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Thierry Bourguignon, Lauriane Benoist, Stéphanie Chadet, Elodie Miquelestorena-Standley, Gaëlle Fromont, Fabrice Ivanes, Denis Angoulvant
OBJECTIVE: Myocardial ischemia reperfusion is a major cause of cell injury during cardiac transplantation and is responsible for increased graft rejection. Several in vitro studies demonstrated the protective effect of P2Y11-like purinoreceptor stimulation in the context of myocardial ischemia/reperfusion. In this study, we hypothesized a possible cardioprotective role of P2Y11R stimulation against ischemia/reperfusion lesions and validated its clinical effect in vivo in a heart transplantation model...
December 21, 2018: Journal of Thoracic and Cardiovascular Surgery
Rareş-Petru Moldovan, Barbara Wenzel, Rodrigo Teodoro, Wilma Neumann, Sladjana Dukic-Stefanovic, Werner Kraus, Peijing Rong, Winnie Deuther-Conrad, Evamarie Hey-Hawkins, Ute Krügel, Peter Brust
Purine nucleotides such as ATP and ADP are important extracellular signaling molecules in almost all tissues activating various subtypes of purinoreceptors. In the brain, the P2Y1 receptor (P2Y1 R) subtype mediates trophic functions like differentiation and proliferation, and modulates fast synaptic transmission, both suggested to be affected in diseases of the central nervous system. Research on P2Y1 R is limited because suitable brain-penetrating P2Y1 R-selective tracers are not yet available. Here, we describe the first efforts to develop an 18 F-labeled PET tracer based on the structure of the highly affine and selective, non-nucleotidic P2Y1 R allosteric modulator 1-(2-[2-(tert-butyl)phenoxy]pyridin-3-yl)-3-[4-(trifluoromethoxy)phenyl]urea (7)...
January 7, 2019: European Journal of Medicinal Chemistry
Tamara Berdyyeva, Chunfang Xia, Natalie Taylor, Yingbo He, Gang Chen, Chaofeng Huang, Wei Zhang, Hartmuth Kolb, Michael Letavic, Anindya Bhattacharya, Anna Katrin Szardenings
PURPOSE: The P2X7 receptor, an adenosine triphosphate (ATP)-gated purinoreceptor, has emerged as one of the key players in neuroinflammatory processes. Therefore, developing a positron emission tomography (PET) tracer for imaging of P2X7 receptors in vivo presents a promising approach to diagnose, monitor, and study neuroinflammation in a variety of brain disorders. To fulfill the goal of developing a P2X7 PET ligand as a biomarker of neuroinflammation, [18 F]JNJ-64413739 has been recently disclosed...
January 10, 2019: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Veronika E Winkelmann, Kristin E Thompson, Kathrin Neuland, Ana-Maria Jaramillo, Giorgio Fois, Hanna Schmidt, Oliver H Wittekindt, Wei Han, Michael J Tuvim, Burton F Dickey, Paul Dietl, Manfred Frick
Mucus clearance provides an essential innate defense mechanism to keep the airways and lungs free of particles and pathogens. Baseline and stimulated mucin secretion from secretory airway epithelial cells need to be tightly regulated to prevent mucus hypersecretion and mucus plugging of the airways. It is well established that extracellular ATP is a potent stimulus for regulated mucus secretion. Previous studies revealed that ATP acts via metabotropic P2Y2 purinoreceptors on goblet cells. Extracellular ATP, however, is also a potent agonist for ionotropic P2X purinoreceptors...
October 25, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
Andrzej Bak, Violetta Kozik, Malgorzata Walczak, Justyna Fraczyk, Zbigniew Kaminski, Beata Kolesinska, Adam Smolinski, Josef Jampilek
The pharmacophore properties of a new series of potential purinoreceptor (P2X) inhibitors determined using a coupled neural network and the partial least squares method with iterative variable elimination (IVE-PLS) are presented in a ligand-based comparative study of the molecular surface by comparative molecular surface analysis (CoMSA). Moreover, we focused on the interpretation of noticeable variations in the potential selectiveness of interactions of individual inhibitor-receptors due to their physicochemical properties; therefore, the library of artificial dipeptide receptors (ADP) was designed and examined...
August 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Krisandra Kneer, Michael B Green, Jenna Meyer, Celeste B Rich, Martin S Minns, Vickery Trinkaus-Randall
Type 2 diabetes is one of the leading pathologies that increases the risk of improper wound healing. Obesity has become a major risk factor for this disease that is now considered to be the 4th highest cause of preventable blindness according to the World Health Organization. The cornea is the most densely innervated structure in the human body and senses even the slightest injury. In diabetes, decreased corneal sensitivity secondary to diabetic peripheral neuropathy can lead to increased corneal abrasion, ulceration, and even blindness...
