Th.--Méd.--Reims, 1981. N°: 20.

Thèse (M.Sc.)--Université Laval, 2007. / Bibliogr.: f. [57]-60. Publié aussi en version électronique dans la Collection Mémoires et thèses électroniques.

Thèses (M.Sc.)--Université de Sherbrooke (Canada), 1999. / Titre de l'écran-titre (visionné le 20 juin 2006). Publié aussi en version papier.

Adipose tissue plays an essential role in the regulation of many metabolic processes. Excess caloric intake and decreased energy expenditure cause adipocyte hypertrophy and hyperplasia, leading to inflammation of the adipose tissue, which contributes to obesity. Recent data link the Receptor for Advanced Glycation End-products (RAGE) to high fat diet (HFD)-induced obesity and subsequent metabolic dysfunction, but its function is incompletely understood. On HFD, the concentration of RAGE ligands, such as carboxy methyl lysine (CML) - advanced glycation end-products (AGE) epitopes, S100 calcium binding protein B (S100b), and high mobility group box 1 (HMGB1) increases, activating RAGE and resulting in inflammation. However, deletion of RAGE protected against the HFD-induced obesity and resulted in increased overall energy expenditure. In this study, we tested the hypothesis that the protective mechanism of RAGE deletion is due, in part, to browning which involves inducing brown adipose tissue (BAT)-like properties in white adipose tissue (WAT). The expression of uncoupling protein 1 (UCP1), which is usually only expressed in BAT, is increased in the WAT of RAGE knockout (RKO) mice. This effect was reproduced in vitro, by silencing the Ager gene in the adipocyte cell line C3H10T1/2. We propose that RAGE affects adipocyte phenotype by downregulating the expression of browning genes such as UCP1, and therefore is a key determinant of energy expenditure and adiposity. Thus, RAGE antagonism may promote BAT phenotype and function in WAT, reducing adiposity, which may have potential therapeutic implications for treating obesity. / 2017-03-31T00:00:00Z

In this project we study the role of RAGE in the melanoma and pancreatic cancer progression. Based on published studies, we hypothesized that RAGE localization in melanoma varies with different cellular architectures. To test this hypothesis, we utilized an in vitro spheroid model and a lung colonization mice model to compare the RAGE localization in 3D architecture vs 2D monolayer culture. RAGE was found at the cell surface in WM115 and B16F10 spheroids, whereas RAGE is mostly distributed intracellularly in WM266. We also observed that RAGE is present at the surface of B16F10 melanoma cells within tumor nodules in the lungs of mice colonized with B16F10 cells. Previously, our group has demonstrated that RAGE promotes pancreatic tumor cell survival under normoxic conditions, upon gemcitabine administration. Hypoxia is also associated with increased tumor aggressiveness. Based on published reports, we hypothesized that RAGE upregulation under hypoxic conditions contributes to autophagy and migration in pancreatic cancer cells. We observed that autophagy decreases after RAGE inhibition by FPSZM1. Moreover, we observed decreased cell migration after RAGE blockage, indicating that RAGE also mediates migration under hypoxia. We also investigated Advanced Glycation Endproducts (AGEs) on proliferation and migration of pancreatic cancer cells. Based on published reports, we hypothesized that RAGE activation by AGEs contributes to the proliferation and migration in pancreatic cancer cells. We employed ribose modified BSA to activate RAGE in the murine KPC 5517 pancreatic cancer cell line. We observed that AGE-treated samples showed significant increase in migration but no change in proliferation. As RAGE is involved in the progression of melanoma and pancreatic cancer, our results will help researchers to better understand the biology of RAGE. Our research can help to design RAGE-specific antibodies and inhibitors that could target RAGE more effectively. Moreover, our findings on AGE-RAGE interactions, and on the role of RAGE in pancreatic cancer progression under hypoxia, may contribute to reduce the progression of pancreatic cancer. Our results showing that a RAGE inhibitor can reduce autophagy and migration of pancreatic tumor cells, suggest that FPS-ZM1 could be utilized as a potential therapeutic aid for the treatment of pancreatic cancer.

