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https://www.readbyqxmd.com/read/28529484/targeting-adenosine-receptors-for-the-treatment-of-cardiac-fibrosis
#1
REVIEW
Elizabeth A Vecchio, Paul J White, Lauren T May
Adenosine is a ubiquitous molecule with key regulatory and cytoprotective mechanisms at times of metabolic imbalance in the body. Among a plethora of physiological actions, adenosine has an important role in attenuating ischaemia-reperfusion injury and modulating the ensuing fibrosis and tissue remodeling following myocardial damage. Adenosine exerts these actions through interaction with four adenosine G protein-coupled receptors expressed in the heart. The adenosine A2B receptor (A2BAR) is the most abundant adenosine receptor (AR) in cardiac fibroblasts and is largely responsible for the influence of adenosine on cardiac fibrosis...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28368607/enantiospecific-recognition-at-the-a2b-adenosine-receptor-by-alkyl-2-cyanoimino-4-substituted-6-methyl-1-2-3-4-tetrahydropyrimidine-5-carboxylates
#2
Carlos Carbajales, Jhonny Azuaje, Ana Oliveira, María I Loza, José Brea, María I Cadavid, Christian F Masaguer, Xerardo García-Mera, Hugo Gutiérrez-de-Terán, Eddy Sotelo
A novel family of structurally simple, potent, and selective nonxanthine A2BAR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)16b, Ki = 24...
April 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28344125/capadenoson-a-clinically-trialed-partial-adenosine-a1-receptor-agonist-can-stimulate-adenosine-a2b-receptor-biased-agonism
#3
Jo-Anne Baltos, Elizabeth A Vecchio, Matthew A Harris, Cheng Xue Qin, Rebecca H Ritchie, Arthur Christopoulos, Paul J White, Lauren T May
The adenosine A2B receptor (A2BAR) has been identified as an important therapeutic target in cardiovascular disease, however in vitro and in vivo targeting has been limited by the paucity of pharmacological tools, particularly potent agonists. Interestingly, 2-((6-amino-3,5-dicyano-4-(4-(cyclopropylmethoxy)phenyl)-2-pyridinyl)thio)acetamide (BAY60-6583), a potent and subtype-selective A2BAR agonist, has the same core structure as 2-amino-6-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl]-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitril (capadenoson)...
July 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28266889/lung-injury-pathways-adenosine-receptor-2b-signaling-limits-development-of-ischemic-bronchiolitis-obliterans-organizing-pneumonia
#4
John C Densmore, Terry R Schaid, Paul M Jeziorczak, Meetha Medhora, Said Audi, Shraddha Nayak, John Auchampach, Melinda R Dwinell, Aron M Geurts, Elizabeth R Jacobs
Purpose/Aim of the Study: Adenosine signaling was studied in bronchiolitis obliterans organizing pneumonia (BOOP) resulting from unilateral lung ischemia. MATERIALS AND METHODS: Ischemia was achieved by either left main pulmonary artery or complete hilar ligation. Sprague-Dawley (SD) rats, Dahl salt sensitive (SS) rats and SS mutant rat strains containing a mutation in the A2B adenosine receptor gene (Adora2b) were studied. Adenosine concentrations were measured in bronchoalveolar lavage (BAL) by HPLC...
February 2017: Experimental Lung Research
https://www.readbyqxmd.com/read/28137910/osteogenesis-is-improved-by-low-tumor-necrosis-factor-alpha-concentration-through-the-modulation-of-gs-coupled-receptor-signals
#5
Simona Daniele, Letizia Natali, Chiara Giacomelli, Pietro Campiglia, Ettore Novellino, Claudia Martini, Maria Letizia Trincavelli
In the early phase of bone damage, low concentrations of the cytokine tumor necrosis factor alpha (TNF-α) favor osteoblast differentiation. In contrast, chronic high doses of the same cytokine contribute to bone loss, demonstrating opposite effects depending on its concentration and on the time of exposure. In the bone microenvironment, TNF-α modulates the expression/function of different G protein-coupled receptors (GPCRs) and of their regulatory proteins, GPCR-regulated kinases (GRKs), thus dictating their final biological outcome in controlling bone anabolic processes...