October 2018: Experimental Eye Research
Jaekwang Lee, Jin Young Bae, C Justin Lee, Yong Chul Bae
Recently, we reported that astrocytes in the trigeminal caudal nucleus (Vc) of the brain stem express a purinergic receptor P2X3 , which is involved in the craniofacial pathologic pain. Although we observed protein expression of P2X3 receptors (P2X3 Rs) in the astrocyte of the Vc, it is still unclear that astrocyte has functional P2X3 Rs in Vc. To address this issue, we recorded asrtocytic P2X3 Rs by using whole cell voltage-clamp recording in the Vc of the GFAP-GFP mice, which was used as a guide to astrocytes with green fluorescence...
April 2018: Experimental Neurobiology
Nicole Reichenbach, Andrea Delekate, Björn Breithausen, Kevin Keppler, Stefanie Poll, Theresa Schulte, Jan Peter, Monika Plescher, Jan N Hansen, Nelli Blank, Armin Keller, Martin Fuhrmann, Christian Henneberger, Annett Halle, Gabor C Petzold
Astrocytic hyperactivity is an important contributor to neuronal-glial network dysfunction in Alzheimer's disease (AD). We have previously shown that astrocyte hyperactivity is mediated by signaling through the P2Y1 purinoreceptor (P2Y1R) pathway. Using the APPPS1 mouse model of AD, we here find that chronic intracerebroventricular infusion of P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, as measured by in vivo two-photon microscopy, augments structural synaptic integrity, and preserves hippocampal long-term potentiation...
June 4, 2018: Journal of Experimental Medicine
Polina D Kotova, Marina F Bystrova, Olga A Rogachevskaja, Alexander A Khokhlov, Veronika Yu Sysoeva, Vsevolod A Tkachuk, Stanislav S Kolesnikov
The purinergic transduction was examined in mesenchymal stromal cells (MSCs) from the human adipose tissue, and several nucleotides, including ATP, UTP, and ADP, were found to mobilize cytosolic Ca2+ . Transcripts for multiple purinoreceptors were detected in MSC preparations, including A1 , A2A , A2B , P2Y1 , P2Y2 , P2Y4 , P2Y6 , P2Y11 , P2Y13 , P2Y14 , P2X2 , P2X4 , and P2X7 . Cellular responses to nucleotides were insignificantly sensitive to bath Ca2+ , pointing at a minor contribution of Ca2+ entry, and were suppressed by U73122 and 2-APB, implicating the phosphoinositide cascade in coupling P2Y receptors to Ca2+ release...
May 2018: Cell Calcium
Atsushi Uekawa, Hitoki Yamanaka, Liesbet Lieben, Yoshifumi Kimira, Mariko Uehara, Yoko Yamamoto, Shigeaki Kato, Kosei Ito, Geert Carmeliet, Ritsuko Masuyama
Extracellular low phosphate strongly enhances intestinal calcium absorption independently of active vitamin D [1,25(OH)2 D3 ] signaling, but the underlying mechanisms remain poorly characterized. To elucidate the phosphate-dependent regulation of calcium transport, we investigated part of the enteral environment that is involved in 1,25(OH)2 D3 -independent calcium absorption, which responds to dietary phosphate levels in mice that lack intestinal vitamin D receptor ( Vdr) activity. Impaired calcium absorption in intestinal Vdr-null mice was improved by dietary phosphate restriction...
April 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Yoshio Yamamoto, Nobuaki Nakamuta
Nerve endings with immunoreactivity for the P2X3 purinoreceptor (P2X3) in the rat tracheal mucosa were examined by immunohistochemistry of whole-mount preparations with confocal scanning laser microscopy. P2X3 immunoreactivity was observed in ramified endings distributed in the whole length of the trachea. The myelinated parent axons of P2X3-immunoreactive nerve endings ramified into several branches that extended two-dimensionally in every direction at the interface between the epithelial layer and lamina propria...
February 15, 2018: Journal of Comparative Neurology
Conner I Sandefur, Richard C Boucher, Timothy C Elston
Mucociliary clearance is composed of three components (i.e., mucin secretion, airway surface hydration, and ciliary-activity) which function coordinately to clear inhaled microbes and other foreign particles from airway surfaces. Airway surface hydration is maintained by water fluxes driven predominantly by active chloride and sodium ion transport. The ion channels that mediate electrogenic ion transport are regulated by extracellular purinergic signals that signal through G protein-coupled receptors. These purinoreceptors and the signaling pathways they activate have been identified as possible therapeutic targets for treating lung disease...
August 29, 2017: Proceedings of the National Academy of Sciences of the United States of America
Frances M Munoz, Ruby Gao, Yuzhen Tian, Brian A Henstenburg, James E Barrett, Huijuan Hu
ATP can activate a variety of pathways through P2 purinoreceptors, leading to neuroprotection and pathology in the CNS. Among all P2X receptors, the P2X7 receptor (P2X7R) is a well-defined therapeutic target for inflammatory and neuropathic pain. Activation of P2X7R can generate reactive oxygen species (ROS) in macrophages and microglia. However, the role of ROS in P2X7R-induced pain remains unexplored. Here, we investigated the downstream effects of neuronal P2X7R activation in the spinal cord. We found that ATP induces ROS production in spinal cord dorsal horn neurons, an effect eliminated by ROS scavenger N-tert-butyl-α-phenylnitrone (PBN) and P2X7R antagonist A438079...
