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https://www.readbyqxmd.com/read/29122954/pregnancy-adapted-uterine-artery-endothelial-cell-ca2-signaling-and-its-relationship-with-membrane-potential
#1
Roxanne E Alvarez, Derek S Boeldt, Bikash R Pattnaik, Hannah L Friedman, Ian M Bird
Pregnancy-derived uterine artery endothelial cells (P-UAEC) express P2Y2 receptors and at high cell density show sustained and synchronous [Ca2+]i burst responses in response to ATP Bursts in turn require coupling of transient receptor potential canonical type3 channel (TRPC3) and inositol 1,4,5-triphosphate receptor type 2 (IP3R2), which is upregulated in P-UAEC in a manner dependent on connexin 43 (Cx43) gap junctions. While there is no known direct interaction of TRPC3 with Cx43, early descriptions of TRPC3 function showed it may also be influenced by altered membrane potential (Vm)...
November 2017: Physiological Reports
https://www.readbyqxmd.com/read/29115551/p2y2-receptor-promotes-the-migration-and-invasion-of-breast-cancer-cells-via-emt-related-genes-snail-and-e-cadherin
#2
Ying Qiu, Yan Liu, Wei-Hua Li, Hong-Quan Zhang, Xin-Xia Tian, Wei-Gang Fang
Adenosine 5'-triphosphate (ATP) is one of the most abundant biochemical constituents within the tumor microenvironment and is postulated to play critical roles in the progression of a number of types of tumors via interaction with the P2Y2 receptor. In the present study, we demonstrated that the P2Y2 receptor was highly expressed in MCF7 and Hs578T breast cancer cells. Downregulation of the P2Y2 receptor by small interfering RNA (siRNA) significantly attenuated ATP- or UTP-driven migration and invasion of the breast cancer cells as well as expression of EMT-related genes Snail and E-cadherin...
November 7, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29031899/synapse-formation-in-the-brain-can-be-enhanced-by-co-administering-three-specific-nutrients
#3
Richard J Wurtman
The memory impairments of early Alzheimer's disease [AD] are thought to result from a deficiency in synapses within the hippocampus and related brain regions. This deficiency could result from an acceleration in synapse turnover - perhaps caused by an endogenous neurotoxin like A-beta oligomers - or from a decrease in the production of the synaptic membrane needed to form new synapses. An AD-associated decrease in synaptogenesis almost certainly does occur, inasmuch as major decreases are also observed in the numbers of hippocampal dendritic spines, the immediate cytologic precursor of glutamatergic synapses...
October 12, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28993732/purinergic-signalling-therapeutic-developments
#4
REVIEW
Geoffrey Burnstock
Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990's when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28976001/inhibition-of-arterial-medial-calcification-and-bone-mineralization-by-extracellular-nucleotides-the-same-functional-effect-mediated-by-different-cellular-mechanisms
#5
Jessal J Patel, Dongxing Zhu, Britt Opdebeeck, Patrick D'Haese, José L Millán, Lucie E Bourne, Caroline P D Wheeler-Jones, Timothy R Arnett, Vicky E MacRae, Isabel R Orriss
Arterial medial calcification (AMC) is thought to share some outward similarities to skeletal mineralization and has been associated with the transdifferentiation of vascular smooth muscle cells (VSMCs) to an osteoblast-like phenotype. ATP and UTP have previously been shown to inhibit bone mineralization. This investigation compared the effects of extracellular nucleotides on calcification in VSMCs with those seen in osteoblasts. ATP, UTP and the ubiquitous mineralization inhibitor, pyrophosphate (PPi ), dose dependently inhibited VSMC calcification by ≤85%...
October 4, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28958619/from-utp-to-ar-c118925-the-discovery-of-a-potent-non-nucleotide-antagonist-of-the-p2y2-receptor
#6
Nicholas Kindon, Andrew Davis, Iain Dougall, John Dixon, Timothy Johnson, Iain Walters, Steve Thom, Kenneth McKechnie, Premji Meghani, Michael J Stocks
The G protein-coupled P2Y2 receptor, activated by ATP and UTP has been reported as a potential drug target for a wide range of important clinical conditions, such as tumor metastasis, kidney disorders, and in the treatment of inflammatory conditions. However, pharmacological studies on this receptor have been impeded by the limited reported availability of stable, potent and selective P2Y2R antagonists. This article describes the design and synthesis of AR-C118925, a potent and selective non-nucleotide antagonist of the P2Y2 receptor discovered using the endogenous P2Y2R agonist UTP as the chemical starting point...
