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Introduction. Obesity and related-metabolic disorders are a major problem of public health. In Western diet, fried foods represent an important part of the excessive caloric intake. Frying oils (thermal treatment at high temperature) – and more particularly vegetables oils riche in polyunsaturated fatty acids – deteriorate them. Degradation products (namely oxidized lipid) appear and accumulate in oils and fried foods. The main objective of this dissertation is the evaluation of the effect of these degradation products on obesity and metabolic disorders in a mouse model of nutritional obesity.
Experimental methods. Mice C57Bl6J (8 per group) were fed with four different diets with different levels of peroxides: either a control diet (CT) of a high-fat diet supplemented with 5% control soybean oil (HF) or a high-fat diet supplemented with 5% thermally treated soybean oil (Px, which increased peroxide level in the diet) of a Px diet supplemented with 1% coenzyme Q10H2 (CoQ, supplementation with antioxidant properties that counteract the increase in peroxide level).
Results. HF mice show a significant increase of body weight gain, associated with a significant increase in adipose tissues weights. In the plasma, non-esterified fatty acids (NEFA) and cholesterol are significantly increased in HF mice. Px mice do not lead to any further inflammatory or oxidative stress in the analysed tissues (liver, jejunum, colon and adipose tissue). Px diet increases relative liver weight, which could be associated with and accumulation of glycogen in the liver. Px diet also modifies lipid metabolism compared to HF diet: in the plasma, total cholesterol and LDL cholesterol are increased and triglycerides and NEFA are decreased; while in the liver, free cholesterol and triglycerides are decreased. These changes could be associated with an activation of LXR pathway following Px treatment. However, the reduced levels of peroxide in the CoQ diet do not induce any modification of lipid metabolism.
Discussion – Conclusion. Chronic ingestion of a diet supplemented with thermally oxidized oil is associated with modification of lipid metabolism. These perturbations are probably linked to the activation of LXR pathways. Those modifications of lipid metabolism seem to be independent of the peroxide level in the diet, as shown by the use of the antioxidant CoQ10H2. The main perspective is the identification of the other degradation products present in the diet and which can be associated with the observed modification of lipid metabolism Introduction. L’obésité et les désordres métaboliques associés constituent actuellement un problème majeur de santé publique. Dans l’alimentation occidentale, les produits cuits par friture représentent une part importante de l’apport calorique excédentaire. Les huiles de friture se dégradent à haute température, surtout les huiles végétales. Des produits issus de l’oxydation lipidique apparaissent alors et s’accumulent à la fois dans l’huile et dans les aliments frits. L’objectif principal de ce mémoire est d’évaluer l’influence de ces composés sur l’obésité et les désordres métaboliques dans un modèle murin d’obésité nutritionnelle. Pour ce faire, la mise au point d’un régime hyperlipidique enrichi de manière contrôlée en produits de dégradation issus de la peroxydation lipidique a été nécessaire.
Matériel & Méthodes. Quatre groupes de souris C57Bl6J ont été nourries avec des diètes présentant des taux variables de peroxydes : une diète standard pauvre en lipides (contrôle) ; une diète hyperlipidique enrichie de 5% d’huile de soja (HF) ; une diète hyperlipidique enrichie de 5% d’huile de soja thermo-oxydée (Px) ; une diète Px enrichie d’1% de coenzyme Q10 (CoQ, ajout d’un antioxydant pour réduire la teneur en peroxydes).
Résultats. L’ingestion de la diète HF provoque un gain de poids corporel important ainsi qu’une augmentation des acides gras libres et du cholestérol sériques. Les animaux ayant reçu la diète Px ne présentent ni un état inflammatoire, ni un état de stress oxydatif dans les différents organes étudiés. Par contre, ils présentent une augmentation du poids du foie associée à une tendance vers une accumulation de glycogène. Cette diète Px est également responsable de modifications du métabolisme lipidique par rapport à la diète HF : on observe une augmentation du cholestérol total et du LDL cholestérol mais une diminution des acides gras libres et des triglycérides au niveau sérique, et une diminution des triglycérides au niveau hépatique. Une activation de la voie LXR, récepteur nucléaire aux oxystérols, est mise en évidence dans le groupe PX ; cette voie étant associée à une augmentation du catabolisme et de la sécrétion du cholestérol. Par contre, la diminution de la teneur en peroxydes de la diète par l’ajout de CoQ10H2 ne contre aucun des effets de la diète Px sur le métabolisme lipidique.
Discussion – Conclusion. L’ingestion chronique d’une diète enrichie en huile thermo-oxydée induit des modifications du métabolisme lipidique via notamment l’activation de la voie LXR. Ces changements métaboliques semblent se produire indépendamment de la teneur en peroxydes dans la diète. La perspective principale de ce mémoire est la détermination des produits de dégradation de la diète pouvant être associés aux modifications du métabolisme lipidique observées (entre autres les oxystérols).

