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Laborda E.,Lhospitalet Of Llobregat | Laborda E.,Autonomous University of Barcelona | Puig-Saus C.,Lhospitalet Of Llobregat | Cascallo M.,VCN Biosciences | And 3 more authors.
Human Gene Therapy Methods | Year: 2013

The contamination of adenovirus (Ad) stocks with adeno-associated viruses (AAV) is usually unnoticed, and it has been associated with lower Ad yields upon large-scale production. During Ad propagation, AAV contamination needs to be detected routinely by polymerase chain reaction without symptomatic suspicion. In this study, we describe that the coinfection of either Ad wild type 5 or oncolytic Ad with AAV results in a large-plaque phenotype associated with an accelerated release of Ad from coinfected cells. This accelerated release was accompanied with the expected decrease in Ad yields in two out of three cell lines tested. Despite this lower Ad yield, coinfection with AAV accelerated cell death and enhanced the cytotoxicity mediated by Ad propagation. Intratumoral coinjection of Ad and AAV in two xenograft tumor models improved antitumor activity and mouse survival. Therefore, we conclude that accidental or intentional AAV coinfection has important implications for Ad-mediated virotherapy. © Mary Ann Liebert, Inc.


Lichtenstein M.P.,Autonomous University of Barcelona | Carriba P.,Autonomous University of Barcelona | Masgrau R.,Autonomous University of Barcelona | Pujol A.,Institute Catala Of Recerca I Estudis Avancats | And 3 more authors.
Frontiers in Aging Neuroscience | Year: 2010

The use of non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD) is controversial because conclusions from numerous epidemiological studies reporting delayed onset of AD in NSAID users have not been corroborated in clinical trials. The purpose of this personal view is to revise the case for NSAIDs in AD therapeutics in light of: (i) the last report from the only primary prevention trial in AD, ADAPT, which, although incomplete, points to significant protection in long-term naproxen users, and (ii) the recently proposed dynamic model of AD evolution. The model contends that there is a clinical silent phase in AD that can last up to 20 years, the duration depending on life style habits, genetic factors, or cognitive reserve. The failure of many purported disease-modifying drugs in AD clinical trials is forcing the view that treatments will only be efficacious if administered pre-clinically. Here we will argue that NSAIDs failed in clinical trials because they are disease-modifying drugs, and they should be administered in early stages of the disease. A complete prevention trial in cognitively normal individuals is thus called for. Further, the shift of anti-inflammatory treatment to early stages uncovers a knowledge void about the targets of NSAIDs in asymptomatic individuals. AD researchers have mostly relied on post-mortem analysis of Aβ plaque-laden brains from demented patients or animal models, thus drawing conclusions about AD pathogenesis based on late symptoms. We will discuss evidence in support that defective, not excessive, inflammation underlies AD pathogenesis, that NSAIDs are multifunctional drugs acting on inflammatory and non-inflammatory targets, and that astrocytes and microglia may play differing roles in disease progression, with an emphasis of ApoEe4 as a key, undervalued target of NSAIDs. According to a meta-analysis of epidemiological data, NSAIDs afford an average protection of 58%. If this figure is true, and translated into patient numbers, NSAID treatment may revive as a worth pursuing strategy to significantly reduce the socio-economical burden imposed by AD. © 2010 Lichtenstein, Carriba, Masgrau, Pujol and Galea.


Boyles M.S.P.,University of Salzburg | Kristl T.,University of Salzburg | Andosch A.,University of Salzburg | Zimmermann M.,University of Salzburg | And 8 more authors.
Journal of Nanobiotechnology | Year: 2015