Les évènements cardiovasculaires sont la première cause de mortalité chez les patients insuffisants rénaux chroniques. Ces complications font suite à des modifications structurelles et fonctionnelles de la paroi vasculaire regroupées sous le terme de vasculopathie urémique. Parallèlement à ces modifications vasculaires, l’urémie s’accompagne d’une accumulation de substances non épurées par le rein appelées toxines urémiques, telles que les produits de la glycation avancée (AGEs) ou les ligands de RAGE. Ces toxines peuvent interagir avec leur récepteur, RAGE, qui est pro- inflammatoire et impliqué dans le remodelage artériel. Cette thèse a consisté en l’étude, chez la souris, du rôle de l’accumulation des ligands de RAGE et de leur interaction avec celui-ci dans le développement de l’athérosclérose, des calcifications vasculaires et de la thrombose artérielle au cours de l’insuffisance rénale chronique (IRC). Dans un premier temps, nous avons montré que l’IRC conduisait à une accumulation des AGEs et des ligands de RAGE sériques et tissulaires, ainsi qu’une augmentation de l’expression de RAGE au sein de la paroi vasculaire participant à la formation des plaques d’athérome. Dans un second temps, nous avons démontré que RAGE participait aux calcifications vasculaires favorisant l’expression de co-transporteur de phosphate inorganique (Pit-1), induisant la différenciation des cellules musculaires lisses en cellules « osteoblast-like ». Enfin, nous avons montré que RAGE participait à la formation d’un thrombus artériel dû à une hyperactivité plaquettaire. En conclusion, cette thèse a permis de renforcer le concept que l’axe ligands de RAGE/RAGE est un acteur important dans la vasculopathie urémique. / Cardiovascular events are the primary cause of morbidity and mortality in chronic kidney disease patients. These complications are due to structural and functional changes in the vascular wall named uraemic vasculopathy. Alongside these vascular changes, uremia is accompanied by the retention of various solutes that are normally excreted by the kidneys called uremic toxins, such as the products of advanced glycation (AGEs) or the ligands of RAGE. These toxins may interact with their receptor, RAGE, which is pro-inflammatory and involved in arterial remodeling. The aim of this thesis was to study, in mice, the role of the accumulation of RAGE ligands and their interaction with it in the development of atherosclerosis, vascular calcification and arterial thrombosis in chronic renal failure (CKD). Initially, we showed that CKD leads to an accumulation of serum and tissue AGEs and RAGE ligands, as well as an increase in RAGE expression in the vascular wall involved in atheroma plaque formation. Secondly, we have demonstrated that RAGE is involved in vascular calcification promoting the expression of inorganic phosphate cotransporter (Pit-1), inducing the differentiation of smooth muscle cells "osteoblast-like". Finally, we showed that RAGE participated in the formation of arterial thrombus due to platelet hyperactivity. In conclusion this thesis consolidates that RAGE-RAGE ligands axis is an important actor in uremic vasculopathy.

Overexpression of the Receptor for Advanced Glycation End Products (RAGE) has been implicated in multiple diseases, including several types of cancer. In different types of cancer, RAGE has been shown to promote cell survival by either autophagy or activation of the transcription factor NF-κB. Based on what is known about RAGE, we hypothesized that the RAGE/ligand interaction at the cell surface promotes pancreatic cancer and melanoma cell survival by both pathways, autophagy and NF-κB activation. To study the role of RAGE in pancreatic cancer resistance to chemotherapy, BxPC-3, MIA PaCa-2, PANC-1, and RAGE overexpressing PANC-1 FLR2 cell-lines were used. A significant decrease in cell viability was observed upon gemcitabine treatment with further significant reduction in cell viability upon combination of gemcitabine with the RAGE inhibitor IgG 2A11. In our studies we showed that RAGE plays a central role in pancreatic cancer cell resistance to gemcitabine by increasing autophagy. To test the importance of RAGE localization in mediating drug resistance, three melanoma cell-lines (WM115, WM266, and SK-MEL2) with their daughters, RAGE overexpressing cells (WM115-RAGE, WM266-RAGE, and SK-MEL2-RAGE) were used. Wild type cell-lines only expressed RAGE intracellularly while RAGE overexpressing cells expressed RAGE both at the cell surface and inside cells. We show in this study that only the cell surface RAGE is involved in melanoma resistance to dacarbazine. We next tested the effects of RAGE/RAGE ligand interaction at the cell surface in pancreatic tumor growth. We used two carcinoma cell-lines, PANC-1 and MIA PaCa-2, for this purpose. Both cell-lines were transiently transfected with a NF-κB/Luciferase reporter plasmid to test the effects of the interaction between RAGE and its ligands on the activation of the NF-κB signaling pathway. We observed higher NF-κB activity upon treatment with RAGE ligands (AGE, S100P, and S100A8/A9) compared to non-treated cells. Higher activity of NF-κB was coupled with a higher expression of cyclin D1 and lower expression of p53, NF-κB target genes. / Cobre grant "P20GM109024"

A dissertation submitted in partial fulfillment of the requirements for the degree of Master of Arts (Counselling Psychology) in the Department of Psychology, University of Zululand, 2010. / The main objective of this study was to find out the self-perceived psychological factors that may contribute to road rage in Empangeni. A phenomenological approach was adopted in this study to facilitate the understanding of the information gathered. The sample consisted of 10 participants, 9 males and 1 female. All participants were the drivers. Open-ended questions were asked from the participants. The findings of this study revealed the following themes: impatience, frustrations and anger; substance abuse contribution to bad driving; bad mood leading to aggressive driving; disrespecting other road users; poor compliance with the rules of the road; prolonged hours of driving leading to fatigue; family and work related problems impacting on drivers; attention and focus; gender issues; and bad driving viewed on media (television) impacting on drivers. The study concluded with a brief discussion on the limitations of the study and recommendations for future research.