April 15, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28054654/aminophylline-suppresses-stress-induced-visceral-hypersensitivity-and-defecation-in-irritable-bowel-syndrome
#6
Teita Asano, Ken-Ichiro Tanaka, Arisa Tada, Hikaru Shimamura, Rikako Tanaka, Hiroki Maruoka, Mitsuko Takenaga, Tohru Mizushima
Pharmacological therapy for irritable bowel syndrome (IBS) has not been established. In order to find candidate drugs for IBS with diarrhea (IBS-D), we screened a compound library of drugs clinically used for their ability to prevent stress-induced defecation and visceral hypersensitivity in rats. We selected the bronchodilator aminophylline from this library. Using a specific inhibitor for each subtype of adenosine receptors (ARs) and phosphodiesterases (PDEs), we found that both A2BARs and PDE4 are probably mediated the inhibitory effect of aminophylline on wrap restraint stress (WRS)-induced defecation...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27974241/a2b-adenosine-receptors-stimulate-il-6-production-in-primary-murine-microglia-through-p38-mapk-kinase-pathway
#7
Stefania Merighi, Serena Bencivenni, Fabrizio Vincenzi, Katia Varani, Pier Andrea Borea, Stefania Gessi
The hallmark of neuroinflammation is the activation of microglia, the immunocompetent cells of the CNS, releasing a number of proinflammatory mediators implicated in the pathogenesis of neuronal diseases. Adenosine is an ubiquitous autacoid regulating several microglia functions through four receptor subtypes named A1, A2A, A2B and A3 (ARs), that represent good targets to suppress inflammation occurring in CNS. Here we investigated the potential role of ARs in the modulation of IL-6 secretion and cell proliferation in primary microglial cells...
December 11, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27871900/insulin-adenosine-axis-linked-signalling
#8
REVIEW
Luis Silva, Mario Subiabre, Joaquín Araos, Tamara Sáez, Rocío Salsoso, Fabián Pardo, Andrea Leiva, Rody San Martín, Fernando Toledo, Luis Sobrevia
Regulation of blood flow depends on systemic and local release of vasoactive molecules such as insulin and adenosine. These molecules cause vasodilation by activation of plasma membrane receptors at the vascular endothelium. Adenosine activates at least four subtypes of adenosine receptors (A1AR, A2AAR, A2BAR, A3AR), of which A2AAR and A2BAR activation leads to increased cAMP level, generation of nitric oxide, and relaxation of the underlying smooth muscle cell layer. Vasodilation caused by adenosine also depends on plasma membrane hyperpolarization due to either activation of intermediate-conductance Ca(2+)-activated K(+) channels in vascular smooth muscle or activation of ATP-activated K(+) channels in the endothelium...
November 19, 2016: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/27606311/adenosine-a2b-receptor-from-cell-biology-to-human-diseases
#9
REVIEW
Ying Sun, Pingbo Huang
Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. Recently, significant advances have been made in our understanding of A2B adenosine receptor (A2BAR). In this review, we first summarize some of the general characteristics of A2BAR, and then we describe the multiple binding partners of the receptor, such as newly identified α-actinin-1 and p105, and discuss how these associated proteins could modulate A2BAR's functions, including certain seemingly paradoxical functions of the receptor...
2016: Frontiers in Chemistry
https://www.readbyqxmd.com/read/27520486/the-hybrid-molecule-vcp746-is-a-potent-adenosine-a2b-receptor-agonist-that-stimulates-anti-fibrotic-signalling
#10
COMPARATIVE STUDY
Elizabeth A Vecchio, Chung Hui Chuo, Jo-Anne Baltos, Leigh Ford, Peter J Scammells, Bing H Wang, Arthur Christopoulos, Paul J White, Lauren T May
We have recently described the rationally-designed adenosine receptor agonist, 4-(5-amino-4-benzoyl-3-(3-(trifluoromethyl)phenyl)thiophen-2-yl)-N-(6-(9-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxylmethyl)tetrahydro-furan-2-yl)-9H-purin-6-ylamino)hexyl)benzamide (VCP746), a hybrid molecule consisting of an adenosine moiety linked to an adenosine A1 receptor (A1AR) allosteric modulator moiety. At the A1AR, VCP746 mediated cardioprotection in the absence of haemodynamic side effects such as bradycardia. The current study has now identified VCP746 as an important pharmacological tool for the adenosine A2B receptor (A2BAR)...