Obesity --- Disease --- Sterol Regulatory Element Binding Proteins --- Lipid Metabolism Disorders --- Lipid Peroxides --- Chylomicrons --- liver X receptor

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The platelet-derived growth factor (PDGF) acts by binding to its tyrosine kinase receptor, thus activating many signalling pathways leading to cellular proliferation, migration and differentiation. In this study, we were interested in the PDGF signalling pathway depending on phosphatidylinositol 3-kinase (PI3kinase), the serine/threonine kinase Akt/PKB and sterol regulatory element-binding protein (SREBP). This pathway leads to the expression of many genes coding for lipogenic enzymes including stearoyl-coenzyme A desaturase (SCD). This enzyme catalyses the Δ9-cis desaturation of saturated fatty acids, thus generating mono unsaturated fatty acids (MUFA). These are implicated in the biosynthesis of membrane phospholipids.By using two shRNA targeting SCD (shSCD) and lentiviral particles, we were capable of reducing SCD expression in human fibroblasts as well as in glioblastoma cells. First, by using a radio-labelled thymidine incorporation assay, we observed a loss of proliferative effect of PDGF on fibroblast expressing shSCD. We also observed that expression of shSCD leads to a decrease in fibroblast migration. To identify how the shSCD can cause these effects, we studied the phosphorylation of some PDGF-regulated proteins. By western blot analysis, we observed that Akt, Erk and Stat3 were phosphorylated to a lesser extent in the presence of shSCD compared to normal cells; while there was no effect for PDGFRβ, Stat5 and PLCγ1. Because of the role played by SCD in the production of MUFA which are important for cellular membrane biosynthesis, we wanted to study the effect of shSCD on membrane fluidity by using the FRAP technology. Our first results do not show any important effect. Finally, as SCD expression was shown to increase in some tumor cells, we investigated whether our shSCD can affect the proliferation of glioblastoma cells. Our results show that there is no effect of shSCD on the proliferation of these cells.To complete this study, we would like to test the localization of PDGFR in cells expressing shSCD and see if there are any differences compared to cells which do not express shSCD. The localization of PDGFR in rafts or non-rafts domains of the membrane might be important for cellular signalling. Altogether, our results suggest that SCD plays an important role in the response of human fibroblasts to PDGF Le PDGF (« Platelet-derived growth factor ») est un facteur de croissance qui agit en se liant sur un récepteur à activité tyrosine kinase permettant ainsi l’initiation de diverses voies de signalisation qui mènent à la prolifération, la migration et la différenciation cellulaire. Dans cette étude, nous nous sommes intéressés à la voie de signalisation du PDGF dépendant de la phosphatidylinositol 3-kinase (PI3kinase), de la sérine/thréonine kinase Akt/PKB et de SREBP (« Sterol regulatory element-binding protein »). Cette voie mène à l’expression de plusieurs gènes codant pour des enzymes lipogéniques telle que la stéaroyl-coenzyme A désaturase (SCD). Cette enzyme catalyse la désaturation Δ9-cis d’acides gras saturés, ce qui génère des acides gras mono-insaturés. Ceux-ci sont nécessaires entre autres pour la synthèse des phospholipides membranaires. A l’aide de deux shRNA ciblant SCD (shSCD) et par l’utilisation de lentivirus, nous sommes parvenus à réduire l’expression de SCD dans des fibroblastes humains et dans des cellules de glioblastomes. Par western blot, nous avons observé qu’en présence de shSCD, la phosphorylation de certaines protéines appartenant à la signalisation du PDGF était réduite (Akt, Erk, STAT3) ; tandis que pour d’autres protéines, il n’y avait pas changement (PDGFRβ, STAT5, PLCγ, SHP2). Grâce à un test d’incorporation de thymidine tritiée, nous avons pu mettre en évidence une perte de l’effet prolifératif du PDGF sur des fibroblastes exprimant les shSCD ; mais pas sur les cellules de glioblastomes. De plus, la migration des fibroblastes est également réduite en présence de shSCD. La protéine SCD étant impliquée dans la synthèse des acides gras insaturés qui sont présents dans la membrane plasmique, nous avons étudié l’effet des shSCD sur la fluidité membranaire par la technique du FRAP. Les premiers résultats obtenus n’ont pas montré d’effet majeur.Nous avons ainsi montré l’importance du rôle de SCD dans la signalisation, la prolifération et la migration des fibroblastes humains en réponse au PDGF

