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P2Y1 and diabetes

N-N Song, H-L Lu, C Lu, L Tong, S-Q Huang, X Huang, J Chen, Y-C Kim, W-X Xu
BACKGROUND: A major complication related to gastrointestinal (GI) symptoms in diabetic patients is chronic constipation. Constipation has serious negative impacts on quality of life; however, without a comprehensive understanding of the disease, currently available treatments cannot provide a cure. Platelet-derived growth factor receptor alpha-positive cells (PDGFRα+ cells), which form the SIP syncytium with interstitial cells of Cajal and smooth muscle cells, play important roles in GI motility...
March 9, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
S M Hassanian, A Avan, A Ardeshirylajimi
Inorganic polyphosphate (PolyP) is a molecule with prothrombotic and proinflammatory properties in blood. PolyP activates the NF-κB signaling pathway, increases the expression of cell surface adhesion molecules and disrupts the vascular barrier integrity of endothelial cells. PolyP-induced NF-κB activation and vascular hyperpermeability are regulated by the mammalian target of rapamycin complex-1 (mTORC1) and mTORC2 pathways, respectively. Through interaction with receptor for advanced glycation end products (RAGE) and P2Y1 receptors, PolyP dramatically amplifies the proinflammatory responses of nuclear proteins...
February 2017: Journal of Thrombosis and Haemostasis: JTH
Stefanie Vogler, Antje Grosche, Thomas Pannicke, Peter Wiedemann, Andreas Reichenbach, Andreas Bringmann
Water accumulation in retinal glial (Müller) and neuronal cells resulting in cellular swelling contributes to the development of retinal edema and neurodegeneration. Here, we show that endothelin-1 (ET-1) dose-dependently inhibits the hypoosmotic swelling of Müller cells in freshly isolated retinal slices of control and diabetic rats, with a maximal inhibition at 100 nM. Osmotic Müller cell swelling was also inhibited by ET-2. The effect of ET-1 was mediated by activation of ETA and ETB receptors resulting in transactivation of metabotropic glutamate receptors, purinergic P2Y1, and adenosine A1 receptors...
October 2016: Neurochemical Research
Michael Amann, Miroslaw Ferenc, Christian M Valina, Timo Bömicke, Christian Stratz, Stefan Leggewie, Dietmar Trenk, Franz-Josef Neumann, Willibald Hochholzer
Testing of P2Y12 -receptor antagonist effects can support clinical decision-making. However, most platelet function assays use only ADP as agonist which is not P2Y12 -receptor specific. For this reason P2Y12 -receptor specific assays have been developed by adding prostaglandin E1 (PGE1) to reduce ADP-induced platelet activation via the P2Y1 -receptor. The present study sought to evaluate a P2Y12 -receptor specific assay for determination of pharmacodynamic and clinical outcomes. This study enrolled 400 patients undergoing coronary stenting after loading with clopidogrel or prasugrel...
November 2016: Platelets
Yael Nadel, Joanna Lecka, Yocheved Gilad, Gal Ben-David, Daniel Förster, Georg Reiser, Sarah Kenigsberg, Jean Camden, Gary A Weisman, Hanoch Senderowitz, Jean Sévigny, Bilha Fischer
Aberrant nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) activity is associated with chondrocalcinosis, osteoarthritis, and type 2 diabetes. The potential of NPP1 inhibitors as therapeutic agents, and the scarceness of their structure-activity relationship, encouraged us to develop new NPP1 inhibitors. Specifically, we synthesized ATP-α-thio-β,γ-CH2 (1), ATP-α-thio-β,γ-CCl2 (2), ATP-α-CH2-γ-thio (3), and 8-SH-ATP (4) and established their resistance to hydrolysis by NPP1,3 and NTPDase1,2,3,8 (<5% hydrolysis) (NTPDase = ectonucleoside triphosphate diphosphohydrolase)...
June 12, 2014: Journal of Medicinal Chemistry
Claire Doyle, Gerard P Sergeant, Mark A Hollywood, Noel G McHale, Keith D Thornbury
INTRODUCTION: Although adenosine triphosphate (ATP) has often been reported to relax the corpus cavernosum, this may be mediated by indirect effects, such as release of nitric oxide from the endothelium. Recent data suggest that P2X(1) receptors may be up-regulated in diabetes, and these exert an anti-erectile effect by causing the corpus cavernosum smooth muscle cells (CCSMCs) to contract. However, to date, there is no functional evidence that ATP can directly stimulate CCSMC. AIMS: This study aims to (i) to directly examine the effect of ATP on membrane currents in freshly isolated CCSMC, where influences of endothelium and other cells are absent; and (ii) to determine the receptor subtypes, ionic currents, and Ca(2+) signals stimulated by ATP...