Background: Gold nanoparticles (AuNPs) are a popular choice for use in medical and biomedical research applications. With suitable functionalisation AuNPs can be applied in drug delivery systems, or can aid in disease diagnosis. One such functionalisation is with chitosan, which enables efficient interaction and permeation of cellular membranes, providing an effective adjuvant. As both AuNPs and chitosan have been shown to have low toxicity and high biocompatibility their proposed use in nanomedicine, either individually or combined, is expanding. However, further toxicological and immunological assessments of AuNP-chitosan conjugates are still needed. Therefore, we have evaluated how AuNP functionalisation with chitosan can affect uptake, cytotoxicity, and immunological responses within mononuclear cells, and influence the interaction of AuNPs with biomolecules within a complex biofluid. The AuNPs used were negatively charged through citrate-coating, or presented either low or high positive charge through chitosan-functionalisation. Uptake by THP-1 cells was assessed via transmission electron microscopy and electron energy loss spectroscopy, pro-inflammatory responses by ELISA and qRT-PCR, and cell death and viability via lactate dehydrogenase release and mitochondrial activity, respectively. Interactions of AuNPs with protein components of a frequently used in vitro cell culture medium supplement, foetal calf serum, were investigated using mass spectrometry. Results: Although cells internalised all AuNPs, uptake rates and specific routes of intracellular trafficking were dependent upon chitosan-functionalisation. Accordingly, an enhanced immune response was found to be chitosan-functionalisation-dependent, in the form of CCL2, IL-1β, TNF-aα and IL-6 secretion, and expression of IL-1β and NLRP3 mRNA. A corresponding increase in cytotoxicity was found in response to chitosan-coated AuNPs. Furthermore, chitosan-functionalisation was shown to induce an increase in unique proteins associating with these highly charged AuNPs. Conclusions: It can be concluded that functionalisation of AuNPs with the perceived non-toxic biocompatible molecule chitosan at a high density can elicit functionalisation-dependent intracellular trafficking mechanisms and provoke strong pro-inflammatory conditions, and that a high affinity of these NP-conjugates for biomolecules may be implicit in these cellular responses. © 2015 Boyles et al.


Ariza L.,Autonomous University of Barcelona | Gimenez-Llort L.,Autonomous University of Barcelona | Cubizolle A.,Montpellier University | Pages G.,Autonomous University of Barcelona | And 8 more authors.
Human Gene Therapy | Year: 2014

Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders because of their preferential transduction of neurons and efficient retrograde axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing β-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in β-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction. After intracranial administration of HD-RIGIE, we show long-term expression of β-glucuronidase that led to correction of neuropathology around the injection site and in distal areas. This phenotypic correction correlated with a decrease in secondary-elevated lysosomal enzyme activity and glycosaminoglycan levels, consistent with global biochemical correction. Moreover, HD-RIGIE-treated mice show significant cognitive improvement. Thus, injections of HD-CAV-2 vectors in the brain allow a global and sustained expression and may have implications for brain therapy in patients with lysosomal storage disease. © Copyright 2014, Mary Ann Liebert, Inc. 2014.


Puntes V.,Institute Catala Of Recerca I Estudis Avancats | Puntes V.,Vall D Hebron Research Institute
British Journal of Radiology | Year: 2015

The potential use of nanoparticles (NPs) in medicine is determined by the pharmacokinetical and biodistribution aspects that govern NP behaviour. In this context, diagnosis (low irradiation dose) and therapy (high irradiation dose) is about the same for the NP, as much as to deliver toxic doses of radiation or toxic doses of a chemotherapeutic agent. The NP effects also have to be correlated with how they interact, evolve and are transformed during their exposure to the human body, during their administration, distribution, metabolization and expulsion. Indeed, owing to interactions between NPs and components from the biological medium, NPs are known to suffer different types of alterations, such as loss of colloidal stability (aggregation and sedimentation), protein adsorption (and consequent exposure to or escape from the immune system) and chemical transformation (oxidation, corrosion and dissolution). Their original performance and these alterations have a major impact on NP behaviour and have to be taken into account for any intended use of them in medicine, also including their use for enhanced radiodiagnosis, radiotherapy and radiochemotherapy. © 2015 The Authors. Published by the British Institute of Radiology.


Sanchez A.,Autonomous University of Barcelona | Recillas S.,Autonomous University of Barcelona | Font X.,Autonomous University of Barcelona | Casals E.,Autonomous University of Barcelona | And 3 more authors.
TrAC - Trends in Analytical Chemistry | Year: 2011

This article presents recent developments on the use of inorganic nanoparticles (NPs) for environmental remediation in polluted soil, water and gas. The number of publications on these topics has grown exponentially in recent years, especially those focused on wastewater treatment. Among these topics, removal of metals has become the most popular, although some works relate to the use of nanomaterials for the elimination of nutrients (e.g., nitrogen and some persistent organic pollutants). However, this growth has not been accompanied by knowledge about the behavior of NPs once used and released into the environment. In this article, we also comment upon the current situation with respect to NP toxicology (nanotoxicology). A remarkable number of different toxicology tests has been applied to NPs, often making it very difficult to interpret or to generalize the results. We analyze in detail the bioluminescence, Daphnia magna and other tests, and give some preliminary results obtained in our work. © 2011.