October 1, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27347331/sesamin-protects-against-renal-ischemia-reperfusion-injury-by-promoting-cd39-adenosine-a2ar-signal-pathway-in-mice
#11
Ke Li, Xia Gong, Ge Kuang, Rong Jiang, Jingyuan Wan, Bin Wang
Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury with high morbidity and mortality due to limited therapy. Here, we examine whether sesamin attenuates renal IRI in an animal model and explore the underlying mechanisms. Male mice were subjected to right renal ischemia for 30 min followed by reperfusion for 24 h with sesamin (100 mg/kg) during which the left kidney was removed. Renal damage and function were assessed subsequently. The results showed that sesamin reduced kidney ischemia reperfusion injury, as assessed by decreased serum creatinine (Scr) and Blood urea nitrogen (BUN), alleviated tubular damage and apoptosis...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27208173/actinin-1-binds-to-the-c-terminus-of-a2b-adenosine-receptor-a2bar-and-enhances-a2bar-cell-surface-expression
#12
Ying Sun, Wenbao Hu, Xiaojie Yu, Zhengzhao Liu, Robert Tarran, Katya Ravid, Pingbo Huang
A2BAR (A2B adenosine receptor) has been implicated in several physiological conditions, such as allergic or inflammatory disorders, vasodilation, cell growth and epithelial electrolyte secretion. For mediating the protein-protein interactions of A2BAR, the receptor's C-terminus is recognized to be crucial. In the present study, we unexpectedly found that two point mutations in the A2BAR C-terminus (F297A and R298A) drastically impaired the expression of A2BAR protein by accelerating its degradation. Thus we tested the hypothesis that these two point mutations disrupt A2BAR's interaction with a protein essential for A2BAR stability...
July 15, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27199507/correlation-of-a2bar-and-klf4-klf15-with-obesity-dyslipidemia-induced-inflammation-in-uygur-population
#13
Cuizhe Wang, Xiaodan Ha, Wei Li, Peng Xu, Yajuan Gu, Tingting Wang, Yan Wang, Jianxin Xie, Jun Zhang
In this paper, the researchers collected visceral adipose tissue from the Uygur population, which were divided into two groups: the normal control group (NC, n = 50, 18.0 kg/m(2) ≤ BMI ≤ 23.9 kg/m(2)) and the obese group (OB, n = 45, BMI ≥ 28 kg/m(2)), and then use real-time PCR to detect the mRNA expression level of key genes involved in inflammation signaling pathway. The findings suggest that, in obese status, the lower expression level of A2bAR, KLF4, and KLF15 of visceral adipose tissue may correlate with obese-dyslipidemia induced inflammation in Uygur population...
2016: Mediators of Inflammation
https://www.readbyqxmd.com/read/26969588/role-of-extracellular-cysteine-residues-in-the-adenosine-a2a-receptor
#14
Elisabetta De Filippo, Vigneshwaran Namasivayam, Lukas Zappe, Ali El-Tayeb, Anke C Schiedel, Christa E Müller
The G protein-coupled A2A adenosine receptor represents an important drug target. Crystal structures and modeling studies indicated that three disulfide bonds are formed between ECL1 and ECL2 (I, Cys71(2.69)-Cys159(45.43); II, Cys74(3.22)-Cys146(45.30), and III, Cys77(3.25)-Cys166(45.50)). However, the A2BAR subtype appears to require only disulfide bond III for proper function. In this study, each of the three disulfide bonds in the A2AAR was disrupted by mutation of one of the cysteine residues to serine...
June 2016: Purinergic Signalling
https://www.readbyqxmd.com/read/26791603/ligand-independent-adenosine-a2b-receptor-constitutive-activity-as-a-promoter-of-prostate-cancer-cell-proliferation
#15
Elizabeth A Vecchio, Christina Y R Tan, Karen J Gregory, Arthur Christopoulos, Paul J White, Lauren T May
Aberrant ligand-independent G protein-coupled receptor constitutive activity has been implicated in the pathophysiology of a number of cancers. The adenosine A2B receptor (A2BAR) is dynamically upregulated under pathologic conditions associated with a hypoxic microenvironment, including solid tumors. This, in turn, may amplify ligand-independent A2BAR signal transduction. The contribution of A2BAR constitutive activity to disease progression is currently unknown yet of fundamental importance, as the preferred therapeutic modality for drugs designed to reduce A2BAR constitutive activity would be inverse agonism as opposed to neutral antagonism...
