<p>Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanism mediating the negative influence of hyperglycaemia on renal function is unclear, although several hypotheses have been postulated. Glucose-induced excessive formation of reactive oxygen species (ROS) and increased glucose flux through the polyol pathway are two major mechanisms that have recently gained increasing support. In order to investigate the development of hyperglycaemia-induced renal alterations further, it is of great importance to use an animal model in agreement with the pathological development in diabetic patients.</p><p>The aims of these investigations were to evaluate the streptozotocin (STZ)-diabetic Wistar Furth rat as a model for human diabetic nephropathy and to investigate involvement of ROS and the polyol pathway in development of diabetes-induced renal alterations.</p><p>The used STZ-diabetic animal model displayed several similarities with the progression of human disease, including initial hyperfiltration and albuminuria. However, the observed proteinuria could be partly linked to the STZ treatment <i>per se</i>, making the use of this animal model less suitable for research concerning diabetes-induced urinary protein leakage.</p><p>The diabetic state induced numerous alterations in renal function and metabolism, including increased oxygen consumption, decreased renal oxygen tension (pO₂), and altered lactate/pyruvate ratio. These renal alterations were preventable by daily treatment with either a radical scavenger (α-tocopherol) or an aldose reductase inhibitor (AL-1576).</p><p>In separate experiments the influence of nitric oxide (NO) on renal blood perfusion and pO₂ was investigated. The diabetic animals displayed a larger increase in renal NO activity after injecting the NO substrate L-arginine compared to non-diabetic animals, suggesting substrate limitation of the nitric oxide synthase during chronic hyperglycaemia.</p><p>In conclusion, the results from these investigations show that both ROS and the polyol pathway are involved in the development of diabetes-induced renal alterations in the STZ- diabetic Wistar Furth rat.</p>

Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanism mediating the negative influence of hyperglycaemia on renal function is unclear, although several hypotheses have been postulated. Glucose-induced excessive formation of reactive oxygen species (ROS) and increased glucose flux through the polyol pathway are two major mechanisms that have recently gained increasing support. In order to investigate the development of hyperglycaemia-induced renal alterations further, it is of great importance to use an animal model in agreement with the pathological development in diabetic patients. The aims of these investigations were to evaluate the streptozotocin (STZ)-diabetic Wistar Furth rat as a model for human diabetic nephropathy and to investigate involvement of ROS and the polyol pathway in development of diabetes-induced renal alterations. The used STZ-diabetic animal model displayed several similarities with the progression of human disease, including initial hyperfiltration and albuminuria. However, the observed proteinuria could be partly linked to the STZ treatment per se, making the use of this animal model less suitable for research concerning diabetes-induced urinary protein leakage. The diabetic state induced numerous alterations in renal function and metabolism, including increased oxygen consumption, decreased renal oxygen tension (pO2), and altered lactate/pyruvate ratio. These renal alterations were preventable by daily treatment with either a radical scavenger (α-tocopherol) or an aldose reductase inhibitor (AL-1576). In separate experiments the influence of nitric oxide (NO) on renal blood perfusion and pO2 was investigated. The diabetic animals displayed a larger increase in renal NO activity after injecting the NO substrate L-arginine compared to non-diabetic animals, suggesting substrate limitation of the nitric oxide synthase during chronic hyperglycaemia. In conclusion, the results from these investigations show that both ROS and the polyol pathway are involved in the development of diabetes-induced renal alterations in the STZ- diabetic Wistar Furth rat.

Les cancers des Voies Aérodigestives Supérieures sont classés parmi les dix cancers les plus agressifs du fait de leur radioresistance intrinsèque et leur forte probabilité de récurrence. L’objectif de ce travail a été d’étudier le potentiel radiosensibilisant de nanoparticules à base de gadolinium, AGuIX®, sur un modèle cellulaire de cancer des VADS. Après avoir déterminé et validé les conditions optimales de radiosensibilisation de notre modèle par les AGuIX®, leur localisation après internalisation ainsi que les conséquences biologiques générées à l’échelle subcellulaire ont été successivement étudiées. Enfin, une approche préliminaire protéomique a été initiée afin d’identifier des cibles moléculaires potentielles impliquées dans cette radiosensibilisation. Le traitement des cellules SQ20B avec 0.8mM Gd pendant 24h se sont révélées être optimales avec un DEF (dose enhancement factor) de 1.3. Les AGuIX® sont localisées presque exclusivement dans les lysosomes après internalisation. La radiosensibilisation est liée à une surproduction de radicaux libres oxygénés, minimisée toutefois par des défenses antioxydantes endogènes élevées. Le traitement combiné (AGuIX®+ irradiation) déclenche spécifiquement la mort cellulaire autophagique et s’accompagne d’une augmentation significative du nombre de cassures double brins résiduelles complexes. L’étude protéomique préliminaire a permis d’identifier une cible moléculaire potentiellement impliquée dans cette radiosensibilisation (la ribonucléotide réductase), cible qui fera l’objet d’une suite à ce travail. De plus, la prochaine étape sera de comprendre les mécanismes qui relient les AGuIX® internalisées dans les lysosomes avec l’augmentation de la mort cellulaire autophagique après irradiation / Head and Neck Squamous Cell Carcinoma is ranked among the top ten deadliest cancers due to its high radioresistance and recurrence. One radiosensitizing strategy is the use of high-Z metal nanoparticles. In this study, ultrasmall gadolinium-based nanoparticles, AGuIX®, were used for their potential as a radiosensitizing agent. The objectives of this work were to determine the radiosensitizing conditions of AGuIX® in an HNSCC cell model, their localization after uptake, and the biological consequences generated at the subcellular level after the combined treatment. A preliminary proteomic approach was initiated in order to identify potential molecular targets involved in radiosensitization. The treatment of SQ20B cells with 0.8mM Gd for 24h resulted in a dose enhancement factor (DEF) of 1.3. AGuIX® were predominantly localized in lysosomes. The overproduction of radical oxygen species following AGuIX® + radiation was intimately involved in the radiosensitization, although largely subdued by the high level of endogenous antioxidant defenses. Autophagy was specifically triggered after the combined treatment, while other irradiation-induced cell deaths remained unchanged. The number of complex, residual double strand breaks (DSBs) was specifically increased with AGuIX® combined to radiation. Lastly, our preliminary proteomic analysis allowed the isolation of potential molecular targets with great promise. Collectively, it seems that the radiosensitizing effect observed in this work may result from a combination of events.Future work is required to understand the mechanisms linking lysosomes-entrapped AGuIX® with the upregulation of autophagic cell death after radiation