Stereoselective synthesis of tetrahydroindolizines via catalytic formation of pyridinium ylides from diazo compounds

Commercially available iron (III) and copper (I) complexes catalyze new multicomponent cycloadditions between diazo compounds, pyridines and electrophilic alkenes to give alkaloid-inspired tetrahydroindolizidines in high yields and diastereoselectivities. Hitherto, catalytic formation of versatile pyridinium ylides from metal carbenes has been poorly developed; the broad utility demonstrated herein sets the stage for invention of further multicomponent reactions in future

Rapid hemodilution induced by desmopressin after erythropoietin administration in humans

We have shown that treatment with desmopressin has a very effective hemodilution effect in healthy humans. These results led us to suggest the possible role of desmopressin to mask blood doping in sports. Based on our results, the World Anti-Doping Agency included the desmopressin in the 2011 List of Prohibited Substances and Methods. On this occasion, the aim of our study was to test the desmopressin-induced hemodilution after rHuEpo administration in humans. This was an intra-subject, crossover study in which five physically active males acted as their own controls. A basal blood sample was taken on their first visit to the laboratory. The next day, the subjects began the treatment. They received a subcutaneous rHuEpo injection three times/week for a two-week period. On the second visit to the laboratory, seventeen days later, a blood sample was taken. Thereafter, the subjects received an oral dose of 4.3 μg/kg of desmopressin and were instructed to ingest 1.5 liters of mineral water during the following fifteen minutes. Three hours after the water ingestion a second blood sample was obtained. The samples were analyzed for hematocrit (HCT), hemoglobin (Hb), reticulocytes (Ret%) and OFF Hr-Score. We found significantly higher HCT, Hb and Ret% levels after rHuEpo administration. Administration of desmopressin significantly decreased the HCT and Hb values but we did not find significant changes in Ret%. The values of the OFF Hr-Score also decreased after treatment with desmopressin. Desmopressin has a very effective hemodilution effect after rHuEpo administration and significantly modifies the hematological values measured by the anti-doping authorities to detect blood doping. We consider that these results reinforce the conclusions reported in our first study and confirm that desmopressin is a very effective masking agent for blood doping.This work was supported by grants SAF2008-00270; SAF2009-08334; BFU2007-65803/BFI; from the Spanish Ministry of Education and Science (MEC); PROMETEO/2010/074 from the Consellería de Educación de la Generalitat Valenciana. ISCIII2006-RED13-027 from the “Red Temática de investigación cooperativa en envejecimiento y fragilidad (RETICEF)”, EU Funded COSTB35 and DPS2008-06968 from Spanish Ministry of Innovation and Science. This study has been co-financed by FEDER funds from the European Union

(Bio)isosteres of Nucleotides: When the Furanosyl Unit is Modified

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Sarcopenie : mécanismes et prévention : rôle de l'exercice et de l'hormone de croissance : implication du stress oxydant et de la glucose-6-phosphate déshydrogénase

Aging is characterized by a decrease in muscle mass and strength causing a deterioration of physical performance, called sarcopenia. Muscle atrophy can be explained by a negative protein turnover, impaired mitochondrial dynamics, a decreased muscle regeneration capacity and myonuclei apoptosis. A decreased production of anabolic hormones and a chronic oxidative stress (OS) which leads to excessive oxidative damage would be involved in these alterations. Physical exercise and hormone replacement therapies are effective to combat sarcopenia. The restoration of a redox homeostasis may play a central role in their beneficial effects and would involve an up-regulation of the glucose-6-phosphate dehydrogenase enzyme.The main objectives of this thesis were to determine in vivo to what extent a pro-oxidant redox status in aged muscle may modulate signaling pathways involved in sarcopenia, and to investigate whether return to their normal functioning requires a restoration of the redox homeostasis. The third objective was to identify actors and their possible cellular mechanisms in the maintenance and/or the restoration of the redox status.In a first study in old rats, we first confirmed that sarcopenia is associated with OS. In a second time, we found that a growth hormone replacement therapy in olds rats prevents sarcopenia by acting as a double-edged sword, antioxidant as well as myogenic, associated with an up-regulation of G6DPH.Le vieillissement est caractérisé par une diminution de la masse et la force musculaire entraînant une détérioration des performances physiques, appelée sarcopénie. L'atrophie musculaire peut être expliquée par un turnover protéique négatif, une détérioration des dynamiques mitochondriales, une diminution de la capacité de régénération du muscle ainsi que par l'apoptose des noyaux musculaires. La diminution de la sécrétion d'hormones anabolisantes et un stress oxydant (OS) chronique conduisant à des dommages oxydatifs excessifs, seraient impliqués dans ces modifications. L’Exercice physique et les thérapies de remplacement hormonales sont efficaces pour lutter contre la sarcopénie. Une restauration de l’homéostasie redox pourrait avoir un rôle central dans la lutte contre la sarcopénie et impliquerait une activation de la glucose-6-phosphate déshydrogénase.Les principaux objectifs de cette thèse étaient de déterminer in vivo, si un SO chronique dans le muscle âgé altère les voies de signalisation impliquées dans la sarcopénie, et de chercher si le retour à un fonctionnement normal de ces voies nécessite une restauration de l'homéostasie redox. Certains paramètres et leurs mécanismes pouvant intervenir sur le maintien ou la restauration du SO ont été recherchés.Dans une première, nous avons confirmé que la sarcopénie est associée au OS chez le rat. Puis nous avons constaté qu’un traitement à l'hormone de croissance chez le rat peut prévenir la sarcopénie via un effet antioxydant et myogénique, associé à une activation de la G6DPH.Une seconde étude a monté des souris transgéniques surexprimant G6PDH présentaient une amélioration de la composition corporelle et des performances physiques.Une dernière étude a montré que la surexpression de G6DPH diminuait les dommages oxydatifs de l'ADN au repos. De façon surprenante, la surexpression de la G6PDH n’a pas d’effet protecteur vis à vis du SO induit par les divers stimuli pro-oxydants