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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...
June 5, 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
Gerard Higgins, Fiona Ringholz, Paul Buchanan, Paul McNally, Valérie Urbach
Lipoxin A4 has been described as a major signal for the resolution of inflammation and is abnormally produced in the lungs of patients with cystic fibrosis (CF). In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF...
2015: BioMed Research International
Jolanta Barańska
First nucleotide receptors were discovered by Geoffrey Burnstock in 70ties of the last century, as a purinoreceptors activated by ATP. It was further found that they may be activated both by purine and pyrimidine nucleotides and their name was changed to nucleotide receptors. They are divided into two fsamilies: P1, activated by adenosine and P2, activated by nucleotides which are further divided into P2X and P2Y subfamilies. P2X are ionotropic receptors activated by ATP, P2Y (as the P1) are metabotropic receptors coupled with protein G...
2014: Postepy Biochemii
Yuri Inose, Yoichiro Kato, Kazuo Kitagawa, Shinichiro Uchiyama, Noriyuki Shibata
In acute stage of ischemic stroke, the surrounding zone of fresh infarcts is termed penumbra, where microglia are activated in response to damaged cell-derived proinflammatory mediators. Rescuing penumbra by regulating inflammatory activity would minimize infarct volume, which positively correlates with functional outcome. To elucidate mechanisms by which inflammation occurs in penumbra, we performed immunohistochemical investigations using autopsied human brains affected by acute, subacute and chronic stages of cerebral infarction as well as cell culture experiments using a murine microglia-derived cell line (BV-2)...
June 2015: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Andrea Delekate, Martina Füchtemeier, Toni Schumacher, Cordula Ulbrich, Marco Foddis, Gabor C Petzold
Astrocytic network alterations have been reported in Alzheimer's disease (AD), but the underlying pathways have remained undefined. Here we measure astrocytic calcium, cerebral blood flow and amyloid-β plaques in vivo in a mouse model of AD using multiphoton microscopy. We find that astrocytic hyperactivity, consisting of single-cell transients and calcium waves, is most pronounced in reactive astrogliosis around plaques and is sometimes associated with local blood flow changes. We show that astroglial hyperactivity is reduced after P2 purinoreceptor blockade or nucleotide release through connexin hemichannels, but is augmented by increasing cortical ADP concentration...
2014: Nature Communications
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