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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
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
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
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
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
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
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
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
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
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
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
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
Jianjuan Ke, Bo Yao, Tao Li, Shanshan Cui, Huang Ding
This study was undertaken to determine and confer the cardioprotective effects of the adenosine A2 receptor (A2AR) and its impact on myocardial autophagy in the setting of reperfusion. We established a rat ischemia model by subjecting rats to 30 minutes of ischemia (I) and 120 minutes of reperfusion (R). The A2AR agonists CGS21680 (A2aAR specific) and BAY60-6583 (A2bAR specific) were administered separately and in combination 5 minutes before reperfusion (postconditioning). No visible improvements in the rats' hemodynamic changes in response to either CGS or BAY were observed compared with untreated control groups (I/R)...
July 2015: Journal of Cardiovascular Pharmacology
Qinghe Gao, Jingjing Zhang, Xia Wu, Shan Liu, Anxin Wu
The first C3-dicarbonylation of indoles was realized through direct oxidative cross-coupling of indoles with methyl ketones in the presence of molecular iodine and pyrrolidine. This reaction constructed a highly efficient indolyl diketones scaffold, which might be regarded as a useful biological and pharmacological tool in the exploration of therapeutic A2BAR modulators. The use of inexpensive molecular iodine and pyrrolidine and a broad substrate scope make this protocol very practical. Preliminary mechanistic studies indicate that two paths are involved in this process...
January 2, 2015: Organic Letters
S Daniele, E Zappelli, L Natali, C Martini, M L Trincavelli
Therapies that target the signal transduction and biological characteristics of cancer stem cells (CSCs) are innovative strategies that are used in combination with conventional chemotherapy and radiotherapy to effectively reduce the recurrence and significantly improve the treatment of glioblastoma multiforme (GBM). The two main strategies that are currently being exploited to eradicate CSCs are (a) chemotherapeutic regimens that specifically drive CSCs toward cell death and (b) those that promote the differentiation of CSCs, thereby depleting the tumour reservoir...
2014: Cell Death & Disease
Xueping Zhou, Bunyen Teng, Stephen Tilley, Catherine Ledent, S Jamal Mustafa
We have previously demonstrated that adenosine-mediated H2O2 production and opening of ATP-sensitive K(+) (KATP) channels contributes to coronary reactive hyperemia. The present study aimed to investigate the roles of adenosine, H2O2, and KATP channels in coronary metabolic hyperemia (MH). Experiments were conducted on isolated Langendorff-perfused mouse hearts using combined pharmacological approaches with adenosine receptor (AR) knockout mice. MH was induced by electrical pacing at graded frequencies. Coronary flow increased linearly from 14...
October 1, 2014: American Journal of Physiology. Heart and Circulatory Physiology
Na Li, Geng Wang, Xiuhua Yao, Qingfei Kong, Xiaoyu Shang, Xiaoli Xie, Jinghua Wang, Xiaoying Kang, Lianhong Jin, Guangyou Wang, Hulun Li, Lili Mu, Bo Sun
Extracellular adenosine is an essential negative regulator of immune reactions that acts by signaling via 4 distinct adenosine receptors. We evaluated adenosine receptor expression in Lewis rats presenting with experimental autoimmune myasthenia gravis (EAMG) to determine whether the expression of adenosine receptors are changed in the development and progression of EAMG. Lymphocyte A1AR and A2AAR mRNA and protein levels from lymphocytes harvested from the lymph nodes, spleen, and peripheral blood mononuclear cells (PBMCs) of EAMG rats were decreased...
August 2014: Cellular Immunology
Yang Yang, Yuan Qiu, Wensheng Wang, Weidong Xiao, Hongyin Liang, Chaojun Zhang, Hanwenbo Yang, Daniel H Teitelbaum, Li-Hua Sun, Hua Yang
BACKGROUND: Intestinal barrier function failure from ischemia/reperfusion (I/R) and acute hypoxia has been implicated as a critical determinant in the predisposition to intestinal inflammation and a number of inflammatory disorders. Here, we identified the role of Adenosine A2B receptor (A2BAR) in the regulation of intestinal barrier function under I/R and acute hypoxic conditions. METHODS: C57BL/6J mice were used, and were randomized into three groups: Sham, I/R, IR+PSB1115 (a specific A2BAR antagonist) groups...
2014: International Journal of Clinical and Experimental Pathology
Anna Eisenstein, Shannon H Carroll, Hillary Johnston-Cox, Melissa Farb, Noyan Gokce, Katya Ravid
Adipogenesis represents a key process in adipose tissue development and remodeling, including during obesity. Exploring the regulation of adipogenesis by extracellular ligands is fundamental to our understanding of this process. Adenosine, an extracellular nucleoside signaling molecule found in adipose tissue depots, acts on adenosine receptors. Here we report that, among these receptors, the A2b adenosine receptor (A2bAR) is highly expressed in adipocyte progenitors. Activation of the A2bAR potently inhibits differentiation of mouse stromal vascular cells into adipocytes, whereas A2bAR knockdown stimulates adipogenesis...
July 25, 2014: Journal of Biological Chemistry
Hillary Johnston-Cox, Anna S Eisenstein, Milka Koupenova, Shannon Carroll, Katya Ravid
High fat diet (HFD)-induced type 2 diabetes continues to be an epidemic with significant risk for various pathologies. Previously, we identified the A2b adenosine receptor (A2bAR), an established regulator of inflammation, as a regulator of HFD-induced insulin resistance. In particular, HFD was associated with vast upregulation of liver A2bAR in control mice, and while mice lacking this receptor showed augmented liver inflammation and tissue insulin resistance. As the A2bAR is expressed in different tissues, here, we provide the first lead to cellular mechanism by demonstrating that the receptor's influence on tissue insulin sensitivity is mediated via its expression in macrophages...
2014: PloS One
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