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https://www.readbyqxmd.com/read/29298990/gsk3%C3%AE-negatively-regulates-trax-a-scaffold-protein-implicated-in-mental-disorders-for-nhej-mediated-dna-repair-in-neurons
#1
Ting Chien, Yu-Ting Weng, Shu-Yung Chang, Hsing-Lin Lai, Feng-Lan Chiu, Hung-Chih Kuo, De-Maw Chuang, Yijuang Chern
Translin-associated protein X (TRAX) is a scaffold protein with various functions and has been associated with mental illnesses, including schizophrenia. We have previously demonstrated that TRAX interacts with a Gsα protein-coupled receptor, the A2A adenosine receptor (A2AR), and mediates the function of this receptor in neuritogenesis. In addition, stimulation of the A2AR markedly ameliorates DNA damage evoked by elevated oxidative stress in neurons derived from induced pluripotent stem cells (iPSCs). Here, we report that glycogen synthase kinase 3 beta (GSK3β) and disrupted-in-schizophrenia 1 (DISC1) are two novel interacting proteins of TRAX...
January 3, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/29296811/randomized-phase-2-trial-of-regadenoson-for-treatment-of-acute-vaso-occlusive-crises-in-sickle-cell-disease
#2
Joshua J Field, Elaine Majerus, Victor R Gordeuk, Michel Gowhari, Carolyn Hoppe, Matthew M Heeney, Maureen Achebe, Alex George, Hillary Chu, Brian Sheehan, Maneka Puligandla, Donna Neuberg, Gene Lin, Joel Linden, David G Nathan
Adenosine A2A receptor (A2AR) agonists have been shown to decrease tissue inflammation induced by hypoxia/reoxygenation in mice with sickle cell disease (SCD). The key mediator of the A2AR agonist's anti-inflammatory effects is a minor lymphocyte subset, invariant natural killer T (iNKT) cells. We tested the hypothesis that administration of an A2AR agonist in patients with SCD would decrease iNKT cell activation and dampen the severity of vaso-occlusive (VO) crises. In a phase 2, randomized, placebo-controlled trial, we administered a 48-hour infusion of the A2AR agonist regadenoson (1...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29290010/computer-aided-design-of-multi-target-ligands-at-a1r-a2ar-and-pde10a-key-proteins-in-neurodegenerative-diseases
#3
Leen Kalash, Cristina Val, Jhonny Azuaje, María I Loza, Fredrik Svensson, Azedine Zoufir, Lewis Mervin, Graham Ladds, José Brea, Robert Glen, Eddy Sotelo, Andreas Bender
Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A1 and A2A receptors (A1R and A2AR) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A1 and A2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes...
December 30, 2017: Journal of Cheminformatics
https://www.readbyqxmd.com/read/29229601/a2ar-adenosine-signaling-suppresses-natural-killer-cell-maturation-in-the-tumor-microenvironment
#4
Arabella Young, Shin Foong Ngiow, Yulong Gao, Ann-Marie Patch, Deborah S Barkauskas, Meriem Messaoudene, Gene Lin, Jerome David Coudert, Kimberley A Stannard, Laurence Zitvogel, Mariapia A Degli-Esposti, Eric Vivier, Nicola Waddell, Joel Linden, Nicholas D Huntington, Fernando Souza-Fonseca Guimaraes, Mark J Smyth
Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs anti-tumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK cell-specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays...
December 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/29217157/functional-histamine-h3-and-adenosine-a2a-receptor-heteromers-in-recombinant-cells-and-rat-striatum
#5
Ricardo Márquez-Gómez, Meridith T Robins, Citlaly Gutiérrez-Rodelo, Juan-Manuel Arias, Jesús-Alberto Olivares-Reyes, Richard M van Rijn, José-Antonio Arias-Montaño
In the striatum, histamine H3 receptors (H3Rs) are co-expressed with adenosine A2A receptors (A2ARs) in the cortico-striatal glutamatergic afferents and the GABAergic medium-sized spiny neurons that originate from the indirect pathway of the basal ganglia. This location allows H3Rs and A2ARs to regulate the striatal GABAergic and glutamatergic transmission. However, whether these receptors can physically interact has not yet been assessed. To test this hypothesis, a heteromer-selective in vitro assay was used to detect functional complementation between a chimeric A2AR302-Gαqi4 and wild-type H3Rs in transfected HEK-293 cells...