Platelet-Derived Growth Factor --- Receptors, Platelet-Derived Growth Factor --- Stearoyl-CoA Desaturase --- Humans --- Sterol Regulatory Element Binding Proteins --- Cell Membrane

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G-quadruplexes (G4s) are nucleic acids secondary structures that form in DNA or RNA guanine (G)-rich strands. In recent years, the presence of G4s in microorganisms has attracted increasing interest. In prokaryotes, G4 sequences have been reported in several human pathogens. Bacterial enzymes able to process G4s have been identified. In viruses, G4s have been suggested to be involved in key steps of the viral life cycle: They have been associated with the human immunodeficiency virus (HIV), herpes simplex virus 1 (HSV-1), human papilloma virus, swine pseudorabies virus, and other viruses' genomes. New evidence shows the presence of G4s in parasitic protozoa, such as the causative agent of malaria. G4 binding proteins and mRNA G4s have been implicated in the regulation of microorganisms' genome replication and translation. G4 ligands have been developed and tested both as tools to study the complexity of G4-mediated mechanisms in the viral life cycle and as therapeutic agents. Moreover, new techniques to study G4 folding and their interactions with proteins have been developed. This Special Issue will focus on G4s present in microorganisms, addressing all the above aspects.

bacteria --- folding --- co-translational refolding --- RecQ helicase --- regulatory element --- conformational dynamics --- G4Hunter --- NDPK --- fluorescence --- pseudorabies virus --- Epstein-Barr virus (EBV) --- structure-activity relationship --- PhenDC3 --- eukaryotic hosts --- Herpesvirus --- translation suppression --- turn-on ligands --- co-transcriptional folding --- Herpesviridae --- G-quadruplex --- nucleoside diphosphate kinase --- nucleic acids --- nucleic acids conformation --- bioinformatics --- protein–DNA interaction --- aptamers --- deinococcus --- Alphaherpesvirinae --- EBNA1 --- G4 --- virus --- human papillomaviruses --- S. cerevisiae --- genome stability --- G-quadruplexes --- metastable structure --- genome evolution --- pyridostatin --- alphaherpesviruses --- structure --- protozoa --- genome --- G-quadruplex ligand --- NMR --- microbes --- DNA --- protein-mRNA interactions --- G-quadruplex formation --- immediate early promoters

