The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Holger K. Eltzschig - One of the best experts on this subject based on the ideXlab platform.
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Adenosine receptors as drug targets what are the challenges
Nature Reviews Drug Discovery, 2013Co-Authors: Jiangfan Chen, Holger K. Eltzschig, Bertil B FredholmAbstract:Adenosine signalling has long been a target for drug development, with Adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at Adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of Adenosine receptors. There is strong evidence that Adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual Adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one Adenosine receptor-specific agent — the Adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of Adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting Adenosine receptors and discuss strategies to overcome these challenges.
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Transcriptional control of Adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease
Journal of Molecular Medicine, 2013Co-Authors: Jens M. Poth, Kelley Brodsky, Heidi Ehrentraut, Almut Grenz, Holger K. EltzschigAbstract:Inflammatory lesions, ischemic tissues, or solid tumors are characterized by the occurrence of severe tissue hypoxia within the diseased tissue. Subsequent stabilization of hypoxia-inducible transcription factors—particularly of hypoxia-inducible factor 1α (HIF1A)—results in significant alterations of gene expression of resident cells or inflammatory cells that have been recruited into such lesions. Interestingly, studies of hypoxia-induced changes of gene expression identified a transcriptional program that promotes extracellular Adenosine signaling. Adenosine is a signaling molecule that functions through the activation of four distinct Adenosine receptors—the ADORA1, ADORA2A, ADORA2B, and ADORA3 receptors. Extracellular Adenosine is predominantly derived from the phosphohydrolysis of precursor nucleotides, such as Adenosine triphosphate or Adenosine monophosphate. HIF1A-elicited alterations in gene expression enhance the enzymatic capacity within inflamed tissues to produce extracellular Adenosine. Moreover, hypoxia-elicited induction of Adenosine receptors—particularly of ADORA2B—results in increased signal transduction. Functional studies in genetic models for HIF1A or Adenosine receptors implicate this pathway in an endogenous feedback loop that dampens excessive inflammation and promotes injury resolution, while at the same time enhancing ischemia tolerance. Therefore, pharmacological strategies to enhance HIF-elicited Adenosine production or to promote Adenosine signaling through Adenosine receptors are being investigated for the treatment of acute inflammatory or ischemic diseases characterized by tissue hypoxia.
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endogenous Adenosine produced during hypoxia attenuates neutrophil accumulation coordination by extracellular nucleotide metabolism
Blood, 2004Co-Authors: Holger K. Eltzschig, Richard J Cotta, Juan C Ibla, Jorn Karhausen, Linda F. Thompson, Simon C. Robson, Sean P ColganAbstract:Hypoxia is a well-documented inflammatory stimulus and results in tissue polymorphonuclear leukocyte (PMN) accumulation. Likewise, increased tissue Adenosine levels are commonly associated with hypoxia, and given the anti-inflammatory properties of Adenosine, we hypothesized that Adenosine production via adenine nucleotide metabolism at the vascular surface triggers an endogenous anti-inflammatory response during hypoxia. Initial in vitro studies indicated that endogenously generated Adenosine, through activation of PMN Adenosine A2A and A2B receptors, functions as an antiadhesive signal for PMN binding to microvascular endothelia. Intravascular nucleotides released by inflammatory cells undergo phosphohydrolysis via hypoxia-induced CD39 ectoapyrase (CD39 converts Adenosine triphosphate/Adenosine diphosphate [ATP/ADP] to Adenosine monophosphate [AMP]) and CD73 ecto-5′-nucleotidase (CD73 converts AMP to Adenosine). Extensions of our in vitro findings using cd39 - and cd73 -null animals revealed that extracellular Adenosine produced through adenine nucleotide metabolism during hypoxia is a potent anti-inflammatory signal for PMNs in vivo. These findings identify CD39 and CD73 as critical control points for endogenous Adenosine generation and implicate this pathway as an innate mechanism to attenuate excessive tissue PMN accumulation. (Blood. 2004;104:3986-3992)
Jens M. Poth - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional control of Adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease
Journal of Molecular Medicine, 2013Co-Authors: Jens M. Poth, Kelley Brodsky, Heidi Ehrentraut, Almut Grenz, Holger K. EltzschigAbstract:Inflammatory lesions, ischemic tissues, or solid tumors are characterized by the occurrence of severe tissue hypoxia within the diseased tissue. Subsequent stabilization of hypoxia-inducible transcription factors—particularly of hypoxia-inducible factor 1α (HIF1A)—results in significant alterations of gene expression of resident cells or inflammatory cells that have been recruited into such lesions. Interestingly, studies of hypoxia-induced changes of gene expression identified a transcriptional program that promotes extracellular Adenosine signaling. Adenosine is a signaling molecule that functions through the activation of four distinct Adenosine receptors—the ADORA1, ADORA2A, ADORA2B, and ADORA3 receptors. Extracellular Adenosine is predominantly derived from the phosphohydrolysis of precursor nucleotides, such as Adenosine triphosphate or Adenosine monophosphate. HIF1A-elicited alterations in gene expression enhance the enzymatic capacity within inflamed tissues to produce extracellular Adenosine. Moreover, hypoxia-elicited induction of Adenosine receptors—particularly of ADORA2B—results in increased signal transduction. Functional studies in genetic models for HIF1A or Adenosine receptors implicate this pathway in an endogenous feedback loop that dampens excessive inflammation and promotes injury resolution, while at the same time enhancing ischemia tolerance. Therefore, pharmacological strategies to enhance HIF-elicited Adenosine production or to promote Adenosine signaling through Adenosine receptors are being investigated for the treatment of acute inflammatory or ischemic diseases characterized by tissue hypoxia.