April 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/26385692/characterization-of-dahl-salt-sensitive-rats-with-genetic-disruption-of-the-a2b-adenosine-receptor-gene-implications-for-a2b-adenosine-receptor-signaling-during-hypertension
#16
Shraddha Nayak, Md Abdul H Khan, Tina C Wan, Hong Pei, Joel Linden, Melinda R Dwinell, Aron M Geurts, John D Imig, John A Auchampach
The A(2B) adenosine receptor (AR) has emerged as a unique member of the AR family with contrasting roles during acute and chronic disease states. We utilized zinc-finger nuclease technology to create A(2B)AR gene (Adora2b)-disrupted rats on the Dahl salt-sensitive (SS) genetic background. This strategy yielded a rat strain (SS-Adora2b mutant rats) with a 162-base pair in-frame deletion of Adora2b that included the start codon. Disruption of A(2B)AR function in SS-Adora2b mutant rats was confirmed by loss of agonist (BAY 60-6583 or NECA)-induced cAMP accumulation and loss of interleukin-6 release from isolated fibroblasts...
December 2015: Purinergic Signalling
https://www.readbyqxmd.com/read/26142494/adenosine-receptors-and-diabetes-focus-on-the-a-2b-adenosine-receptor-subtype
#17
REVIEW
Stefania Merighi, Pier Andrea Borea, Stefania Gessi
Over the last two decades, diabetes mellitus has become one of the most challenging health problems worldwide. Diabetes mellitus, classified as type I and II, is a pathology concerning blood glucose level in the body. The nucleoside adenosine has long been known to affect insulin secretion, glucose homeostasis and lipid metabolism, through activation of four G protein coupled adenosine receptors (ARs), named A1, A2A, A2B and A3. Currently, the novel promising subtype to develop new drugs for diabetes treatment is the A2BAR subtype...
September 2015: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/25975415/the-many-faces-of-the-a2b-adenosine-receptor-in-cardiovascular-and-metabolic-diseases
#18
REVIEW
Anna Eisenstein, Shenia Patterson, Katya Ravid
Modulation of the low affinity adenosine receptor subtype, the A2b adenosine receptor (A2bAR), has gained interest as a therapeutic target in various pathologic areas associated with cardiovascular disease. The actions of the A2bAR are diverse and at times conflicting depending on cell and tissue type and the timing of activation or inhibition of the receptor. The A2bAR is a promising and exciting pharmacologic target, however, a thorough understanding of A2bAR action is necessary to reach the therapeutic potential of this receptor...
December 2015: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/25911169/involvement-of-nadph-oxidase-in-a2a-adenosine-receptor-mediated-increase-in-coronary-flow-in-isolated-mouse-hearts
#19
Zhichao Zhou, Uthra Rajamani, Hicham Labazi, Stephen L Tilley, Catherine Ledent, Bunyen Teng, S Jamal Mustafa
Adenosine increases coronary flow mainly through the activation of A2A and A2B adenosine receptors (ARs). However, the mechanisms for the regulation of coronary flow are not fully understood. We previously demonstrated that adenosine-induced increase in coronary flow is in part through NADPH oxidase (Nox) activation, which is independent of activation of either A1 or A3ARs. In this study, we hypothesize that adenosine-mediated increase in coronary flow through Nox activation depends on A2A but not A2BARs. Functional studies were conducted using isolated Langendorff-perfused mouse hearts...
June 2015: Purinergic Signalling
https://www.readbyqxmd.com/read/25877700/activation-of-a2b-adenosine-receptor-regulates-ovarian-cancer-cell-growth-involvement-of-bax-bcl-2-and-caspase-3
#20
Sima Hajiahmadi, Mojtaba Panjehpour, Mahmoud Aghaei, Mahdi Shabani
A2b adenosine receptor (A2bAR) acts as a potent regulator of cell growth in various cell lines. The present study was designed to understand the controlling mechanism of A2bAR agonist (NECA)-induced apoptosis in ovarian cancer cells. Real-time PCR and western blotting assays were used to evaluate the gene and protein expression profiles of A2bAR, respectively. MTT assay was used to study the cell proliferation effect of A2bAR agonist (NECA). Detection of apoptosis was conducted using annexin V-FITC/PI staining, caspase-3 activation assay, and the expression of Bax and Bcl-2 proteins analysis...
August 2015: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
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