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Les ROS ont depuis toujours été considérés nocifs pour les cellules P pancréatiques car ils altèrent la structure et la fonction des composants moléculaires de la cellule. Cependant, une théorie récente accorde un rôle bénéfique à l'H202. En effet, en agissant en tant que messager secondaire, il aurait la capacité d'activer la stimulation de la sécrétion d'insuline par le glucose. Cette théorie est toutefois controversée. Il a ainsi été démontré que si l'on surexprime dans les cellules p la catalase qui décompose l'H202 en H20 et 02, on ne modifie pas la stimulation de la sécrétion d'insuline par le glucose.L'objectif de mon mémoire est d'étudier de manière approfondie les éventuels changements de la concentration d'H202 dans la cellule p, et plus particulièrement dans le cytosol et la matrice mitochondriale de ces cellules, suite à la stimulation par différents nutriments . Pour cela, nous avons décidé d'utiliser la sonde protéique ratiométrique roGFP2-0rpl, un outil permettant de détecter spécifiquement l'H202, encodée par un adénovirus. Nous avons fabriqué la sonde mitochondriale à partir de la sonde cytosolique à laquelle une séquence d'adressage mitochondriale a été ajoutée.J'ai d'abord montré que la sonde roGFP2-0rpl était effectivement sensible à l'H202 : elle détecte des concentrations d'H202 relativement faibles, 5 µM dans le cytosol et 20 µM dans la matrice mitochondriale. Ensuite, j'ai observé que la stimulation par le glucose ne provoquait pas de modification de la concentration d'H202 dans le cytosol de la cellule p. Néanmoins, enprésence de 15 µM d'H202 d'origine exogène, j'ai observé une augmentation de l'oxydation de la sonde cytosolique lorsque la concentration de glucose est réduite de 10 à 0.5 mM, suggérant que le glucose protège les cellules p pancréatiques en modulant leur capacité dedégradation de l'H202 exogène. Stimuler des cellules p pancréatiques avec des substrats mitochondriaux insulinosécrétagogues semble également les protéger face à l'H202. Dans la mitochondrie, la sonde roGFP2-0rpl est davantage oxydée que dans le cytosol quelle que soit la concentration de glucose à laquelle les cellules sont exposées. Cependant, j'ai observé une augmentation de l'oxydation de la sonde mitochondriale lors d'une diminution de la concentration de glucose de 10 à 2 mM en absence d'H202 exogène. Ceci suggère que la production mitochondriale d'H202 est plus faible en présence d'une concentration stimulantede glucose ou bien que sa dégradation par les défenses antioxydantes est accélérée. Car en effet, après la surexpression de la mitocatalase dans les cellules p pancréatiques, l'effet du G2 sur la sonde mt-roGFP2-0rpl n'est pas modifié, suggérant qu'il n'y a pas d'augmentation de la production mitochondriale d'H202 lors de l'exposition au G2. ROS have always been considered harmful to pancreatic P-cells because they alter the structure and the function of molecular components of the cell. However, a recent theory grants a beneficial role to H202. In fact, by acting as a secondary messenger, it would have the ability to activate glucose-stimulated insulin secretion. This theory is nevertheless controversed. Indeed, it has been shown that P-cells overexpression of catalase, which decomposes H202 in H20 and 02, does not change the glucose-stimulated insulin secretion.The aim of my master thesis is to investigate thoroughly any change in the concentration of H202 in the P-cells, and more particularly in the cytosol and the mitochondrial matrix of these cells, following the stimulation by different nutrients. For this, we decided to use the ratiometric and proteic probe roGFP2-0rpl, a specific tool for the detection of H202, encoded by an adenovirus. We constructed the mitochondrial probe by adding a mitochondrial targeting sequence to that coding the cytosolic probe.I first showed that roGFP2-0rpl was highly sensitive to H202 : it detected relatively low concentrations of H202, 5 µM in the cytosol and 20 µM in the mitochondrial matrix. Then I observed that the glucose stimulation caused no change in the concentration of H202 in the cytosol of pancreatic P-cells. However, in the presence of 15 µM of exogenous H202, I observed an increase in the oxidation of the cytosolic probe when the glucose concentration was reduced from 10 to 0.5 mM, suggesting that the glucose protects P-cells by modulating their ability to degrade exogenous H202. It seems that the stimulation of pancreatic P-cells with insulin secretagogue mitochondrial substrates also protects them against H202. In the mitochondria, the probe roGFP2-0rp 1 is more oxidized than in the cytosol for any glucose concentration to which the cells are exposed. However, I have observed an increase in the mitochondrial oxidation of the probe during a decrease of the glucose concentration from 10 mM to 2 mM in the absence of exogenous H202. This suggests that the mitochondrial production of H202 was lower in the presence of a stimulating glucose concentration or that its degradation by the antioxidant defenses was accelerated. Indeed, after the overexpression of mitocatalase in pancreatic P-cells, the effect of G2 on the probe mt-roGFP2-0rp 1 was not changed, suggesting that H202 production does not increase upon exposure to G2 .