Bertil B Fredholm - One of the best experts on this subject based on the ideXlab platform.
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Adenosine receptors as drug targets what are the challenges
Nature Reviews Drug Discovery, 2013Co-Authors: Jiangfan Chen, Holger K. Eltzschig, Bertil B FredholmAbstract:Adenosine signalling has long been a target for drug development, with Adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at Adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of Adenosine receptors. There is strong evidence that Adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual Adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one Adenosine receptor-specific agent — the Adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of Adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting Adenosine receptors and discuss strategies to overcome these challenges.
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Involvement of Adenosine deaminase and Adenosine kinase in regulating extracellular Adenosine concentration in rat hippocampal slices.
Neurochemistry International, 1995Co-Authors: H.g.e. Lloyd, Bertil B FredholmAbstract:Abstract In this study the relative importance of Adenosine deaminase and Adenosine kinase in regulating extracellular Adenosine concentration was investigated in rat hippocampal slices labelled with [3H]-adenine. The release of [3H]-purines evoked by electrical stimulation or energy depletion (oxygen and glucose deprivation) was measured and, using high-performance liquid chromatography (HPLC), the proportion of [3H]-label in the form of [3H]-Adenosine, [3H]-inosine and [3H]-hypoxanthine was determined. In addition, endogenous purine release was measured by HPLC with UV detection. 10 μM 5-iodotubericidin (5-IT), an inhibitor of Adenosine kinase, significantly increased endogenous Adenosine release and altered the pattern of [3H]-purine release by increasing the proportion released as [3H]-Adenosine, under basal conditions and after electrical stimulation or energy depletion. 5 μM erythro-9-(2-hydroxy-3-nonyl) Adenosine (EHNA), an inhibitor of Adenosine deaminase, also increased endogenous Adenosine release and altered the pattern of [3H]-purine release evoked by energy depletion by decreasing the proportion of [3H]-label released as [3H]-hypoxanthine and [3H]-inosine, whilst approximately doubling that of [3H]-Adenosine. In contrast, Adenosine release was not altered by EHNA under basal conditions or electrical stimulation. It is concluded that under conditions which provide adequate oxygen and glucose, Adenosine kinase plays a much greater role than Adenosine deaminase in regulating the extracellular concentration of Adenosine. However, Adenosine deaminase becomes important in regulating extracellular Adenosine concentration when Adenosine formation is increased by energy depletion.