June 14, 2017: Scientific Reports
Itzhak Binderman, Nasir Gadban, Avinoam Yaffe
Periodontal diseases are initiated by pathogenic bacterial biofilm activity that induces a host inflammatory cells immune response, degradation of dento gingival fibrous tissue and its detachment from root cementum. It is well accepted, that osteoclastic alveolar bone loss is governed exclusively through secretion of proinflammatory cytokines. Nevertheless, our findings suggest that once degradation of collagen fibers by MMPs occurs, a drop of cellular strains cause immediate release of ATP from marginal gingival fibroblasts, cell deformation and influx of Ca+2...
September 2017: Archives of Oral Biology
P Borilova Linhartova, P Cernochova, J Kastovsky, Z Vrankova, M Sirotkova, L Izakovicova Holla
OBJECTIVE: Genes, involved in the modulation of inflammatory response and bone remodeling, play a role in the development of postorthodontic external apical root resorption (EARR). The aim of our study was to analyze possible associations between seven single nucleotide polymorphisms (SNPs) in interleukin-17A (IL-17), osteopontin (SPP1), purinoreceptor P2X7 (P2RX7), and tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) genes and EARR in children after orthodontic treatment...
January 2017: Oral Diseases
Vladislav S Kuzmin, Ksenia B Pustovit, Denis V Abramochkin
BACKGROUND: Recently, NAD+ has been considered as an essential factor, participating in nerve control of physiological functions and intercellular communication. NAD+ also has been supposed as endogenous activator of P1 and P2 purinoreceptors. Effects of extracellular NAD+ remain poorly investigated in cardiac tissue. This study aims to investigate the effects of extracellular NAD+ in different types of supraventricular and ventricular working myocardium from rat and their potential mechanisms...
June 27, 2016: Journal of Biomedical Science
Csaba Matta, János Fodor, László Csernoch, Róza Zákány
It is now widely recognised that changes of the intracellular calcium concentration have deep impact on the differentiation of various non-excitable cells including the elements of the vertebrate skeleton. It has become evident that purinergic signalling is one of the most ancient cellular mechanisms that can cause such alterations in the intracellular Ca(2+)-homeostasis, which are precisely set either spatially or temporally. Purinergic signalling is believed to regulate intracellular Ca(2+)-concentration of developing cartilage and skeletal muscle cells and suggested to play roles in the modulation of various cellular functions...
March 2016: Cell Calcium
Martin S Minns, Gregory Teicher, Celeste B Rich, Vickery Trinkaus-Randall
The process of wound healing involves a complex network of signaling pathways working to promote rapid cell migration and wound closure. Activation of purinergic receptors by secreted nucleotides plays a major role in calcium mobilization and the subsequent calcium-dependent signaling that is essential for proper healing. The role of the purinergic receptor P2X7 in wound healing is still relatively unknown. We demonstrate that P2X7 expression increases at the leading edge of corneal epithelium after injury in an organ culture model, and that this change occurs despite an overall decrease in P2X7 expression throughout the epithelium...
February 2016: American Journal of Pathology
Jia Zhu, Zhen Wang, Nan Zhang, Jiao Ma, Shui-Lin Xu, Yin Wang, Ying Shen, Yun-Hong Li
Microglia clean up dead cells and debris through phagocytosis in the central nervous system. UDP-activated P2Y6 receptors (P2Y6Rs) induce the formation of phagocytic cup-like structure and P2Y6R expression is increased during the phagocytosis. However, it remains unclear how surface expression of P2Y6R is increased. PICK1 (protein interacting with C-kinase-1) interacts with various neurotransmitter receptors, transporters, and enzymes. We here report that PICK1 might interact with P2Y6R. Surface P2Y6R was reduced in microglia from PICK1-knockout mice and PICK1-knockdown BV2 cells, which was also confirmed by electrophysiological recordings, showing that P2Y6R-mediated current was increased by PICK1 overexpression but was reduced by PICK1-knockdown in BV2 microglia...
April 2016: Neurochemical Research
Seonmin Lee, Gee-Young Suh, Stefan W Ryter, Augustine M K Choi
Inflammasomes are specialized inflammatory signaling platforms that govern the maturation and secretion of proinflammatory cytokines, such as IL-1β and IL-18, through the regulation of caspase-1-dependent proteolytic processing. Several nucleotide binding domain leucine-rich repeat-containing receptor (NLR) family members (i.e., NLR family, pyrin domain containing [NLRP] 1, NLRP3, and NLR family, caspase recruitment domain containing-4 [NLRC4]) as well as the pyrin and hemopoietic expression, interferon-inducibility, nuclear localization domain-containing family member, absent in melanoma 2, can form inflammasome complexes in human cells...
February 2016: American Journal of Respiratory Cell and Molecular Biology
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