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Recurrent hyperglycemic episodes in glucose intolerant patients might contribute to the progressive loss of compensatory insulin secretion by the pancreas and thus to the evolution towards type 2 diabetes and to the progressive deterioration of that disease. It should be noted that hypoglycemia is also deleterious for β cells. In rat islets cultured in increasing glucose concentrations (2, 5, 10 or 30 mM further referred to as G2, G5, GlO or G30), oxidative stress response genes expression (Hmox-1, cMyc, Mtla) is minimal in Gb, highly upregulated in G2 and G5, and moderately upregulated in G30. This asymmetric V-shaped expression profile is similar to the profile of later occurring apoptosis, suggesting that oxidative stress might be implicated in the induction of apoptosis in β cells exposed to extreme glucose concentrations. In this context, metallothioneins (MTs) are particularly interesting. Indeed, Mtla expression is one of the most influenced by glucose concentrations. Moreover, in addition to their role in metal detoxification, MTs can act as antioxidant agents in various tissues. The aims of tins master thesis were first to reveal MTs protein expression in β cells exposed to extreme glucose concentrations both in vitro and in vivo, and secondly to evaluate the potentially protective effect of ZnC12, an inducer of MTs expression, on β cell apoptosis under these conditions. Male Wistar rat islets were cultured 18h to 1 week in RPMI medium containing 5g/l BSA and 2, 5, 10 or 30 mlvi of glucose +1- 100 iM of ZnC12. mice were used as a hyperglycemic animal model. In order to induce β cell rest, male Wistar rats were imposed a 1 to 3 days fast. Finally, releasing 1 µl/h of insulin detemir (using subcutaneous osmotic pumps) in NMRI mice permitted me to obtain a hypoglycemic animal model. The levels of mRNA were measured by RT-qPCR. Apoptosis levels were evaluated by 2 DNA fragmentation detection techniques: histone complexed cytosolic DNA fragments measurement by ELISA assay and TUNEL. The protein expression of MTs was revealed by immunohistofluorescence. The culture of rat islets in G2 and G30 induces an increase in Mtla/Tbp mRNA ratio compared to G 10 (C—70 fold in G2 and 25 fold in G30). Results obtained in mice islets are only similar in G2. No increase in MTs protein expression was detected with the antibody I used. In vivo, Mtla expression is upregulated ‘5 fold in 3 days fasting rats and 4 fold in hypoglycemic mice compared to controls. In Leprb mice islets, Mtla/Tbp mRNA ratio upregulation is flot significant while MTs protein expression is reduced compared to controls. The culture of rat islets in G5 and G30 induces an increase in beta-cell apoptosis (12 fold in G5 and 2 to 4 fold in G30) compared to Gb. Adding 100 gM ZnC12 to the medium increases Mtla mRNA and protein levels independently from glucose concentration, and decreases beta-cell apoptosis by 27% in G5 and by 40-65% in G30. Extreme glucose concentrations induce an upregulation of MtIa mRNA expression without any detectable increase in protein expression in islets both in vitro and in vivo. In vitro, these conditions induce an increase in apoptotic f3 ceils levels which is significantly reduced by adding ZnCl2 to the medium La répétition d’épisodes d’hyperglycémie postprandiale chez les patients souffrant d’intolérance glucidique pourrait contribuer à la dégradation progressive de la capacité du pancréas à sécréter l’insuline de façon compensatoire et donc à l’évolution de l’intolérance au glucose vers le diabète de type 2 puis à l’aggravation progressive de ce dernier. Par