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effects of propentofylline on Adenosine a1 and a2 receptors and nitrobenzylthiojnosine sensitive nucleoside transporters quantitative autoradiographic analysis
European Journal of Pharmacology, 1991Co-Authors: Fiona E Parkinson, Bertil B FredholmAbstract:Abstract Previous studies have demonstrated that the xanthine compound, propentofylline, has beneficial effects in models of cerebral ischemia and can enhance some and exhibit other effects of Adenosine. We investigated the in vitro effects of propentofylline and its hydroxy metabolite, A72 0287, on the binding of(3H]cyclohexylAdenosine ([3H]CHA), [3H]2-[p-(2-carbonyl-ethyl)-phenylethyl-amino]-5'-N-ethylcarboxamido Adenosine ([3H]CGS 21680) and [3H]nitrobcnzylthioinosine ([3H]NBMPR) to Adenosine A1 and A2 receptors and NBMPR-sensitive nucleoside transporters, respectively, in 10-μm coronal rat brain sections. Both xanthines had micromolar affinity for each of these sites with approximately 10-fold lower affinity for A2 receptors than for A1 receptors and [3H]NBMPR binding sites. Saturation analysis of [3]CHA or [3h]cgs 21680 binding in the presence of increasing concentrations of propentofylline produced significant increases in Kd values without affecting Bmax values; thus propentofylline is a competitive inhibitor at a1 and A2 receptors. The effects on A2 receptors apparently require higher concentrations (Ki approximately 200 μM) than the effects on A1 receptors (Ki approximately 20 μM). Propentofylline was also found to be a competitive inhibitor of [3h]nbmpr binding. Therefore we conclude that propentofylline interacts with adcnosine-responsive systems to increase interstitial Adenosine concentrations and to selectively inhibit A1 receptors.
Osamu Asano - One of the best experts on this subject based on the ideXlab platform.
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functional characterization of the Adenosine receptor contributing to glycogenolysis and gluconeogenesis in rat hepatocytes
European Journal of Pharmacology, 2003Co-Authors: Nobuyuki Yasuda, Tatsuo Horizoe, Kaya Nagata, Hiroe Minami, Tsutomu Kawata, Yorihisa Hoshino, Hitoshi Harada, Seiji Yoshikawa, Takashi Inoue, Osamu AsanoAbstract:Abstract The Adenosine receptor subtype mediating glucose production by glycogenolysis and gluconeogenesis was studied in primary cultured rat hepatocytes. Adenosine and Adenosine agonists caused cyclic AMP accumulation in rat hepatocytes. The order of potency was 5′- N -ethylcarboxamidoAdenosine (NECA)> R (−)- N 6 -(2-phenylisopropyl)Adenosine (RPIA)>Adenosine>2-[ p -(carboxyethyl)phenylethylamino]-5′- N -ethylcarboxamidoAdenosine (CGS21680). Furthermore, Adenosine agonists stimulated glycogenolysis and gluconeogenesis. The order of potency was NECA>RPIA>CGS21680. The rank order of potency is typical for Adenosine A 2B receptors. Glycogenolysis stimulated by NECA was fully inhibited by nonselective Adenosine antagonists, 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5- c ]quinazolin-5-amine (CGS15943). However, the Adenosine A 2A receptor-selective antagonist, 8-(3-chlorostyryl)caffeine (CSC), and the Adenosine A 1 receptor-selective antagonist, (+)-( R )-[( E )-3-(2-phenylpyrazolo[1,5-alpha]pyridin-3-yl)acryloyl]-2-piperidine ethanol (FK453), had a low inhibitory potency. A strong correlation was found between the inhibitory effect of Adenosine antagonists on NECA-induced glucose production and that on intracellular cyclic AMP generation in rat hepatocytes. Our results suggest that Adenosine stimulates cyclic AMP formation and regulates glycogenolysis and gluconeogenesis, most likely through the Adenosine A 2B receptor subtype in rat hepatocytes.
Brian J Liddicoat - One of the best experts on this subject based on the ideXlab platform.
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Adenosine to inosine rna editing by adar1 is essential for normal murine erythropoiesis
Experimental Hematology, 2016Co-Authors: Brian J Liddicoat, Jochen C Hartner, Robert Piskol, Gokul Ramaswami, Alistair M Chalk, Paul D Kingsley, Vijay G Sankaran, Meaghan WallAbstract:Adenosine deaminases that act on RNA (ADARs) convert Adenosine residues to inosine in double-stranded RNA. In vivo, ADAR1 is essential for the maintenance of hematopoietic stem/progenitors. Whether other hematopoietic cell types also require ADAR1 has not been assessed. Using erythroid- and myeloid-restricted deletion of Adar1, we demonstrate that ADAR1 is dispensable for myelopoiesis but is essential for normal erythropoiesis. Adar1-deficient erythroid cells display a profound activation of innate immune signaling and high levels of cell death. No changes in microRNA levels were found in ADAR1-deficient erythroid cells. Using an editing-deficient allele, we demonstrate that RNA editing is the essential function of ADAR1 during erythropoiesis. Mapping of Adenosine-to-inosine editing in purified erythroid cells identified clusters of hyperedited Adenosines located in long 3'-untranslated regions of erythroid-specific transcripts and these are ADAR1-specific editing events. ADAR1-mediated RNA editing is essential for normal erythropoiesis.