September 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28957808/regulation-of-intracellular-calcium-by-carbon-monoxide-in-human-bronchial-epithelial-cells
#7
Rui-Gang Zhang, Chung-Yin Yip, Wing-Hung Ko
BACKGROUND/AIMS: Carbon monoxide (CO) is an important autocrine/paracrine messenger involved in a variety of physiological and pathological processes. This study aimed to investigate the regulatory role of CO released by CO-releasing molecule-2 (CORM-2) in a P2Y receptor-mediated calcium-signaling pathway in the human bronchial epithelial cell line, 16HBE14o-. METHODS: Intracellular calcium ([Ca2+]i) was measured by fura-2 microspectrofluorimetry. D-myo-inositol-1-phosphate (IP1) levels and cGMP-dependent protein kinase activity (PKG) were also quantified...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28938069/molecular-recognition-of-agonists-and-antagonists-by-the-nucleotide-activated-g-protein-coupled-p2y2-receptor
#8
Muhammad Rafehi, Alexander Neumann, Younis Baqi, Enas M Malik, Michael Wiese, Vigneshwaran Namasivayam, Christa E Müller
A homology model of the nucleotide-activated P2Y2R was created based on the X-ray structures of the P2Y1 receptor. Docking studies were performed, and receptor mutants were created to probe the identified binding interactions. Mutation of residues predicted to interact with the ribose (Arg110) and the phosphates of the nucleotide agonists (Arg265, Arg292) or that contribute indirectly to binding (Tyr288) abolished activity. The Y114F, R194A, and F261A mutations led to inactivity of diadenosine tetraphosphate and to a reduced response of UTP...
October 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923792/p2y2-nucleotide-receptor-prompts-human-cardiac-progenitor-cell-activation-by-modulating-hippo-signaling
#9
Farid G Khalafalla, Steven R Greene, Hashim Khan, Kelli Ilves, Megan M Monsanto, Roberto Alvarez, Monica Chavarria, Jonathan H Nguyen, Benjamin Norman, Walter P Dembitsky, Mark A Sussman
Rationale: Autologous stem cell therapy using human c-Kit(+) cardiac progenitor cells (hCPCs) is a promising therapeutic approach for treatment of heart failure (HF). However, hCPCs derived from aged HF patients with genetic predispositions and/or comorbidities of chronic diseases exhibit poor proliferative and migratory capabilities, which impairs overall reparative potential for injured myocardium. Therefore, empowering functionally compromised hCPCs with pro-regenerative molecules ex vivo is crucial for improving the therapeutic outcome in HF patients...
September 18, 2017: Circulation Research
https://www.readbyqxmd.com/read/28878780/p2y6-receptor-activation-promotes-inflammation-and-tissue-remodeling-in-pulmonary-fibrosis
#10
Tobias Müller, Susanne Fay, Rodolfo Paula Vieira, Harry Karmouty-Quintana, Sanja Cicko, Cemil Korcan Ayata, Gernot Zissel, Torsten Goldmann, Giuseppe Lungarella, Davide Ferrari, Francesco Di Virgilio, Bernard Robaye, Jean-Marie Boeynaems, Eduardo R Lazarowski, Michael R Blackburn, Marco Idzko
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL) cells derived from IPF patients as well as in animals following bleomycin administration...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28828576/bone-turnover-is-altered-in-transgenic-rats-overexpressing-the-p2y2-purinergic-receptor
#11
Maria Ellegaard, Cansu Agca, Solveig Petersen, Ankita Agrawal, Lars Schack Kruse, Ning Wang, Alison Gartland, Jens-Erik Beck Jensen, Niklas Rye Jørgensen, Yuksel Agca
It is now widely recognized that purinergic signaling plays an important role in the regulation of bone remodeling. One receptor subtype, which has been suggested to be involved in this regulation, is the P2Y2 receptor (P2Y2R). In the present study, we investigated the effect of P2Y2R overexpression on bone status and bone cell function using a transgenic rat. Three-month-old female transgenic Sprague Dawley rats overexpressing P2Y2R (P2Y2R-Tg) showed higher bone strength of the femoral neck. Histomorphometry showed increase in resorptive surfaces and reduction in mineralizing surfaces...