January 2014: Journal of Sexual Medicine
Antje Grosche, Thomas Pannicke, Ju Chen, Peter Wiedemann, Andreas Reichenbach, Andreas Bringmann
BACKGROUND/AIMS: Osmotic swelling of Müller cells is a common phenomenon in animal models of ischemic and diabetic retinopathies. Müller cells possess a swelling-inhibitory purinergic signaling cascade which can be activated by various receptor ligands including vascular endothelial growth factor (VEGF) and glutamate. Here, we investigated whether deletion of P2Y1 (P2Y1R) and adenosine A1 receptors (A1AR), and of inositol-1,4,5-trisphosphate-receptor type 2 (IP3R2), in mice affects the inhibitory action of VEGF and glutamate on Müller cell swelling...
2013: Ophthalmic Research
K Ishida, T Matsumoto, K Taguchi, K Kamata, T Kobayashi
AIM: Extracellular nucleotides activate cell-surface purinergic (P2) receptors, contribute to the local regulation of vascular tone and play important roles in pathophysiological states. However, little is known about the vasodilator effects of P2Y(1) -receptor activation in diabetic states. We hypothesized that in a model of established type 1 diabetes, long-term streptozotocin (STZ)-induced diabetic rats, the arterial relaxation elicited by a P2Y(1) -receptor agonist would be impaired...
January 2013: Acta Physiologica
Rolf P Kreutz, Perry Nystrom, Yvonne Kreutz, Jia Miao, Richard Kovacs, Zeruesenay Desta, David A Flockhart, Yan Jin
Diabetes mellitus (DM) is associated with increased platelet activation and reduced platelet inhibition by clopidogrel. Prostaglandin E1 (PGE1) stimulates adenyl cyclase activity in platelets and increases cyclic AMP concentrations, which inhibit Ca(2+)release and platelet aggregation induced by P2Y1 receptor activation. PGE1 is included in the VerifyNow P2Y12 assay to suppress P2Y1 induced platelet aggregation. We hypothesized that diabetes mellitus may be associated with altered response to PGE1 in subjects treated with clopidogrel...
2013: Platelets
A Bornø, T Ploug, L T Bune, J B Rosenmeier, P Thaning
Purinergic receptors are present in most tissues and thought to be involved in various signalling pathways, including neural signalling, cell metabolism and local regulation of the microcirculation in skeletal muscles. The present study aims to determine the distribution and intracellular content of purinergic receptors in skeletal muscle fibres in patients with type 2 diabetes and age-matched controls. Muscle biopsies from vastus lateralis were obtained from six type 2 diabetic patients and seven age-matched controls...
June 2012: Purinergic Signalling
Fei Gao, Zan-Xin Wang, Jian-Long Men, Jing Ren, Min-Xin Wei
BACKGROUND: Aspirin is widely used in the secondary prevention of coronary artery diseases, including myocardial infarction, stroke, and vascular related deaths. However, the antiplatelet effect of aspirin appears to be variable and aspirin resistance (AR) is currently still controversial for Chinese patients. The aim of this study was to describe the prevalence of AR, and identify possible risk factors associated with a lack of response to aspirin treatments in patients with unstable coronary artery disease...
June 2011: Chinese Medical Journal
Vita Ignatovica, Gustavs Latkovskis, Raitis Peculis, Kaspars Megnis, Helgi B Schioth, Iveta Vaivade, Davids Fridmanis, Valdis Pirags, Andrejs Erglis, Janis Klovins
The purinergic 1 receptor (P2RY1) has been implicated in development of heart disease and in individual pharmacodynamic response to anticoagulant therapies. However, the association of polymorphisms in the P2RY1 gene with myocardial infarction (MI), and its associated conditions, has yet to be reported in the literature. We evaluated seven known SNPs in P2RY1 for association with MI in a Latvian population. Seven independent parameters that are related to MI [body mass index (BMI), type 2 diabetes (T2D), angina pectoris, hypertension, hyperlipidemia, atrial fibrillation and heart failure] were investigated...
February 2012: Molecular Biology Reports
S Amisten, S Meidute-Abaraviciene, C Tan, B Olde, I Lundquist, A Salehi, D Erlinge
AIMS/HYPOTHESES: To investigate the effects of extracellular purines on insulin secretion from mouse pancreatic islets. METHODS: Mouse islets and beta cells were isolated and examined with mRNA real-time quantification, cAMP quantification and insulin and glucagon secretion. ATP release was measured in MIN6c4 cells. Insulin and glucagon secretion were measured in vivo after glucose injection. RESULTS: Enzymatic removal of extracellular ATP at low glucose levels increased the secretion of both insulin and glucagon, while at high glucose levels insulin secretion was reduced and glucagon secretion was stimulated, indicating an autocrine effect of purines...
September 2010: Diabetologia
Florian Neumann, Antje Wurm, Regina Linnertz, Thomas Pannicke, Ianors Iandiev, Peter Wiedemann, Andreas Reichenbach, Andreas Bringmann
Osmotic swelling of glial cells may contribute to the development of retinal edema. We investigated whether sex steroids inhibit the swelling of glial somata in acutely isolated retinal slices and glial cells of the rat. Superfusion of retinal slices or cells from control animals with a hypoosmolar solution did not induce glial swelling, whereas glial swelling was observed in slices of postischemic and diabetic retinas. Progesterone, testosterone, estriol, and 17beta-estradiol prevented glial swelling with half-maximal effects at approximately 0...
