Letteratura scientifica selezionata sul tema "Agonistes des récepteurs purinergiques P2Y"
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Articoli di riviste sul tema "Agonistes des récepteurs purinergiques P2Y":
Gur, Serap, e Wayne J. G. Hellstrom. "Activation of P2Y1 and P2Y2 nucleotide receptors by adenosine 5′-triphosphate analogues augmented nerve-mediated relaxation of human corpus cavernosum". Canadian Urological Association Journal 3, n. 4 (1 maggio 2013): 314. http://dx.doi.org/10.5489/cuaj.1127.
Tesi sul tema "Agonistes des récepteurs purinergiques P2Y":
Dance, Arnaud. "Exploration du rôle du récepteur purinergique P2RY1 dans le risque et la physiopathologie du diabète de type 2 : perspectives de la génomique fonctionnelle humaine". Electronic Thesis or Diss., Université de Lille (2022-....), 2023. http://www.theses.fr/2023ULILS072.
Genome-wide association studies (GWAS) have shown that the P2RY1 locus is associated with type 2 diabetes (T2D) risk and with glucose levels. P2RY1 is a G-protein coupled receptor (GPCR) activated by ATP and ADP, which is highly expressed in pancreatic islets, particularly in β cells where, ATP/ADP stimulate insulin secretion by activating the ATP-dependent potassium channels. Through functional genetics, we aimed to analyze the putative contributions of genetic variants of P2RY1 to T2D risk and to other metabolic traits. We then characterized the downstream signaling pathways of P2RY1 in human pancreatic beta cells and deciphered its putative role in insulin secretion.P2YR1 was sequenced in 9,266 adults including cases with T2D and normal glucose controls. To assess the functional effect of each identified variant, we performed 1) luciferase assays (NFAT-RE system) on HEK293 cells overexpressing each variant, followed by P2YR1 activation by increasing doses of MRS2365 (methanocarba-2MeSADP) that is a specific agonist of P2RY1, and 2) immunofluorescence to assess cellular localization and expression of each mutant. We also performed expression quantitative trait loci (eQTL) analysis in 103 donors based on RNA-seq of pancreatic islets and DNA microrrays genotyping. In human pancreatic β cells (EndoCBH5), we performed glucose-stimulated insulin secretion (GSIS) assays coupled to P2YR1 activation by MRS2365 or inhibition by MRS2500.We identified 22 rare missense variants in P2RY1 (including 10 novel variants). Our in vitro analyses highlighted 7 loss-of-function mutations. 87% of the mutation carriers presented with T2D. Expression QTL analyses showed that a block of single nucleotide polymorphisms (SNPs; n=63) located in an enhancer of human islets was significantly associated with increased islet expression of P2RY1 and decreased T2D risk while another block of SNPs (n=51) was significantly associated with decreased expression of P2RY1 in human islets and increased T2D risk. In EndoCBH5, the GSIS assay showed that the P2RY1 specific agonist MRS2365 led to a 30% increase of insulin secretion when stimulated with 20mM of glucose. A kinome analysis (through PAMGENE technology) and transcriptomic analysis (through RNA sequencing) of the P2RY1 pathway in the EndoCBH5 cells in response to MRS2365 agonist orevealed that the activation of P2RY1 led to a decrease in the expression of TXNIP.Our genetic, functional genomic and pharamacological studies suggest that P2RY1 dysfunction is causatively associated with T2D riskand that P2RY1 contributes to the activation of the insulin secretion pathway. P2RY1 potent and selective agonists that cannot cross the blood-brain barrier are available, and could be tested as a potential new class of insulin secretagogues
Lugo, García Laura. "Caractérisation moléculaire et biochimique des récepteurs purinergiques P2Y de la cellule β pancréatique". Montpellier 1, 2007. http://www.theses.fr/2007MON1T031.
Farret, Anne. "Effets et mécanismes de l'activation des récepteurs purinergiques P2Y de la cellule beta pancréatique". Thesis, Montpellier 1, 2010. http://www.theses.fr/2010MON1T020/document.