ailleurs, l’hypoglycémie est également néfaste pour la cellule β. Dans des îlots de rat cultivés en présence de concentrations croissantes de glucose (2, 5, 10 ou 30 mM soit G2, G5, G 10 ou G30), l’expression de gènes de la réponse au stress oxydatif (Hmox-1, c-Myc, Mt1a) est minimale en G1 0, fortement augmentée en G2 et G5, et modérément augmentée en G30. Ce profil d’expression en V asymétrique est semblable à celui de l’apoptose qui survient ultérieurement, suggérant un possible lien causal entre stress oxydatif et apoptose des cellules β exposées à des concentrations extrêmes de glucose. Dans ce contexte, les métallothionéines (MTs) sont particulièrement intéressantes. En effet, Mtla est un des gènes dont l’expression est la plus modifiée en présence de concentrations faibles et élevées de glucose. D’autre part, les MTs exercent, en plus de leur rôle de détoxification des métaux, des effets antioxydants dans divers tissus. L’objectif de ce mémoire était double. Primo, étudier l’expression des MTs dans les cellules β exposées à des concentrations extrêmes de glucose in vitro et in vivo. Secundo, évaluer l’effet potentiellement protecteur du ZnC12, un inducteur de l’expression des MTs, sur l’apoptose des cellules β dans ces conditions. Des îlots de rats Wistar mâles ont été cultivés de 18h à 1 semaine dans un milieu RPMI contenant 5g/l de BSA et 2, 5, 10 ou 30 mM de glucose +1- 100 iM de ZnCl2. Comme modèle d’animaux hyperglycémiques, j’ai utilisé des souris Leprb. Afin d’engendrer une situation de repos des cellules f3, des rats Wistar mâles ont été mis à jeun de 1 à 3 jours. Enfin, un modèle de souris hypoglycémiques a été mis au point par implantation sous-cutanée, chez des souris NMRI, de pompes osmotiques diffusant de l’insuline detemir (Levemir®, 100 UlIml) à un débit de 1 i1Iheure durant 3 à 7 jours. Les taux d’ARNm ont été mesurés par RTq-PCR. Les taux d’apoptose ont été évalués par 2 techniques de détection de la fragmentation de l’ADN: la mesure par ELISA des fragments cytosoliques d’ADN associés aux histones et la méthode TUNEL. L’expression protéique des MTs a été révélée par immunohistofluorescence. La culture d’îlots de rat en G2 et G30 entraîne une élévation du ratio d’ARNm de Mtla/Tbp par rapport à GlO (70 fois en G2 et 25 fois en G30). Dans des îlots de souris, on obtient des résultats similaires lors de la culture en G2. L’augmentation de l’expression protéique des MTs n’a pas été détectée avec l’anticorps utilisé. In vivo, l’expression de Mt]a est augmentée de 5 fois chez des rats mis à jeun 3 jours et de 4 fois chez des souris hypoglycémiques par rapport à leurs contrôles respectifs. Dans des îlots isolés de souris Leprb, le ratio d’ARNm de Mt1a/Tbp est augmenté de manière non significative alors que l’expression protéique des MTs diminue par rapport aux contrôles. Comparée à Gb, la culture d’îlots de rats en G5 et G30 entraîne une augmentation du pourcentage de cellules apoptotiques (l2 fois en G5 et 2 à 4 fois en G30). L’addition de 100 jtM de ZnC12 au milieu augmente l’expression de l’ARNm et de la protéine codés par Mtla quelle que soit la concentration de glucose, et réduit de 27% l’apoptose induite par G5 et de 40-65% l’apoptose induite par G30 dans les cellules β. En conclusion, l’exposition d’îlots de Langerhans à des concentrations extrêmes de glucose in vitro et in vivo entraîne une augmentation de l’expression de l’ARNm de Mtla sans augmentation détectable de la protéine. In vitro, ces mêmes conditions provoquent une augmentation du pourcentage de cellules 13 apoptotiques. Cette augmentation est réduite de manière significative par l’addition de ZnCl2 au milieu de culture.