April 2010: Neurochemical Research
Shay Eliahu, Haim M Barr, Jean Camden, Gary A Weisman, Bilha Fischer
Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and specificity compared to nucleotides, the most common P2 receptor ligands. The activation of pancreatic P2Y receptors by nucleotides increases insulin secretion. Therefore, in the current study, dinucleoside polyphosphate analogues (di-(2-MeS)-adenosine-5',5''-P(1),P(4),alpha,beta-methylene-tetraphosphate), 8, (di-(2-MeS)-adenosine-5',5''-P(1),P(4),beta,gamma-methylene-tetraphosphate), 9, and di-(2-MeS)-adenosine-5',5''-P(1),P(3),alpha,beta-methylene triphosphate, 10, were developed as potential insulin secretagogues...
March 25, 2010: Journal of Medicinal Chemistry
Grace Lee, Zhaoying Xiang, Thomas H Brannagan, Russell L Chin, Norman Latov
Gene expression analysis previously identified molecular markers that are up-regulated in sural nerve biopsies from patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To determine whether the same or additional genes are also up-regulated in skin, we applied gene microarray profiling and quantitative real-time PCR (qPCR) analysis to skin punch biopsies from patients with CIDP and controls. Five genes, allograft inflammatory factor 1 (AIF-1), lymphatic hyaluronan receptor (LYVE-1/XLKD1), FYN binding protein (FYB), P2RY1 (purinergic receptor P2Y, G-protein-coupled, 1), and MLLT3 (myeloid/lymphoid or mixed-lineage leukemia translocated to, 3), all associated with immune cells or inflammatory processes, were elevated in punch skin biopsies from patients with CIDP as compared to normal subjects or patients with Charcot-Marie-Tooth Type 1 (CMT1)...
March 15, 2010: Journal of the Neurological Sciences
Chanyuan Tan, Albert Salehi, Siv Svensson, Björn Olde, David Erlinge
Pancreatic beta-cell loss represents a key factor in the pathogenesis of diabetes. Since the influence of purinergic signaling in beta-cell apoptosis has not been much investigated, we examined the role of the ADP receptor P2Y(13) using the pancreatic insulinoma-cell line MIN6c4 as a model system. Real time-PCR revealed high expression of the ADP receptors P2Y(1) and P2Y(13). Adding the ADP analogue, 2MeSADP, to MIN6c4 cells induced calcium influx/mobilization and inhibition of cAMP production by activation of P2Y(1) and P2Y(13), respectively...
February 2010: Cellular and Molecular Life Sciences: CMLS
Serap Gur, Philip J Kadowitz, Asim B Abdel-Mageed, Muammer Kendirci, Suresh C Sikka, Geoffrey Burnstock, Wayne J G Hellstrom
PURPOSE: We determined the role of purine and pyrimidine nucleotides in erectile function in diabetic rats. MATERIALS AND METHODS: A total of 60 adult male rats were divided into 2 groups, including 30 controls and 30 treated with streptozotocin (60 mg/kg) for 8 weeks to induce hyperglycemia. Changes in intracavernous pressure after intracrural injections of adenosine 5'triphosphate and adenosine 5'triphosphate analogues in control and diabetic rats, and the relaxant response to electrical field stimulation of precontracted corpus cavernosum smooth muscle in organ baths were investigated...
May 2009: Journal of Urology
Yue Zhang, Raoul D Nelson, Noel G Carlson, Craig D Kamerath, Donald E Kohan, Bellamkonda K Kishore
Lithium (Li)-induced nephrogenic diabetes insipidus (NDI) has been attributed to the increased production of renal prostaglandin (PG)E(2). Previously we reported that extracellular nucleotides (ATP/UTP), acting through P(2y2) receptor in rat medullary collecting duct (mCD), produce and release PGE(2). Hence we hypothesized that increased production of PGE(2) in Li-induced NDI may be mediated by enhanced purinergic signaling in the mCD. Sprague-Dawley rats were fed either control or Li-added diet for 14 or 21 days...
May 2009: American Journal of Physiology. Renal Physiology
Cleide Gonçalves da Silva, Anke Specht, Barbara Wegiel, Christiane Ferran, Elzbieta Kaczmarek
BACKGROUND: Decreased endothelial nitric oxide (NO) synthase (eNOS) activity and NO production are critical contributors to the endothelial dysfunction and vascular complications observed in many diseases, including diabetes mellitus. Extracellular nucleotides activate eNOS and increase NO generation; however, the mechanism of this observation is not fully clarified. METHODS AND RESULTS: To elucidate the signaling pathway(s) leading to nucleotide-mediated eNOS phosphorylation at Ser-1177, human umbilical vein endothelial cells were treated with several nucleotides, including ATP, UTP, and ADP, in the presence or absence of selective inhibitors...
February 17, 2009: Circulation
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