P2Y purinergic receptors play a role in the modulation of insulin secretion and represent a potential therapeutic target for new antidiabetic drugs. In the model of isolated perfused rat pancreas, in functional conditions close to physiology, we have shown that the activation of these receptors amplify the glucose-induced insulin secretion. This effect requires the metabolism of glucose; it is probably related to a rise in intracellular Ca2+ concentration, and is independent from a direct effect on ATP-dependent potassium channels. We have also studied the pancreatic effects of new P2Y receptor agonists, synthesized by the group of Prof. B. Fischer: among these compounds, 2-methylthio-ATP-a-S (A isomer) is a glucose-dependent insulin secretagogue, with high efficacy and potency (EC50 at 28.1 nmol/l), and with very good tissue selectivity. On the other hand, we have investigated the implication of P2Y receptors in cell proliferation, using a model of insulin secreting cell line from rat insulinoma (INS-1E cell line): at the doses used, ATP-a-S (a P2Y receptor agonist) and GLP-1 induce a similar insulin response, but an increase in intracellular cAMP of different magnitude; moreover, in contrast to GLP-1, ATP-a-S is ineffective on cell proliferation. Finally, in collaboration with the group of Prof. C. Gachet, we have shown that the P2Y1 receptor subtype was involved in the insulin response of mice pancreatic islets. Thus, our studies contributed to the improvement of knowledge on P2Y purinergic receptors of pancreatic ß-cells, as regards their mechanisms of action, their effects on insulin secretion and on cell proliferation; we also contributed to the development of specific agonists, potentially interesting for the treatment of type 2 diabetes
Lemin, David. "Synthèse d'analogues des ligands naturels de récepteurs nicotiniques et purinergiques". Doctoral thesis, Universite Libre de Bruxelles, 2004. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211158.
Dans la première partie de cette thèse, nous avons réalisé la synthèse d’analogues de la 11-homosédinone, alcaloïde isolé de la plante Sedum acre, qui présente une activité agoniste sur différents récepteurs nicotiniques du système nerveux central. Les différents analogues ont été synthétisé par application de la méthoxylation anodique pour introduire succesivement deux substituants en postion 2 et 6 d’un noyau pipéridinique. Les analogues synthétisés se différencient par la nature du noyau aromatique, la présence d’un groupement méthyle sur l’atome d’azote de la pipéridine et l’oxydation du sustituant en position 2. Ce travail a notamment permis de montré l’importance du groupement N-méthyle vis-à-vis de l’activité des analogues. Nous avons également pu mettre en évidence que l’introduction d’un halogène sur le noyau aromatique diminuait l’activité de l’analogue sur le récepteur a7 tout en augmentant l’acitivité sur le récepteur a4b2 et que l’introduction d’un noyau furanique permettait d’augmenter la sélectivité vis-à-vis du récepteur a4b2 tandis que l’introduction sur le noyau aromatique d’un groupement nitro ou méthoxy conduit à une perte totale de l’activité.
Dans la seconde partie de cette thèse, nous avons réalisé la synthèse d’analogues de la dATP, afin d’évaluer leur effet agoniste sur le récepteur P2Y11, impliqué dans différents mécanismes de différentiation cellulaire, dont notamment celui de la maturation des cellules leucémiques HL60 en cellules de type neutrophile. Les analogues synthétisés se différencient de la dATP par la présence d’un groupement méthylène ou dichlorométhylène entre les phosphores b et g de la chaîne polyphosphate, ainsi que par l’estérification de l’alcool en position 3’ du sucre. Ce travail a pu confirmer que les analogues en série 2’-désoxy conduisent à de meilleures activités que ceux de la série 2’-OH. Nous avons également pu montrer que l’estérification de la position 3’ conduit à une diminution de l’activité agoniste, à l’exception du groupement a-naphtoyle qui conduit à une augmentation significative de l’activité sur P2Y11.
Doctorat en sciences, Spécialisation chimie
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Calenzo, Chappe Valérie (19. "Régulation et pharmacologie du canal chlorure CFTR : implication des récepteurs purinergiques de type P2Y dans l'activation du canal CFTR par les dérivés xanthines". Aix-Marseille 1, 1999. http://www.theses.fr/1999AIX11026.
Langlois, Christine. "Analyse de la participation des récepteurs purinergiques P2Y associés à l'épithélium intestinal dans la modulation des molécules d'adhésions et le recrutement des leucocytes à la barrière intestinale". Mémoire, Université de Sherbrooke, 2008. http://savoirs.usherbrooke.ca/handle/11143/3941.
Judice, De Menezes Relva Lia. "Le rôle des récepteurs aux nucléotides P2Y2 dans le développement d'uvéites autoimmunes". Doctoral thesis, Universite Libre de Bruxelles, 2014. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209265.
Doctorat en Sciences médicales
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Feliu, Catherine. "Implication des récepteurs P1 et P2 dans la protection des cellules endothéliales au cours de l’hypoxie-reoxygenation Complementary Role of P2 and adenosine receptors in ATP induced-anti-apoptotic effects against hypoxic injury of HUVECs Current knowledge on the role of P2Y receptors in cardioprotection against ischemia-reperfusion Intra-extracellular quantification of nucleotides and adenosine using UHPLCHRMS: improvement of robustness by the use of ascorbic acid in mobile phase Description of the novel cytoprotective action pathways of ticagrelor against hypoxic lesions at the endothelium". Thesis, Reims, 2019. http://www.theses.fr/2019REIMM202.