August 21, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/28815512/p2y2-receptor-functions-in-cancer-a-perspective-in-the-context-of-colorectal-cancer
#12
Fernand-Pierre Gendron, Morgane Placet, Guillaume Arguin
Purinergic signaling has recently emerged as a network of signaling molecules, enzymes and receptors that coordinates the action and behavior of cancerous cells. Extracellular adenosine 5' triphosphate activates a plethora of P2 nucleotide receptors that can putatively modulate cancer cell proliferation, survival and dissemination. In this context, the G protein-coupled P2Y2 receptor was identified as one of the entities coordinating the cellular and molecular events that characterize cancerous cells. In this chapter, we will look at the contribution of the P2Y2 receptor in cancer outcomes and use this information to demonstrate that the P2Y2 receptor represents a drug target of interest in the setting of colorectal cancer, for which the role and function of this receptor is poorly defined...
August 17, 2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28735873/the-therapeutic-potential-of-purinergic-signalling
#13
REVIEW
Geoffrey Burnstock
This review is focused on the pathophysiology and therapeutic potential of purinergic signalling. A wide range of diseases are considered, including those of the central nervous system, skin, kidney, musculoskeletal, liver gut, lower urinary tract, cardiovascular, airways and reproductive systems, the special senses, infection, diabetes and obesity. Several purinergic drugs are already on the market, including P2Y12 receptor antagonists for stroke and thrombosis, P2Y2 receptor agonists for dry eye, and A1 receptor agonists for supraventricular tachycardia...
July 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28733972/expression-and-function-of-the-metabotropic-purinergic-p2y-receptor-family-in-experimental-seizure-models-and-patients-with-drug-refractory-epilepsy
#14
Mariana Alves, Rosa Gomez-Villafuertes, Norman Delanty, Michael A Farrell, Donncha F O'Brien, Maria Teresa Miras-Portugal, Miguel Diaz Hernandez, David C Henshall, Tobias Engel
OBJECTIVE: ATP is released into the extracellular space during pathologic processes including increased neuronal firing. Once released, ATP acts on P2 receptors including ionotropic P2X and metabotropic P2Y receptors, resulting in changes to glial function and neuronal network excitability. Evidence suggests an involvement of P2Y receptors in the pathogenesis of epilepsy, but there has been no systematic effort to characterize the expression and function of the P2Y receptor family during seizures and in experimental and human epilepsy...
September 2017: Epilepsia
https://www.readbyqxmd.com/read/28729619/effects-of-4-1h-quinolinone-derivative-a-novel-non-nucleotide-allosteric-purinergic-p2y-2-agonist-on-cardiomyocytes-in-neonatal-rats
#15
Kensuke Sakuma, Hideyuki Nakagawa, Tatsuo Oikawa, Masakuni Noda, Shota Ikeda
Purinergic P2Y 2 receptors, G-protein coupled receptors that primarily couple with Gαq/11-proteins, are activated equipotently by adenosine-5'-triphosphate (ATP) and uridine-5'-triphosphate. Evidence suggests that P2Y 2 agonists make potential drug candidates for the treatment of cardiovascular diseases. However, selective non-nucleotide, small-molecule P2Y 2 agonists have yet to be developed. In this report, we discuss Compound 89, a novel non-nucleotide allosteric P2Y 2 agonist that was active in signal transduction and gene induction, and in our in vitro cardiac hypertrophy model...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28677119/atp-evokes-ca-2-signals-in-cultured-foetal-human-cortical-astrocytes-entirely-through-g-protein-coupled-p2y-receptors
#16
Margit S Muller, Colin W Taylor
Extracellular ATP plays important roles in coordinating the activities of astrocytes and neurons, and aberrant signalling is associated with neurodegenerative diseases. In rodents, ATP stimulates opening of Ca(2+) -permeable channels formed by P2X receptor subunits in the plasma membrane. It is widely assumed, but not verified, that P2X receptors also evoke Ca(2+) signals in human astrocytes. Here, we directly assess this hypothesis. We showed that cultured foetal cortical human astrocytes express mRNA for several P2X receptor subunits (P2X4 , P2X5 , P2X6 ) and G protein-coupled P2Y receptors (P2Y1 , P2Y2 , P2Y6 , P2Y11 )...
