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Kevin J Ashton, Melissa E Reichelt, S Jamal Mustafa, Bunyen Teng, Catherine Ledent, Lea M D Delbridge, Polly A Hofmann, R Ray Morrison, John P Headrick
Influences of adenosine 2A receptor (A2AR) activity on the cardiac transcriptome and genesis of endotoxemic myocarditis are unclear. We applied transcriptomic profiling (39 K Affymetrix arrays) to identify A2AR-sensitive molecules, revealed by receptor knockout (KO), in healthy and endotoxemic hearts. Baseline cardiac function was unaltered and only 37 A2AR-sensitive genes modified by A2AR KO (≥1.2-fold change, <5 % FDR); the five most induced are Mtr, Ppbp, Chac1, Ctsk and Cnpy2 and the five most repressed are Hp, Yipf4, Acta1, Cidec and Map3k2...
September 30, 2016: Purinergic Signalling
(no author information available yet)
Cotargeting CD73 and A2AR overcomes host-ablated A2AR-induced CD73 expression.
September 30, 2016: Cancer Discovery
Adriana Pinto de Freitas, Danielle Dias Pinto Ferreira, Arlete Fernandes, Robertta Silva Martins, Vladimir Pedro Peralva Borges-Martins, Matheus Figueiredo Sathler, Maurício Dos-Santos-Pereira, Roberto Paes-de-Carvalho, Elizabeth Giestal-de-Araujo, Ricardo Augusto de Melo Reis, Regina Celia Cussa Kubrusly
l-Glutamate and l-aspartate are the main excitatory amino acids (EAAs) in the Central Nervous System (CNS) and their uptake regulation is critical for the maintenance of the excitatory balance. Excitatory amino acid transporters (EAATs) are widely distributed among central neurons and glial cells. GLAST and GLT1 are expressed in glial cells, whereas excitatory amino acid transporter 3/excitatory amino acid carrier 1 (EAAT3/EAAC1) is neuronal. Different signaling pathways regulate glutamate uptake by modifying the activity and expression of EAATs...
September 20, 2016: Neuroscience
Xiaoying Huang, Yicheng He, Yanfan Chen, Peiliang Wu, Di Gui, Hui Cai, Ali Chen, Mayun Chen, Caijun Dai, Dan Yao, Liangxing Wang
BACKGROUND: Baicalin has been reported to have anti-fibrosis effect; however, its mechanism still remains to be elucidated. Adenosine A2a receptor (A2aR) is a novel inflammation regulator, and transforming growth factor-β1 (TGF-β1)-induced extracellular signal regulated kinase1/2 (ERK1/2) signaling pathway plays an important role in idiopathic pulmonary fibrosis (IPF). This study was to explore the relationship of A2aR and TGF-β1-induced ERK1/2 in bleomycin (BLM)-induced pulmonary fibrosis in mice, and to investigate whether A2aR mediate the anti-fibrosis effect of Baicalin on BLM-induced pulmonary fibrosis...
2016: BMC Pulmonary Medicine
Yang-Wuyue Liu, Ting Yang, Li Zhao, Zhenhong Ni, Nan Yang, Fengtian He, Shuang-Shuang Dai
Systemic inflammatory response syndrome (SIRS) is an overwhelming whole body inflammation caused by infectious diseases or sterile insults. Neutrophils are the dominant participants during inflammation, and their survival and death determine the initiation as well as resolution of SIRS. Apoptosis and autophagy are two fundamental cellular processes that modulating cell fate, but their correlation and regulators in neutrophils under SIRS condition have not been elucidated. In this study, we demonstrated that high dose of LPS induced both apoptosis and autophagy of neutrophils in a mouse SIRS model and LPS-stimulated neutrophils in vitro...
2016: Scientific Reports
Arabella Young, Shin Foong Ngiow, Deborah S Barkauskas, Erin Sult, Carl Hay, Stephen J Blake, Qihui Huang, Jing Liu, Kazuyoshi Takeda, Michele W L Teng, Kris Sachsenmeier, Mark J Smyth
Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors...
September 12, 2016: Cancer Cell
Rony Dahan, Jeffrey V Ravetch
Targeting the signaling pathway of the immunosuppressive metabolite adenosine is an emerging approach for cancer immunotherapy. In this issue of Cancer Cell, Young et al. describe that co-inhibition of the adenosingenic pathway through blockade of both CD73 and A2AR enhances antitumor efficacy through distinct mechanisms.