During cardiac ischemia, the lesion is triggered in the endothelium and progresses to the surrounding cardiomyocytes. Purinergic signalling plays an important role during ischemia/reperfusion (I/R) events. Many studies have been carried out to study the mechanisms of protection of nucleotides and nucleosides, without studying their specific roles on the endothelium. In this work, we report an increase in extracellular concentrations of ATP and adenosine from the endothelium exposed to hypoxia. We report a protective effect of extracellular ATP and a complementary role of the P2 and P1 receptors. P2 receptors protective effects involve the PI3K, ERK1/2, mKATP channel signalling and also involve NOS. The protection mediated by the P1 receptors involves the MEK/ERK1/2, PKA and NOS. In a second step, we describe a new cytoprotective mechanism of ticagrelor, independent of the blood element and its antiplatelet anti-aggregating effect. This mechanism is initiated by the increased of extracellular adenosine bioavailability, which triggers protective effects via its A3 and A2A receptors. This may explain, in part, the reported cardioprotective effects of the ticagrelor in clinical studies. Together, our data support the protective role of ATP and adenosine against deleterious effects ofendothelium hypoxia and suggest a beneficial role for these mediators in different ischemia, including cardiac, renal or cerebral ischemia
Fromonot, Julien. "Implication de l'adénosine en physiopathologie cardiovasculaire". Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM5041.
Adenosine (ADO) is an ubiquitous nucleoside that comes from ATP and from the methionine cycle. Via A1 receptors (A1R), it promotes atrial fibrillation (AF). Via A2A receptors (A2AR), it leads to coronary vasodilatation. Thus, adenosine is a metabolic intermediate and a neurotransmitter of the cardiovascular system.The first study showed that adenosine plasma level (APL) is correlated with homocystein (Hcy) and uric acid in coronary artery disease (CAD) patients. Furthermore, APL and Hcy are correlated with the SYNTAX score which evaluate CAD severity. Finally, in cellulo, ADO induced a dose and time dependant increase of HCY production by human hepatocytes. We concluded that high APL may participate into the high HCY and uric acid levels. These data bring new highlight on the physiopathology of CAD.In the second work, APL increased significantly only in patients with positive exercise stress testing (EST). Furthermore, A2AR expression was lower in positive EST patients compared with those with negative EST. Then, we concluded that the low expression of A2AR in CAD patients with positive EST, participates in the lack of adaptive response (coronary vasodilatation) to the EST. This result suggests that low A2AR expression may be a biological marker of CAD.In the third study, patients with AF and no structural heart disease have a normal APL but an increase in A2AR expression. Because adenosine promotes AF, we concluded that high A2AR expression may participate into the triggering of AF by increasing the sensitivity to adenosine.In conclusion, drugs that modulate the purinergic system should be useful tools for the treatment of CAD or AF
Grosdidier, Charlotte. "Anti-plaquettaires et risque hémorragique : rôle du CD40L". Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5063/document.
Aspirin and thienopyridine are the therapy for patients with percutaneous coronary intervention after ACS. The level of platelet inhibition by thienopyridine varies between patients, this variability, multifactorial, is associated with adverse clinical outcomes. Treatment efficacy was evaluated mainly on the association between poor thienopyridine response and thrombotic events but less on the principal side effect: bleeding complications. Platelet play a key role in atherosclerosis and thrombosis, notably via CD40L.I studied platelet factors that influence the bleeding risk in these patients and brought a new highlight on platelet function less known such as inflammation.P450 cytochrome genetic variants (2C19*2 and 2C19*17) influence platelet response to thienopyridines. There is a relation between platelet reactivity and bleeding events. A very low on-treatment platelet reactivity (VASP<10 %) is a predictor of bleeding and is mainly observed with prasugrel treatment. We then focussed on a marker of platelet inflammatory status, CD40L. Its release by platelets depends on P2Y12 signalling, whereas its surface expression is less dependent on this signalling pathway. A low platelet-CD40L surface expression is associated with bleeding events in these patients We show that genetic background on thienopyridine treatment efficacy is related to bleeding risk and that other platelet parameters influence the bleeding risk independently of platelet aggregation inhibition. Thus, a molecule of inflammation, CD40L, would be a link between inflammation and bleeding/thrombosis equilibrium