December 4, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29212737/astrocytic-lrp4-low-density-lipoprotein-receptor-related-protein-4-contributes-to-ischemia-induced-brain-injury-by-regulating-atp-release-and-adenosine-a2ar-adenosine-a2a-receptor-signaling
#6
Xin-Chun Ye, Jin-Xia Hu, Lei Li, Qiang Li, Fu-Lei Tang, Sen Lin, Dong Sun, Xiang-Dong Sun, Gui-Yun Cui, Lin Mei, Wen-Cheng Xiong
BACKGROUND AND PURPOSE: Lrp4 (low-density lipoprotein receptor-related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4's function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. METHODS: The brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion...
January 2018: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/29205397/effects-of-long-term-alcohol-drinking-on-the-dopamine-d2-receptor-gene-expression-and-heteroreceptor-complexes-in-the-striatum-in-rats
#7
Kristin Feltmann, Dasiel Oscar Borroto-Escuela, Joëlle Rüegg, Luca Pinton, Thatiane de Oliveira Sergio, Manuel Narváez, Antonio Jimenez-Beristain, Tomas J Ekström, Kjell Fuxe, Pia Steensland
BACKGROUND: Reduced dopamine D2 receptor (D2R) ligand binding has repeatedly been demonstrated in the striatum of humans with alcohol use disorder (AUD). The attenuated D2R binding has been suggested to reflect a reduced D2R density, which in turn has been proposed to drive craving and relapse. However, results from rodent studies addressing the effects of alcohol drinking on D2R density have been inconsistent. METHODS: A validated alcohol drinking model (intermittent access to 20% alcohol) in Wistar rats was used to study the effects of voluntary alcohol drinking (at least 12 weeks) on the D2R in the striatum compared to age-matched alcohol-naïve control rats...
December 5, 2017: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/29201000/striatal-g%C3%AE-olf-camp-signal-dependent-mechanism-to-generate-levodopa-induced-dyskinesia-in-parkinson-s-disease
#8
Satoshi Goto
The motor symptoms of Parkinson's disease (PD) result from striatal dopamine (DA) deficiency due to a progressive degeneration of nigral dopaminergic cells. Although DA replacement therapy is the mainstay to treat parkinsonian symptoms, a long-term daily administration of levodopa often develops levodopa-induced dyskinesia (LID). LID is closely linked to the dysregulation of cyclic adenosine monophosphate (cAMP) signaling cascades in the medium spiny neurons (MSNs), the principal neurons of the striatum, which are roughly halved with striatonigral MSNs by striatopallidal MSNs...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29174913/effects-of-cordycepin-on-spontaneous-alternation-behavior-and-adenosine-receptors-expression-in-hippocampus
#9
Zhi-Ping Cao, Dan Dai, Peng-Ju Wei, Yuan-Yuan Han, Yan-Qing Guan, Han-Hang Li, Wen-Xiao Liu, Peng Xiao, Chu-Hua Li
Cordycepin, an adenosine analogue, has been reported to improve cognitive function. Important roles on learning and memory of adenosine and its receptors, such as adenosine A1 and A2A receptors (A1R and A2AR), also have been shown. Therefore, we assume that the improvement of learning and memory induced by cordycepin is likely related to hippocampal adenosine content and adenosine receptor density. Here we investigated the effects of cordycepin on the short-term spatial memory by using a spontaneous alternation behavior (SAB) test in Y-maze, and then examined hippocampal adenosine content and A1R and A2AR densities...
November 23, 2017: Physiology & Behavior
https://www.readbyqxmd.com/read/29145453/the-antiviral-drug-tenofovir-an-inhibitor-of-pannexin-1-mediated-atp-release-prevents-liver-and-skin-fibrosis-by-downregulating-adenosine-levels-in-the-liver-and-skin
#10
Jessica L Feig, Aranzazu Mediero, Carmen Corciulo, Hailing Liu, Jin Zhang, Miguel Perez-Aso, Laura Picard, Tuere Wilder, Bruce Cronstein
BACKGROUND: Fibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection...
2017: PloS One
https://www.readbyqxmd.com/read/29129783/hypoxia-induced-mir-214-expression-promotes-tumour-cell-proliferation-and-migration-by-enhancing-the-warburg-effect-in-gastric-carcinoma-cells
#11
Liuqing Yang, Weijie Zhang, Yanbo Wang, Tianhui Zou, Bin Zhang, Yuanyuan Xu, Taohong Pang, Qingqing Hu, Min Chen, Lei Wang, Ying Lv, Kai Yin, Hongwei Liang, Xi Chen, Guifang Xu, Xiaoping Zou
miR-214 is an important oncomiRNA and is upregulated in various types of cancer, including gastric cancer. However, the molecular mechanism underlying the ectopic expression and function of miR-214 in gastric cancer is largely undefined. In this study, we found that miR-214 induces the Warburg effect and promotes the migration and proliferation of human gastric cancer cells. According to the mechanistic analysis, miR-214 expression is induced by environmental hypoxia, and miR-214 mediates hypoxia-induced functions...