September 12, 2016: Cancer Cell
César Quiroz, Seema Gulyani, Wan Ruiqian, Jordi Bonaventura, Roy Cutler, Virginia Pearson, Richard P Allen, Christopher J Earley, Mark P Mattson, Sergi Ferré
Deficits of sensorimotor integration with periodic limb movements during sleep (PLMS) and hyperarousal and sleep disturbances in Restless Legs Syndrome (RLS) constitute two pathophysiologically distinct but interrelated clinical phenomena, which seem to depend mostly on alterations in dopaminergic and glutamatergic neurotransmission, respectively. Brain iron deficiency is considered as a main pathogenetic mechanism in RLS. Rodents with brain iron deficiency represent a valuable pathophysiological model of RLS, although they do not display motor disturbances...
December 2016: Neuropharmacology
Claudia Sorrentino, Lucio Miele, Amalia Porta, Aldo Pinto, Silvana Morello
The A2B receptor (A2BR) can mediate adenosine-induced tumor proliferation, immunosuppression and angiogenesis. Targeting the A2BR has proved to be therapeutically effective in some murine tumor models, but the mechanisms of these effects are still incompletely understood. Here, we report that pharmacologic inhibition of A2BR with PSB1115, which inhibits tumor growth, decreased the number of fibroblast activation protein (FAP)-expressing cells in tumors in a mouse model of melanoma. This effect was associated with reduced expression of fibroblast growth factor (FGF)-2...
August 31, 2016: Oncotarget
Patrick M McNeely, Andrea N Naranjo, Kimberly Forsten-Williams, Anne Skaja Robinson
Ligand binding plays a fundamental role in stimulating the downstream signaling of membrane receptors. Here, ligand-binding kinetics of the full-length human adenosine A2A receptor (A2AR) reconstituted in detergent micelles were measured using a fluorescently labeled ligand via fluorescence anisotropy. Importantly, to optimize the signal-to-noise ratio, these experiments were conducted in the ligand depletion regime. In the ligand depletion regime, the assumptions used to determine analytical solutions for one-site binding models for either one or two ligands in competition are no longer valid...
August 30, 2016: Journal of Biomolecular Screening
Aura Carole Meirsman, Anne Robé, Alban de Kerchove d'Exaerde, Brigitte Lina Kieffer
GPR88 is an orphan G-protein-coupled receptor highly expressed in striatal dopamine D1 (receptor) R- and D2R-expressing medium spiny neurons. This receptor is involved in activity and motor responses, and we previously showed that this receptor also regulates anxiety-like behaviors. To determine whether GPR88 in D2R-expressing neurons contributes to this emotional phenotype, we generated conditional Gpr88 knock-out mice using adenosine A2AR (A2AR)-Cre-driven recombination, and compared anxiety-related responses in both total and A2AR-Gpr88 KO mice...
July 2016: ENeuro
Xavier Guitart, Jordi Bonaventura, William Rea, Marco Orrú, Lucrezia Cellai, Ilaria Dettori, Felicita Pedata, Marc Brugarolas, Antonio Cortés, Vicent Casadó, Ching-Pang Chang, Manikandan Narayanan, Yijuang Chern, Sergi Ferré
The initial goal of this study was to investigate alterations in adenosine A2A receptor (A2AR) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse...
August 24, 2016: Neurobiology of Disease
Luan D Truong, Jessica Trostel, Rachel McMahan, Jiang-Fan Chen, Gabriela E Garcia
A2A adenosine receptors (A2ARs) are endogenous inhibitor of inflammation. Macrophages that are key effectors of kidney disease progression express A2ARs. We investigated the role of A2ARs in kidney inflammation in a macrophage-mediated anti-glomerular basement membrane reactive serum-induced immune nephritis in A2AR-deficient mice. Sub-threshold doses of glomerular basement membrane-reactive serum induced more severe and prolonged kidney damage with higher levels of proinflammatory cytokines and greater accumulation of inflammatory cells in A2AR(-/-) mice than wild-type (WT) mice...
October 2016: American Journal of Pathology
Aránzazu Mediero, Tuere Wilder, Vishnu S R Reddy, Qian Cheng, Nick Tovar, Paulo G Coelho, Lukasz Witek, Carl Whatling, Bruce N Cronstein
As many as 10% of bone fractures heal poorly, and large bone defects resulting from trauma, tumor, or infection may not heal without surgical intervention. Activation of adenosine A2A receptors (A2AR) stimulates bone formation. Ticagrelor and dipyridamole inhibit platelet function by inhibiting P2Y12 receptors and platelet phosphodiesterase, respectively, but share the capacity to inhibit cellular uptake of adenosine and thereby increase extracellular adenosine levels. Because dipyridamole promotes bone regeneration by an A2AR-mediated mechanism we determined whether ticagrelor could regulate the cells involved in bone homeostasis and regeneration in a murine model and whether inhibition of P2Y12 or indirect A2AR activation via adenosine was involved...
