destruction of targets in a temporally and spatially defined manner. Specificity in APC/C targeting is conferred through recognition of substrate D-box and KEN degrons, while the specificity of ubiquitination sites, as another possible regulated dimension, has not yet been explored. Here, we present the first analysis of ubiquitination sites in the APC/C substrate ubiquitome. We show that KEN is a preferred ubiquitin acceptor in APC/C substrates and that acceptor sites are enriched in predicted disordered regions and flanked by serine residues. Our experimental data confirm a role for the KEN lysine as an ubiquitin acceptor contributing to substrate destruction during mitotic progression. Using Aurora A and Nek2 kinases as examples, we show that phosphorylation on the flanking serine residue could directly regulate ubiquitination and subsequent degradation of substrates. We propose a novel layer of regulation in substrate ubiquitination, via phosphorylation adjacent to the KEN motif, in APC/C-mediated targeting. © 2013 The Authors.

Herboso L.,CIC bioGUNE | Talamillo A.,CIC bioGUNE | Perez C.,CIC bioGUNE | Barrio R.,CIC bioGUNE
International Journal of Developmental Biology | Year: 2011

In mammals, cholesterol is transformed into steroid hormones in the adrenal gland, the ovaries or the testes. The Scavenger Receptors Class B Type I (SR-BI) are membrane proteins that belong to the CD36 family and participate in the selective uptake of high density lipoprotein cholesteryl ester in the mammalian steroidogenic tissues. Fourteen members of the CD36 family have been identified in Diptera, although their expression patterns remain uncharacterized. Using in situ hybridization we have characterized the expression patterns of the fourteen SR-BIs in Dro-sophila melanogaster. We analyzed three different developmental larval stages prior to and during the peak of the insect steroid hormone ecdysone, which triggers the larval to pupal transition. We focused on the steroidogenic tissues, such as the prothoracic gland, the ovaries and the testes, and extended our analysis to non-steroidogenic tissues, such as the fat body, salivary glands, the gut, the gastric caeca or the central nervous system. Our results show highly regulated expression patterns, with three genes crq, pes and Snmp being upregulated in steroidogenic tissues at the onset of pupariation when steroidogenesis is crucial. This study underlines the importance of the transport of cholesterol and steroids in the process of ecdysone synthesis. © 2011 UBC Press.

Nunez-O'Mara A.,CIC BioGUNE | Berra E.,CIC BioGUNE
Biological Chemistry | Year: 2013

By driving the primary transcriptional response, the h ypoxia i nducible f actor (HIF) is a master player of the hypoxia-signaling cascade, activation of which is essential to maintain oxygen homeostasis. HIF is formed by the interaction of a constitutive HIF-1 β subunit with a HIF- α subunit tightly regulated through the concerted action of the p rolyl h ydroxylase d omain containing proteins (PHDs) and factor inhibiting HIF. In welloxygenated cells, HIF- α prolyl-hydroxylation by PHDs is the recognition signal for the binding of the ubiquitin E3 ligase pVHL, allowing protein poly-ubiquitination and degradation by the proteasome. Factor inhibiting HIFmediated asparaginyl hydroxylation prevents interaction with the CBP/p300 coactivator and hence reduces HIF-dependent transcriptional activity. Upon low oxygen availability, HIF- α hydroxylation is blocked, resulting in protein stabilization and HIF complex activation. Post-translational modifications other than hydroxylation appear to be important in the cellular response to hypoxia. S mall ubiquitin-like mo difier (SUMO) is a 10 kDa protein readily conjugated to the lysine (K) residues of numerous cellular substrates in a sequential process termed SUMOylation. Recent data support the idea that a fine balance in SUMOylation/deSUMOylation is required for the adequate activation of the hypoxiasignaling cascade. In the present review, we will concentrate on the mechanisms of SUMOylation and its consequences in the cellular response to hypoxia.

Carnero E.,University of Navarra | Sutherland J.D.,CIC bioGUNE | Fortes P.,University of Navarra
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2011

Adenovirus infection has a tremendous impact on the cellular silencing machinery. Adenoviruses express high amounts of non-coding virus associated (VA) RNAs able to saturate key factors of the RNA interference (RNAi) processing pathway, such as Exportin 5 and Dicer. Furthermore, a proportion of VA RNAs is cleaved by Dicer into viral microRNAs (mivaRNAs) that can saturate Argonaute, an essential protein for miRNA function. Thus, processing and function of cellular miRNAs is blocked in adenoviral-infected cells. However, viral miRNAs actively target the expression of cellular genes involved in relevant functions such as cell proliferation, DNA repair or RNA regulation. Interestingly, the cellular silencing machinery is active at early times post-infection and can be used to control the adenovirus cell cycle. This is relevant for therapeutic purposes against adenoviral infections or when recombinant adenoviruses are used as vectors for gene therapy. Manipulation of the viral genome allows the use of adenoviral vectors to express therapeutic miRNAs or to be silenced by the RNAi machinery leading to safer vectors with a specific tropism. This article is part of a "Special Issue entitled:MicroRNAs in viral gene regulation". © 2011 Elsevier B.V.

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