November 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29126977/enhancement-of-inosine-mediated-a2ar-signaling-through-positive-allosteric-modulation
#12
Ajith A Welihinda, Manmeet Kaur, Kaviya S Raveendran, Edward P Amento
Inosine is an endogenous nucleoside that is produced by metabolic deamination of adenosine. Inosine is metabolically more stable (half-life 15h) than adenosine (half-life <10s). Inosine exerts anti-inflammatory and immunomodulatory effects similar to those observed with adenosine. These effects are mediated in part through the adenosine A2A receptor (A2AR). Relative to adenosine inosine exhibits a lower affinity towards the A2AR. Therefore, it is generally believed that inosine is incapable of activating the A2AR through direct engagement, but indirectly activates the A2AR upon metabolic conversion to higher affinity adenosine...
November 8, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29079454/the-adenosine-a2a-receptor-agonist-t1-11-ameliorates-neurovisceral-symptoms-and-extends-the-lifespan-of-a-mouse-model-of-niemann-pick-type-c-disease
#13
Antonella Ferrante, Antonella Pezzola, Andrea Matteucci, Antonella Di Biase, Lucilla Attorri, Monica Armida, Alberto Martire, Yijuang Chern, Patrizia Popoli
Niemann-Pick C is a fatal neurovisceral disorder caused, in 95% of cases, by mutation of NPC1 gene. Therapeutic options are extremely limited and new "druggable" targets are highly warranted. We previously demonstrated that the stimulation of the adenosine A2A receptor (A2AR) normalized the pathological phenotype of cellular models of NPC1. Since the validation of A2ARs as a therapeutic target for NPC1 can be obtained only conducting studies in in vivo models of the disease, in the present paper, the effects of two agonists of A2ARs were evaluated in the mouse model Balb/c Npc1(nih), hereafter indicated as NPC1-/-...
October 25, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29071996/-effect-of-electroacupuncture-on-adenosine-receptor-expression-in-white-adipose-tissue-of-diet-induced-obese-mice
#14
Yue-Xia Tang, Jian-Zhong Meng, Ya-Juan Ding, Hao Hong, Mei-Ling Yu, Xin-Yue Jing, Sheng-Feng Lu, Bing-Mei Zhu
OBJECTIVE: To investigate the effects of electroacupuncture (EA) on the expression of adenosine receptor (AR) in the white adipose tissue (WAT) of diet-induced obese (DIO) mice, so as to reveal a peripheral mechanism of EA underlying improvement of body weight. METHODS: Forty three-week-old C 57 BL/6 male mice were divided into normal diet group (n=12) and high fat diet group (n=28) randomly, and fed by normal diet and high fat diet for 12 weeks, respectively. In the high fat diet group, mice with body weight over 20% heavier than that of the normal diet group were considered as obese mice...
February 25, 2017: Zhen Ci Yan Jiu, Acupuncture Research
https://www.readbyqxmd.com/read/29064819/age-related-decline-of-the-acute-local-inflammation-response-a-mitigating-role-for-the-adenosine-a2a-receptor
#15
Cynthia Laflamme, Geneviève Bertheau Mailhot, Marc Pouliot
Aging is accompanied by an increase in markers of innate immunity. How aging affects neutrophil functions remains of debate.The adenosine A2A receptor (A2AR), essential to the resolution of inflammation, modulates neutrophil functions. We sought to determine whether or not A2AR protects against the effects of aging. We monitored neutrophil influx, viability, and activation as well as cytokine accumulation in wild-type (WT) and A2AR-knockout mice (KO) at three different ages.Several readouts decreased with aging: neutrophil counts in dorsal air pouches (by up to 55%), neutrophil viability (by up to 56%), elastase and total protein in exudates (by up to 80%), and local levels of cytokines (by up to 90%)...