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Acute kidney injury (AKI) is still associated with high morbidity and mortality incidence rates, and also bears an elevated risk of subsequent chronic kidney disease. Although the kidney has a remarkable capacity for regeneration after injury and may recover completely depending on the type of renal lesions, the options for clinical intervention are restricted to fluid management and extracorporeal kidney support. The development of novel therapies to prevent AKI, to improve renal regeneration capacity after AKI, and to preserve renal function is urgently needed. The Special Issue covers research articles that investigated the molecular mechanisms of inflammation and injury during different renal pathologies, renal regeneration, diagnostics using new biomarkers, and the effects of different stimuli like medication or bacterial components on isolated renal cells or in vivo models. The Special Issue contains important reviews that consider the current knowledge of cell death and regeneration, inflammation, and the molecular mechanisms of kidney diseases. In addition, the potential of cell-based therapy approaches that use mesenchymal stromal/stem cells or their derivates is summarized. This edition is complemented by reviews that deal with the current data situation on other specific topics like diabetes and diabetic nephropathy or new therapeutic targets.

microRNAs --- n/a --- transcription --- ischemia/reperfusion injury --- DSS-colitis --- kidney inflammation --- therapeutics targets --- CXCL13 --- glomerulus --- interleukin-6 --- rhabdomyolysis --- IgA nephropathy --- CREB Regulated Transcriptional Coactivators (CRTC) --- slit diaphragm --- injury --- xanthine oxidase --- Salt Inducible Kinase (SIK) --- acute and chronic kidney disease --- therapeutic target --- KIT-IgA score --- G-protein-coupled bile acid receptor (TGR5) --- lysophosphatidic acid --- glomerular injury --- IL-18 --- mesenchymal stem cells --- Taiwan --- acute kidney injury --- renal ischemia-reperfusion --- long non-coding RNA --- fibrosis --- acute kidney failure --- diabetic kidney diseases --- chronic kidney disease --- lncRNA --- LPS-binding protein --- endotoxemia-induced oliguric kidney injury --- dapagliflozin --- cPLA2 and COX-2 --- NLRP3 inflammasome --- CmklR1 --- haem --- chronic kidney injury --- omega-3 fatty acid --- noninvasive --- inflammation --- regulated necrosis --- GLP-1 receptor agonists --- miRNA --- AKI --- SGLT2 inhibitors --- diabetic kidney disease --- extracellular vesicles --- podocin --- type IV collagen --- epithelial cells --- nephrin --- 2-kidney-1-clip --- renal fibrosis --- papilla --- diagnostics --- necrosis --- non-coding RNAs --- podocyte --- Thy1.1 nephritis --- KIT assay --- oxidative stress --- conditioned medium --- C-reactive protein --- pericyte --- myofibroblast --- Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-?B) --- endotoxemia --- modifier gene --- polymorphism --- renal stem cells --- kidney --- polyploidization --- Class IIa Histone Deacetylases (HDAC) --- 2k1c --- molecular signaling --- proximal tubule --- arachidonic acid --- empagliflozin --- tubular injury --- signaling cascade --- signal transduction --- inflammatory maker --- niches --- biomarkers --- renal progenitors --- type V collagen --- cyclooxygenase --- focal segmental glomerulosclerosis --- inflammatory bowel disease (IBD) --- chronic kidney disease (CKD) --- allograft rejection --- renovascular hypertension --- genotype --- molecular mechanisms --- ROS --- prediction --- glomerular filtration barrier (GFB) --- alport syndrome --- scattered tubular cells --- long non-coding RNAs --- renal inflammation --- lysophosphatidic acid receptor --- cAMP Regulatory Element Binding Protein (CREB) --- Farnesiferol B --- differentiation --- mesenchymal stromal cells --- modified-MSCs --- kidney transplantation --- polyunsaturated fatty acids --- apoptosis --- type I collagen --- diabetes mellitus --- natural products --- lipoxygenase --- stem cell --- T cell-mediated rejection --- exosomes --- renal injury --- obese kidney fibrosis --- kidney injury --- cytotoxicity --- mesenchymal stem cell --- pigment nephropathy --- mesodermal stem cell --- ischemia-reperfusion --- cytochrome P450 --- renal cell carcinoma --- hematuria --- B-cell attracting chemokine --- microRNA --- chemerin --- glomerular basement membrane --- glomerular damage --- renal tubular cells --- kidney proximal tubule --- exosome --- hypertension --- diabetic nephropathy