July 5, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28659615/kca3-1-activation-via-p2y2-purinergic-receptors-promotes-human-ovarian-cancer-cell-skov-3-migration
#17
L Robles-Martínez, E Garay, M G Martel-Gallegos, A Cisneros-Mejorado, D Pérez-Montiel, A Lara, R O Arellano
Disorders in cell signaling mediated by ATP or histamine, activating specific membrane receptors, have been frequently associated with tumorigenesis. Among the elements of response to purinergic (and histaminergic) signaling, ion channel activation controls essential cellular processes in cancer, such as cell proliferation, motility, and death. Here, we studied the effects that ATP had on electrical properties of human ovarian adenocarcinoma cells named SKOV-3. ATP caused increase in intracellular Ca(2+) concentration ([Ca(2+)]i) and, concurrently, it evoked a complex electrical response with a conspicuous outward component...
June 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28652182/ulinastatin-attenuates-neuropathic-pain-via-the-atp-p2y2-receptor-pathway-in-rat-models
#18
Ying Shi, Wanxiang Qin, Fachuan Nie, Huizhong Wen, Kaizhi Lu, Jian Cui
Ulinastatin, a serine protease inhibitor, which has anti-inflammatory properties and neuroprotective effects, is used to treat acute inflammatory disorders. Recent evidence indicates that administration of ulinastatin alleviates pain in rat model of neuropathic pain (NPP). However, its effect on NPP and the underlying mechanism requires further study. In this study, we evaluated the role of intrathecal administration of ulinastatin in rats with sciatic nerve ligation and observed the effect of ulinastatin on the ATP/P2Y2 receptor pathway...
September 5, 2017: Gene
https://www.readbyqxmd.com/read/28611772/bovine-polymorphonuclear-neutrophils-cast-neutrophil-extracellular-traps-against-the-abortive-parasite-neospora-caninum
#19
Rodolfo Villagra-Blanco, Liliana M R Silva, Tamara Muñoz-Caro, Zhengtao Yang, Jianhua Li, Ulrich Gärtner, Anja Taubert, Xichen Zhang, Carlos Hermosilla
Neospora caninum represents a relevant apicomplexan parasite causing severe reproductive disorders in cattle worldwide. Neutrophil extracellular trap (NET) generation was recently described as an efficient defense mechanism of polymorphonuclear neutrophils (PMN) acting against different parasites. In vitro interactions of bovine PMN with N. caninum were analyzed at different ratios and time spans. Extracellular DNA staining was used to illustrate the typical molecules of NETs [i.e., histones (H3), neutrophil elastase (NE), myeloperoxidase (MPO), pentraxin] via antibody-based immunofluorescence analyses...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28550303/anti-proliferative-effects-of-nucleotides-on-gastric-cancer-via-a-novel-p2y6-soce-ca-2-%C3%AE-catenin-pathway
#20
Hanxing Wan, Rui Xie, Jiangyu Xu, Jialin He, Bo Tang, Qingqing Liu, Sumin Wang, Yanjun Guo, Xin Yang, Tobias Xiao Dong, John M Carethers, Shiming Yang, Hui Dong
Although purinegic signaling is important in regulating gastric physiological functions, it is currently unknown for its role in gastric cancer (GC). We demonstrate for the first time that the expression of P2Y6 receptors was markedly down-regulated in human GC cells and primary GC tissues compared to normal tissues, while the expression of P2Y2 and P2Y4 receptors was up-regulated in GC cells. Moreover, the expression levels of P2Y6 receptors in GC tissues were correlated to tumor size, differentiation, metastasis to lymph nodes, and the survival rate of the patients with GC...
May 26, 2017: Scientific Reports
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