October 18, 2017: Aging
https://www.readbyqxmd.com/read/29042444/development-of-novel-biosensors-to-study-receptor-mediated-activation-of-gs-and-golf
#16
Hideaki Yano, Davide Provasi, Ning Sheng Cai, Marta Filizola, Sergi Ferre, Jonathan A Javitch
Gαs (Gs) and Gαolf (Golf) are highly homologous G protein α; subunits that activate adenylate cyclase, thereby serving as crucial mediators of intracellular signaling. Owing to their dramatically different brain expression patterns, we studied similarities and differences between their activation processes with the aim of comparing their receptor coupling mechanisms. We engineered novel luciferase- and Venus-fused Gα constructs that can be used in bioluminescence resonance energy transfer (BRET) assays...
October 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29022877/striatal-adenosine-a2a-receptor-neurons-control-active-period-sleep-via-parvalbumin-neurons-in-external-globus-pallidus
#17
Xiang-Shan Yuan, Lu Wang, Hui Dong, Wei-Min Qu, Su-Rong Yang, Yoan Cherasse, Michael Lazarus, Serge N Schiffmann, Alban de Kerchove d'Exaerde, Rui-Xi Li, Zhi-Li Huang
Dysfunction of the striatum is frequently associated with sleep disturbances. However, its role in sleep-wake regulation has been paid little attention even though the striatum densely expresses adenosine A2A receptors (A2ARs), which are essential for adenosine-induced sleep. Here we showed that chemogenetic activation of A2AR neurons in specific subregions of the striatum induced a remarkable increase in non-rapid eye movement (NREM) sleep. Anatomical mapping and immunoelectron microscopy revealed that striatal A2AR neurons innervated the external globus pallidus (GPe) in a topographically organized manner and preferentially formed inhibitory synapses with GPe parvalbumin (PV) neurons...
October 12, 2017: ELife
https://www.readbyqxmd.com/read/28984574/ligand-modulation-of-sidechain-dynamics-in-a-wild-type-human-gpcr
#18
Lindsay D Clark, Igor Dikiy, Karen Chapman, Karin Ej Rödström, James Aramini, Michael V LeVine, George Khelashvili, Søren Gf Rasmussen, Kevin H Gardner, Daniel M Rosenbaum
GPCRs regulate all aspects of human physiology, and biophysical studies have deepened our understanding of GPCR conformational regulation by different ligands. Yet there is no experimental evidence for how sidechain dynamics control allosteric transitions between GPCR conformations. To address this deficit, we generated samples of a wild-type GPCR (A2AR) that are deuterated apart from (1)H/(13)C NMR probes at isoleucine δ1 methyl groups, which facilitated (1)H/(13)C methyl TROSY NMR measurements with opposing ligands...
October 6, 2017: ELife
https://www.readbyqxmd.com/read/28981089/treatment-with-a2a-receptor-antagonist-kw6002-and-caffeine-intake-regulate-microglia-reactivity-and-protect-retina-against-transient-ischemic-damage
#19
Raquel Boia, Filipe Elvas, Maria H Madeira, Inês D Aires, Ana C Rodrigues-Neves, Pedro Tralhão, Eszter C Szabó, Younis Baqi, Christa E Müller, Ângelo R Tomé, Rodrigo A Cunha, António F Ambrósio, Ana R Santiago
Transient retinal ischemia is a major complication of retinal degenerative diseases and contributes to visual impairment and blindness. Evidences indicate that microglia-mediated neuroinflammation has a key role in the neurodegenerative process, prompting the hypothesis that the control of microglia reactivity may afford neuroprotection to the retina against the damage induced by ischemia-reperfusion (I-R). The available therapeutic strategies for retinal degenerative diseases have limited potential, but the blockade of adenosine A2A receptor (A2AR) emerges as candidate strategy...
October 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28979687/activation-of-a2ar-attenuates-bleomycin-induced-pulmonary-fibrosis-via-the-sdf-1-cxcr4-axis-related-pathway
#20
Yanfan Chen, Xiaoming Yu, Yicheng He, Lin Zhang, Xiaoying Huang, Xiaomei Xu, Mayun Chen, Xiang Chen, Liangxing Wang
Previous studies in our lab have demonstrated that Adenosine A2a receptor (A2aR) gene-knockout mice were vulnerable to pulmonary fibrosis induced by bleomycin (BLM). Inhibition of the SDF-1/CXCR4 axis has been reported to protect the lungs from fibrogenesis in BLM-exposed mice. Little is yet known about the relationships between A2aR and the SDF-1/CXCR4 axis in idiopathic pulmonary fibrosis (IPF). This study probes the role of A2aR in the fibrotic process and explores the relationship between A2aR and the SDF-1/CXCR4 axis in BLM-induced pulmonary fibrosis in mice...
2017: American Journal of Translational Research
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