Oxidative Stress --- Metallothionein --- Insulin-Secreting Cells --- Glucose Intolerance --- Hyperglycemia

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Yeast metallothionein --- Metalloenzymes --- Enzyme metabolism --- Gene expression regulation(Drug effect) --- Metalloproteins --- Bioinorganic chemistry --- Metalloenzymes. --- Metalloproteins. --- Metal ions --- Enzymes --- Gene Expression Regulation --- Ions --- Metals

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Metallothioneins (MTs) represent a large family of proteins characterized by high heavy metal content (mainly CuII and ZnII) and by an unusual cysteine abundance. They have a powerful protective function in all animal tissues, due most likely to their properties as free radical scavengers protecting against oxidative damage. Moreover, the presence and overexpression of MTs in various pathological conditions, such as metal dyshomeostasis, cell proliferation, neurological disorders, and chemotherapy and radiotherapy resistance, could be used as an important prognostic marker, as a histopathologi

Cardiovascular system --- Liver --- Metallothionein. --- Nervous system --- Tumors --- Abdomen --- Biliary tract --- Circulatory system --- Vascular system --- Blood --- Neoplasms --- Tumours --- Pathology --- Cysts (Pathology) --- Oncology --- Organs (Anatomy) --- Neurosciences --- Metallothein --- Metalloproteins --- Organosulfur compounds --- Diseases --- Etiology. --- Circulation

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Bio-indicateurs --- Bio-indicatoren --- Biological environmental indicators --- Biological indicators --- Biological monitoring --- Biologisch elektronisch toezicht --- Ecological indicators --- Ecological risk assessment --- Environmental indicators [Biological ] --- Estimation des risques écologiques --- Indicateurs (Biologie) --- Indicatoren (Biologie) --- Indicators (Biology) --- Monitoring [Biological ] --- Schatting van het ecologisch risico --- Sentinel organisms --- Surveillance électronique biologique --- Environnement --- Marqueurs biologiques --- Ecotoxicologie --- Surveillance --- Écosystème --- ecosystems --- Substance toxique --- toxic substances --- Toxicité --- toxicity --- Bioaccumulation --- Marqueur génétique --- genetic markers --- Immunogénétique --- Immunogenetics --- Substance cancérigène --- Carcinogens --- Organisme aquatique --- Aquatic organisms --- Biochimie --- biochemistry --- Voie biochimique du métabolisme --- Biochemical pathways --- Métallothionéine --- Metallothionein --- Poisson --- Cytochrome p4501a1 --- ALGAE --- ANNELIDA --- AQUATIC ANIMALS --- BIOACCUMULATIVE POLLUTANTS --- BIOMARKERS --- CHOLINESTERASE --- CYTOCHROME P-450 --- ECOSYSTEMS --- ECOTOXICOLOGY --- BIOTRANSFORMATION --- ENERGY METABOLISM --- ENVIRONMENTAL ASSESSMENT --- GENOTOXICITY --- FISHES --- IMMUNITY --- METALLOTHIONEIN --- NEUROTOXICITY --- PLANTS --- STRESS --- STRESS RESPONSE --- POLLUTANTS --- MOLLUSCA --- LIVER --- MOLECULAR BIOLOGY

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The focus on dopamine-sensitive motor symptoms, in association with the improvement of motor complications in the heterogeneous disease entity Parkinson's disease, has led to a certain standstill in research. This Special Issue provides new concepts and new ideas on the pathogenesis, genetics, and clinical maintenance of Parkinson's disease and related disorders. Not only new experimental findings, but also clinical outcomes, case series, and research on alternative, non-pharmacological therapies are included. The objective is to bridge the currently increasing gap between experimental and clinical research on Parkinson's disease and related disorders.

microRNAs --- disease-modifying effects --- SH-SY5Y --- inpatient treatment --- sphingolipids --- neurodegeneration --- magnetic resonance spectroscopy --- MO3.13 --- schizophrenia --- epigenetics --- long-chain acylcarnitine --- molecular mimicry --- curli --- multimodal complex treatment --- chlorogenic acid --- glycerophospholipids --- caffeic acid --- lipoproteins --- myenteric plexus --- neurometabolites --- HOG --- immature oligodendrocyte --- autophagy --- oligodendrocyte --- hypochlorite --- alpha-synuclein --- microbiome --- glucocerebrosidase --- Lewy Body Dementia --- brain iron --- mesenchymal stem cells --- fatty acid ?-oxidation --- GABA --- enteric glial cell --- gut-brain axis --- microbiota --- REM sleep behavior disorders --- redox cycling --- magnetic resonance imaging --- differentiation --- ?-synuclein-mediated pathology --- Parkinson disease --- Gaucher’s disease --- metallothionein --- [123I]FP-CIT-SPECT --- dopaminergic neuron --- mature oligodendrocyte --- glycerolipids --- spectroscopy --- neuroinflammation --- exosomes --- immunotherapy --- DNA methylation --- sterol lipids --- nigral cells --- cell line --- cysteinyl-dopamine --- myelin --- parkinsonisms --- multiple sclerosis --- rotenone --- brain --- fatty acyls --- Krabbe’s disease --- neuroprotection --- DAT --- motor dysfunction --- secretome --- multiprofessional therapy --- Parkinson’s disease --- oxidative stress --- alpha-Synuclein