Insulin-Secreting Cells --- Cytosol --- mitochondrial processing peptidase

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Diabetes Mellitus, Type 2 --- Dipeptidyl-Peptidase IV Inhibitors

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Cardiovascular disease (CVD) is the most common cause of morbidity and mortality worldwide, putting a major burden on life quality and social health care systems. Type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) have been identified as important risk factors for CVD, severely increasing the risk on e.g. myocardial infarction, and cardiovascular complications constitute the main cause of death in patients presenting with T2DM, CKD or a combination of both. As these pathologies are expected to rise alarmingly in the next decades, a better understanding of molecular and cellular mechanisms contributing to T2DM, CKD and CVD is required to improve prevention and treatment of these diseases. Furthermore, insight into the interplay between these pathologies and identification of molecular players interconnecting these comorbidities is of tremendous importance for optimal health management in the future. This Research Topic will focus on the chemokine receptor CXCR4 and its ligands CXCL12/SDF-1a and macrophage migration inhibitory factor (MIF) in the context of CVD and its link with T2DM and CKD, as well as address dipeptidyl peptidase-4 (DPP4) as an important protease destabilizing CXCL12. Chemokines and their receptors are important mediators of cell mobilization, recruitment and arrest, and also more broadly induce cell activation by triggering various intracellular signalling tracks. They control homeostatic conditions, but are also critically involved in inflammatory and pathological processes. Genome-wide association studies revealed single nucleotide polymorphisms connecting CXCL12 as well as MIF with CVD, and a role for both chemokines in T2DM and CKD has also been reported. In this review collection, current knowledge on molecular aspects of the CXCR4 ligand/receptor family and associated signalling pathways will be discussed. The physiological roles of CXCR4, CXCL12, MIF and DPP4 will be summarized, and recent findings on their function in pathological conditions of CVD, T2DM and CKD will be highlighted. This is combined with an extensive introduction providing insight into the pathologies of CVD, T2DM and CKD, discussing clinical features and common pathological aspects of these comorbidities on cellular and molecular level. Also, an overview of available animal models to study these diseases will be provided. This way, this Research Topic summarizes latest knowledge on this crucial molecular axis and its relationship with cardiovascular pathologies for both specialists and interested non-specialists and aims to stimulate further initiatives to unravel the mechanistic involvement of the CXCR4 ligand/receptor family in these morbidities, potentially paving the way for new therapeutical initiatives in the future.

cardiovascular disease --- chemokine --- CXCL12/SDF-1 --- dipeptidyl peptidase --- CXCR4 --- kidney disease --- MIF --- DPP4/CD26 --- diabetes --- chemokine receptor

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Cardiovascular disease (CVD) is the most common cause of morbidity and mortality worldwide, putting a major burden on life quality and social health care systems. Type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) have been identified as important risk factors for CVD, severely increasing the risk on e.g. myocardial infarction, and cardiovascular complications constitute the main cause of death in patients presenting with T2DM, CKD or a combination of both. As these pathologies are expected to rise alarmingly in the next decades, a better understanding of molecular and cellular mechanisms contributing to T2DM, CKD and CVD is required to improve prevention and treatment of these diseases. Furthermore, insight into the interplay between these pathologies and identification of molecular players interconnecting these comorbidities is of tremendous importance for optimal health management in the future. This Research Topic will focus on the chemokine receptor CXCR4 and its ligands CXCL12/SDF-1a and macrophage migration inhibitory factor (MIF) in the context of CVD and its link with T2DM and CKD, as well as address dipeptidyl peptidase-4 (DPP4) as an important protease destabilizing CXCL12. Chemokines and their receptors are important mediators of cell mobilization, recruitment and arrest, and also more broadly induce cell activation by triggering various intracellular signalling tracks. They control homeostatic conditions, but are also critically involved in inflammatory and pathological processes. Genome-wide association studies revealed single nucleotide polymorphisms connecting CXCL12 as well as MIF with CVD, and a role for both chemokines in T2DM and CKD has also been reported. In this review collection, current knowledge on molecular aspects of the CXCR4 ligand/receptor family and associated signalling pathways will be discussed. The physiological roles of CXCR4, CXCL12, MIF and DPP4 will be summarized, and recent findings on their function in pathological conditions of CVD, T2DM and CKD will be highlighted. This is combined with an extensive introduction providing insight into the pathologies of CVD, T2DM and CKD, discussing clinical features and common pathological aspects of these comorbidities on cellular and molecular level. Also, an overview of available animal models to study these diseases will be provided. This way, this Research Topic summarizes latest knowledge on this crucial molecular axis and its relationship with cardiovascular pathologies for both specialists and interested non-specialists and aims to stimulate further initiatives to unravel the mechanistic involvement of the CXCR4 ligand/receptor family in these morbidities, potentially paving the way for new therapeutical initiatives in the future.

cardiovascular disease --- chemokine --- CXCL12/SDF-1 --- dipeptidyl peptidase --- CXCR4 --- kidney disease --- MIF --- DPP4/CD26 --- diabetes --- chemokine receptor

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Proteolytic enzymes. --- Peptide Hydrolases --- Esteroproteases --- Peptidases --- Proteases --- Proteinases --- Proteolytic Enzymes --- Gene Products, pol --- Peptide hydrolases --- Hydrolases --- Peptidase --- Peptide Hydrolase --- Protease --- Proteinase --- Proteolytic Enzyme --- Enzyme, Proteolytic --- Hydrolase, Peptide