Résumé : Les maladies cardiovasculaires représentent, par une large mesure, la première cause de morbidité et de mortalité chez les diabétiques. L’activation de RAGE par les produits de glycation avancée (AGE) générés en conditions hyperglycémiques est associée à une multitude de complications diabétiques vasculaires, notamment par une signalisation favorisant l’inflammation chronique ainsi que la mort des cellules formant les tissus et les organes exposés aux AGE. La surexpression de RAGE dans les cellules musculaires lisses des plaques athérosclérotiques vulnérables suggère que le récepteur pourrait contribuer à la survenue des accidents vasculaires. Nous avons donc émis l’hypothèse que l’activation de RAGE dans les cellules musculaires lisses était impliquée dans leur apoptose. Pour le vérifier, nous avons, dans un premier temps, mis au point une nouvelle méthode de détection sans marqueur basée sur le principe de la résonance des plasmons de surface (SPR) pour mesurer l’apoptose d’une monocouche cellulaire en temps réel et caractériser avec précision les paramètres cinétiques des phases d’initiation et d’exécution. Cet essai a permis de montrer que l’activation de RAGE induit l’apoptose dans plus de 75,6% des cellules musculaires lisses stimulées avec le CML-HSA pendant 20 heures. De surcroît, nous avons remarqué que l’activation de RAGE générait un fort stress du réticulum endoplasmique, indiqué par la formation d’un grand nombre de granules de stress ainsi que par l’augmentation de l’expression du marqueur de stress réticulaire HuR et de la caspase-9, deux importants régulateurs de l’apoptose induite par le stress réticulaire endoplasmique. Afin de vérifier le potentiel d’un antagoniste à bloquer l’activation du récepteur, nous avons ensuite synthétisé le peptide iRAGE dont la séquence est dérivée d’un site de liaison du CML-HSA ayant la particularité de posséder de nombreuses charges négatives à pH physiologique. Le prétraitement avec iRAGE s’est montré efficace pour prévenir l’activation de NF-κB, l’induction de l’apoptose et l’augmentation du stress réticulaire endoplasmique. Nous suggérons un modèle de fonctionnement par lequel iRAGE inhibe la signalisation de RAGE en empêchant la liaison des ligands multimériques et en stabilisant les récepteurs sous forme de monomères. À terme, la synthèse d’un antagoniste de RAGE utilisable en clinique pourrait constituer une avancée majeure dans la prévention des complications vasculaires et l’amélioration de la qualité de vie chez les diabétiques. / Abstract : Cardiovascular diseases represent, to a large extent, the first cause of morbidity and mortality among people with diabetes. RAGE activation by advanced glycation end products (AGE) generated in hyperglycemic conditions is associated to a multitude of vascular diabetic complications, in particular by a signaling promoting chronic inflammation as well as death of cells forming tissues and organs exposed to AGE. Overexpression of RAGE in smooth muscle cells of vulnerable atheromatous plaques suggests the receptor could contribute to heart attacks and strokes. Therefore, we hypothesize that RAGE activation in smooth muscle cells is involved in apoptosis. To verify this hypothesis, we first designed a new label-free assay based of surface plasmon resonance (SPR) to measure apoptosis of a cell monolayer in real-time and to characterize precisely the kinetic parameters of the initiation and execution phases. This assay showed that RAGE activation induces apoptosis of more than 75.6% of smooth muscle cells stimulated with CML-HSA for 20 hours. Moreover, we noticed that RAGE activation generated strong endoplasmic reticular stress, indicated by the formation of a great number of stress granules as well as the increased expression of stress marker HuR and caspase-9, two important regulators of reticular stress-induced apoptosis. In order, to assess the potential of an antagonist to block RAGE activation, we then synthesized the iRAGE peptide whose sequence is derived from a binding site of CML-HSA that has the particularity of owning numerous negative charges at physiological pH. Pretreatment with iRAGE was successful to prevent activation of NF-κB, induction of apoptosis and generation of endoplasmic reticular stress. We suggest a model by which iRAGE inhibits RAGE signaling by hindering the binding of multimeric ligands and by stabilizing the receptors in a monomer state. Ultimately, the synthesis of a RAGE antagonist usable in clinic could constitute a major progress in the prevention of vascular complications and in the quality of life of people with diabetes.

Thesis (Ph.D.)--York University, 1999. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 99-120). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:NQ39272