August 10, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Vânia L Batalha, Diana G Ferreira, Joana E Coelho, Jorge S Valadas, Rui Gomes, Mariana Temido-Ferreira, Tatiana Shmidt, Younis Baqi, Luc Buée, Christa E Müller, Malika Hamdane, Tiago F Outeiro, Michael Bader, Sebastiaan H Meijsing, Ghazaleh Sadri-Vakili, David Blum, Luísa V Lopes
Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer's disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored...
2016: Scientific Reports
Yi-Qun Wang, Rui Li, Dian-Ru Wang, Yoan Cherasse, Ze Zhang, Meng-Qi Zhang, Oriana Lavielle, Kristopher McEown, Serge N Schiffmann, Alban de Kerchove d'Exaerde, Wei-Min Qu, Michael Lazarus, Zhi-Li Huang
Rapid eye movement (REM) sleep behavior disorder in humans is often accompanied by a reduced ability to smell and detect odors, and olfactory bulbectomized rats exhibit increased REM sleep, suggesting that the olfactory bulb (OB) is involved in REM-sleep regulation. However, the molecular mechanism of REM-sleep regulation by the OB is unknown. Adenosine promotes sleep and its A2A receptors (A2AR) are expressed in the OB. We hypothesized that A2AR in the OB regulate REM sleep. Bilateral microinjections of the A2AR antagonist SCH58261 into the rat OB increased REM sleep, whereas microinjections of the A2AR agonist CGS21680 decreased REM sleep...
August 2, 2016: Brain Structure & Function
Jean Ruf, Franck Paganelli, Laurent Bonello, Nathalie Kipson, Giovanna Mottola, Julien Fromonot, Jocelyne Condo, Alain Boussuges, Laurie Bruzzese, François Kerbaul, Yves Jammes, Vlad Gariboldi, Frédéric Franceschi, Emmanuel Fenouillet, Régis Guieu
During exercise, cardiac oxygen-consumption increases and the resulting low oxygen level in myocardium triggers coronary vasodilation. This response to hypoxia is controlled notably by the vasodilator adenosine and its A2A receptor (A2AR). According to the "spare receptor" pharmacological model, a strong A2AR-mediated response can occur in the context of a large number of receptors remaining unoccupied, activation of only a weak fraction of A2AR (evaluated using KD) resulting in maximal cAMP production (evaluated using EC50), and hence in maximal coronary vasodilation...
July 19, 2016: Molecular Medicine
Byron Carpenter, Rony Nehmé, Tony Warne, Andrew G W Leslie, Christopher G Tate
G-protein-coupled receptors (GPCRs) are essential components of the signalling network throughout the body. To understand the molecular mechanism of G-protein-mediated signalling, solved structures of receptors in inactive conformations and in the active conformation coupled to a G protein are necessary. Here we present the structure of the adenosine A(2A) receptor (A(2A)R) bound to an engineered G protein, mini-Gs, at 3.4 Å resolution. Mini-Gs binds to A(2A)R through an extensive interface (1,048 Å2) that is similar, but not identical, to the interface between Gs and the β2-adrenergic receptor...
August 4, 2016: Nature
Po-Yuan Hsiao, Jay Kalin, Im-Hong Sun, Mohammed Amin, Ying-Chun Lo, Meng-Jung Chiang, John Giddens, Polina Sysa-Shah, Kathleen Gabrielson, Lai-Xi Wang, Jonathan Powell, Philip A Cole
The adenosine A2A receptor (A2AR) is expressed in immune cells as well as heart and lung tissue and has been intensively studied as a therapeutic target for multiple disease indications.Inhibitors of the A2AR have the potential for stimulating immune response which could be valuable for cancer immune surveillance and mounting a response against pathogens. One well-established potent and selective small-molecule A2AR antagonist, ZM-241385 (ZM), has a short pharmacokinetic half-life and has the potential for systemic toxicity due to A2AR effects in the brain and the heart...
July 19, 2016: Chembiochem: a European Journal of Chemical Biology
Stephen M Hatfield, Michail Sitkovsky
Hypoxic and adenosine rich tumor microenvironments represent an important barrier that must be overcome to enable T and NK cells to reject tumors. The A2A adenosine receptor (A2AR) on activated immune cells was identified as a critical and non-redundant mediator of physiological immunosuppression. Observations showing that tumor-protecting A2AR also suppress and redirect the anti-tumor immune response pointed to the importance of inhibiting this pathway to improve cancer immunotherapy. We advocated (i) blocking immunosuppressive adenosine-A2AR-cAMP-mediated intracellular signaling by A2AR antagonists and (ii) weakening hypoxia-HIF-1α-mediated accumulation of extracellular adenosine by oxygenation agents that also inhibits CD39/CD73 adenosine-generating enzymes...
August 2016: Current Opinion in Pharmacology
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