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Oxygen is a powerful trigger for cellular reactions and is used in many pathologies, including oxidative stress. However, the effects of oxygen over time and at different partial pressures remain poorly understood. In this study, the metabolic responses of normobaric oxygen intake for 1 h to mild (30%) and high (100%) inspired fractions were investigated. Fourteen healthy non-smoking subjects (7 males and 7 females; age: 29.9 ± 11.1 years, height: 168.2 ± 9.37 cm; weight: 64.4 ± 12.3 kg; BMI: 22.7 ± 4.1) were randomly assigned in the two groups. Blood samples were taken before the intake at 30 min, 2 h, 8 h, 24 h, and 48 h after the single oxygen exposure. The level of oxidation was evaluated by the rate of reactive oxygen species (ROS) and the levels of isoprostane. Antioxidant reactions were observed by total antioxidant capacity (TAC), superoxide dismutase (SOD), and catalase (CAT). The inflammatory response was measured using interleukin-6 (IL-6), neopterin, creatinine, and urates. Oxidation markers increased from 30 min on to reach a peak at 8 h. From 8 h post intake, the markers of inflammation took over, and more significantly with 100% than with 30%. This study suggests a biphasic response over time characterized by an initial "permissive oxidation" followed by increased inflammation. The antioxidant protection system seems not to be the leading actor in the first place. The kinetics of enzymatic reactions need to be better studied to establish therapeutic, training, or rehabilitation protocols aiming at a more targeted use of oxygen., SCOPUS: ar.j, info:eu-repo/semantics/published

Vaccination of dendritic cells (DC) combined with GM-CSF secreting tumor cells has shown good therapeutic efficacy in several tumor models. Nevertheless, the engineering of GM-CSF secreting tumor cell line could represent a tedious step limiting its application for treatment in patients. We therefore developed in rats, an "all in vivo" strategy of combined vaccination using an in vivo local irradiation of the tumor as a source of tumor antigens for DC vaccines and an exogenous source of GM-CSF. We report here that supplying recombinant mGM-CSF by local injections or surgical implantation of osmotic pumps did not allow reproducing the therapeutic efficacy observed with in vitro prepared combined vaccines. To bypass this limitation possibly due to the short half-life of recombinant GM-CSF, we have generated adeno-associated virus coding for mGM-CSF and tested their efficacy to transduce tumor cells in vitro and in vivo. The in vivo vaccines combining local irradiation and AAV2/1-mGM-CSF vectors showed high therapeutic efficacy allowing to cure 60% of the rats with pre-implanted tumors, as previously observed with in vitro prepared vaccines. Same efficacy has been observed with a second generation of vaccines combining DC, local tumor irradiation, and the controlled supply of recombinant mGM-CSF in poloxamer 407, a biocompatible thermoreversible hydrogel. By generating a successful "all in vivo" vaccination protocol combining tumor radiotherapy with DC vaccines and a straightforward supply of GM-CSF, we have developed a therapeutic strategy easily translatable to clinic that could become accessible to a much bigger number of cancer patients. © 2010 Springer-Verlag., SCOPUS: ar.j, info:eu-repo/semantics/published

Huntington's disease (HD) is a progressive neurodegenerative genetic disorder that leads to motor, cognitive, and psychiatric disturbances. The primary neuropathological hallmark is atrophy of the striatum. HD preferentially affects efferent striato-pallidal neurons that express enkephalin as well as dopamine D2 and A(2A) adenosine receptors (A(2A)Rs). Expression and function of A(2A)Rs are altered in HD but, despite being an important modulator of the striato-pallidal function, the subsequent pathophysiological consequence of such changes remains unclear. Whether blockade of A(2A)Rs is of therapeutic interest in HD remains ill-defined. In the present work, we aimed to determine the pathophysiological consequences of genetic deletion of A(2A)Rs in HD by crossing A(2A)R knockout mice with the N171-82Q HD transgenic model. Our data demonstrate that knockout of A(2A)Rs moderately but significantly worsens motor performances and survival of N171-82Q mice and leads to a decrease in striatal enkephalin expression. These results support that early and chronic blockade of A(2A)Rs might not be beneficial in HD., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

We have evaluated the neuroprotective effects of citicoline in relevant phenotypic models of Huntington's disease induced by either the mitochondrial inhibitor 3-nitropropionic acid or the N-methyl-D-aspartate agonist quinolinic acid, which, respectively, reproduce the metabolic defect or the excitotoxicity seen in the disease. We found that citicoline failed to reverse behavioural and histological alterations induced by both neurotoxins. In addition, citicoline did not reduce PC12 cell death induced by the expression of an N-terminal fragment of mutated Huntingtin. Altogether, our results suggest that citicoline is not a potential therapeutic agent for the treatment of Huntington's disease., Journal Article, info:eu-repo/semantics/published