Contreras A.R.,Autonomous University of Barcelona | Casals E.,Autonomous University of Barcelona | Puntes V.,Autonomous University of Barcelona | Puntes V.,Institute Catala Of Recerca I Estudis Avancats | And 3 more authors.
Global Nest Journal | Year: 2015

Cerium oxide (CeO2) nanoparticles (NPs) were used for the removal of cadmium (II), lead (II) and chromium (VI) ions in single aqueous solutions and in solutions with mixtures of the three metals. The adsorption studies were carried out at pH 5 and 7 using a systematic factorial experimental design that considered the metal concentration from 1 mg l-1 to 10 mg l-1 and NP concentration from 0.064 g l-1 to 0.640 g l-1. The highest adsorption capacity was obtained in the removal of lead (II) (128.1 mg g-1), followed by cadmium (II) (93.4 mg g-1) and finally chromium (VI) (34.4 mg g-1). Data were fitted to a polynomial function obtaining the best reduced models. The type of system (single, multi-component) did not affect sorption capacity, whilst pH affected the sorption of Cd and Cr, but not that of lead. CeO2 nanoparticles proved to be effective adsorbents in removing all three heavy metals in multi-component systems, which opens a new window for their use as sorbent materials in complex waters contaminated with mixtures of heavy metals. © 2015 Global NEST Printed in Greece. All rights reserved.


Garcia A.,Autonomous University of Barcelona | Delgado L.,Autonomous University of Barcelona | Tora J.A.,Autonomous University of Barcelona | Casals E.,Autonomous University of Barcelona | And 6 more authors.
Journal of Hazardous Materials | Year: 2012

Growth in production and use of nanoparticles (NPs) will result increased concentrations of these in industrial and urban wastewaters and, consequently, in wastewater-treatment facilities. The effect of this increase on the performance of the wastewater-treatment process has not been studied systematically and including all the microbial communities involved in wastewater treatment. The present work investigates, by using respiration tests and biogas-production analysis, the inhibitory effect of four different commonly used metal oxide (CeO 2 and TiO 2) and zero-valent metal (Ag and Au) nanoparticles on the activity of the most important microbial communities present in a modern wastewater-treatment plant. Specifically, the actions of ordinary heterotrophic organisms, ammonia oxidizing bacteria, and thermophilic and mesophilic anaerobic bacteria were tested in the presence and absence of the nanoparticles. In general, CeO 2 nanoparticles caused the greatest inhibition in biogas production (nearly 100%) and a strong inhibitory action of other biomasses; Ag nanoparticles caused an intermediate inhibition in biogas production (within 33-50%) and a slight inhibition in the action of other biomasses, and Au and TiO 2 nanoparticles caused only slight or no inhibition for all tested biomasses. © 2011 Elsevier B.V.


Piedra J.,Autonomous University of Barcelona | Ontiveros M.,Autonomous University of Barcelona | Miravet S.,Autonomous University of Barcelona | Penalva C.,Autonomous University of Barcelona | And 3 more authors.
Human Gene Therapy Methods | Year: 2015

Recombinant adeno-associated viruses (rAAVs) are promising vectors in preclinical and clinical assays for the treatment of diseases with gene therapy strategies. Recent technological advances in amplification and purification have allowed the production of highly purified rAAV vector preparations. Although quantitative polymerase chain reaction (qPCR) is the current method of choice for titrating rAAV genomes, it shows high variability. In this work, we report a rapid and robust rAAV titration method based on the quantitation of encapsidated DNA with the fluorescent dye PicoGreen®. This method allows detection from 3×1010 viral genome/ml up to 2.4×1013 viral genome/ml in a linear range. Contrasted with dot blot or qPCR, the PicoGreen-based assay has less intra- and interassay variability. Moreover, quantitation is rapid, does not require specific primers or probes, and is independent of the rAAV pseudotype analyzed. In summary, development of this universal rAAV-titering method may have substantive implications in rAAV technology. © Mary Ann Liebert, Inc. 2015.

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