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Molecular Research on Adenosine Receptors: From Cell Biology to Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 April 2024) | Viewed by 3891

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Guest Editor
Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy
Interests: pharmacology; natural products; oxidative stress; inflammatory disease; atherosclerosis; metabolic disease; neurodegenerative diseases; autophagy; proliferation and differentiation process
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Special Issue Information

Dear Colleagues,

Adenosine is a ubiquitous endogenous cell signaling and modulator agent that plays a key role in the regulation of many physiological cell-signaling pathways; this nucleoside triggers a cellular response, activating four G-protein-coupled receptors (GPCRs) named the A1, A2A, A2B and A3 adenosine receptors (ARs). ARs are expressed in several tissues and organs, such as the brain, heart, bones, eyes, kidneys, skin, adipose tissue, immune cells, lungs and liver; due to their body distribution, ARs are implicated in several human disease, such as neurodegenerative disorders, chronic inflammatory diseases, cancer, hypoxia and ischemia. In many pathophysiological conditions, adenosine acts as a sensor for tissue damage, binding several AR-activating signaling pathways for the protection of damaged tissues or organs. Therefore, ARs could be considered a promising therapeutic target.

The purpose of this Special Issue of the International Journal of Molecular Sciences, entitled “Molecular Research on Adenosine Receptors: From Cell Biology to Human Diseases”, is to include original research papers and/or relevant literature data updates on novel insights into the pathogenesis, molecular pathways and beneficial effects of novel and safe AR agonist treatments.

Dr. Federica Mannino
Guest Editor

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Keywords

  • adenosine
  • ARs
  • AR agonists
  • chronic diseases
  • therapeutic strategy
  • AR antagonists

Published Papers (3 papers)

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Research

30 pages, 8337 KiB  
Article
Anti-Inflammatory Activities of 8-Benzylaminoxanthines Showing High Adenosine A2A and Dual A1/A2A Receptor Affinity
by Michał Załuski, Dorota Łażewska, Piotr Jaśko, Ewelina Honkisz-Orzechowska, Kamil J. Kuder, Andreas Brockmann, Gniewomir Latacz, Małgorzata Zygmunt, Maria Kaleta, Beril Anita Greser, Agnieszka Olejarz-Maciej, Magdalena Jastrzębska-Więsek, Christin Vielmuth, Christa E. Müller and Katarzyna Kieć-Kononowicz
Int. J. Mol. Sci. 2023, 24(18), 13707; https://doi.org/10.3390/ijms241813707 - 5 Sep 2023
Cited by 1 | Viewed by 1038
Abstract
Chronic inflammation plays an important role in the development of neurodegenerative diseases, such as Parkinson’s disease (PD). In the present study, we synthesized 25 novel xanthine derivatives with variable substituents at the N1-, N3- and C8-position as adenosine receptor antagonists with potential [...] Read more.
Chronic inflammation plays an important role in the development of neurodegenerative diseases, such as Parkinson’s disease (PD). In the present study, we synthesized 25 novel xanthine derivatives with variable substituents at the N1-, N3- and C8-position as adenosine receptor antagonists with potential anti-inflammatory activity. The compounds were investigated in radioligand binding studies at all four human adenosine receptor subtypes, A1, A2A, A2B and A3. Compounds showing nanomolar A2A and dual A1/A2A affinities were obtained. Three compounds, 19, 22 and 24, were selected for further studies. Docking and molecular dynamics simulation studies indicated binding poses and interactions within the orthosteric site of adenosine A1 and A2A receptors. In vitro studies confirmed the high metabolic stability of the compounds, and the absence of toxicity at concentrations of up to 12.5 µM in various cell lines (SH-SY5Y, HepG2 and BV2). Compounds 19 and 22 showed anti-inflammatory activity in vitro. In vivo studies in mice investigating carrageenan- and formalin-induced inflammation identified compound 24 as the most potent anti-inflammatory derivative. Future studies are warranted to further optimize the compounds and to explore their therapeutic potential in neurodegenerative diseases. Full article
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15 pages, 5486 KiB  
Article
Antiplatelet Effects of Selected Xanthine-Based Adenosine A2A and A2B Receptor Antagonists Determined in Rat Blood
by Monika Kubacka, Szczepan Mogilski, Marek Bednarski, Krzysztof Pociecha, Artur Świerczek, Noemi Nicosia, Jakub Schabikowski, Michał Załuski, Grażyna Chłoń-Rzepa, Jörg Hockemeyer, Christa E. Müller, Katarzyna Kieć-Kononowicz and Magdalena Kotańska
Int. J. Mol. Sci. 2023, 24(17), 13378; https://doi.org/10.3390/ijms241713378 - 29 Aug 2023
Cited by 2 | Viewed by 1039
Abstract
The platelet aggregation inhibitory activity of selected xanthine-based adenosine A2A and A2B receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A2B receptor antagonist PSB-603 and the A2A receptor antagonist TB-42 inhibited platelet [...] Read more.
The platelet aggregation inhibitory activity of selected xanthine-based adenosine A2A and A2B receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A2B receptor antagonist PSB-603 and the A2A receptor antagonist TB-42 inhibited platelet aggregation induced by collagen or ADP. In addition to adenosine receptor blockade, the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). TB-42 showed the highest inhibitory activity against PDE3A along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of PSB-603 and TB-42 may be due to inhibition of PDEs, which induces an increase in cAMP and/or cGMP concentrations in platelets. The xanthine-based adenosine receptor antagonists were found to be non-cytotoxic for platelets. Some of the compounds showed anti-oxidative properties reducing lipid peroxidation. These results may provide a basis for the future development of multi-target xanthine derivatives for the treatment of inflammation and atherosclerosis and the prevention of heart infarction and stroke. Full article
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11 pages, 1738 KiB  
Article
Increased Density of Endogenous Adenosine A2A Receptors in Atrial Fibrillation: From Cellular and Porcine Models to Human Patients
by Héctor Godoy-Marín, Verónica Jiménez-Sábado, Carmen Tarifa, Antonino Ginel, Joana Larupa Dos Santos, Bo Hjorth Bentzen, Leif Hove-Madsen and Francisco Ciruela
Int. J. Mol. Sci. 2023, 24(4), 3668; https://doi.org/10.3390/ijms24043668 - 11 Feb 2023
Cited by 1 | Viewed by 1319
Abstract
Adenosine, an endogenous nucleoside, plays a critical role in maintaining homeostasis during stressful situations, such as energy deprivation or cellular damage. Therefore, extracellular adenosine is generated locally in tissues under conditions such as hypoxia, ischemia, or inflammation. In fact, plasma levels of adenosine [...] Read more.
Adenosine, an endogenous nucleoside, plays a critical role in maintaining homeostasis during stressful situations, such as energy deprivation or cellular damage. Therefore, extracellular adenosine is generated locally in tissues under conditions such as hypoxia, ischemia, or inflammation. In fact, plasma levels of adenosine in patients with atrial fibrillation (AF) are elevated, which also correlates with an increased density of adenosine A2A receptors (A2ARs) both in the right atrium and in peripheral blood mononuclear cells (PBMCs). The complexity of adenosine-mediated effects in health and disease requires simple and reproducible experimental models of AF. Here, we generate two AF models, namely the cardiomyocyte cell line HL-1 submitted to Anemonia toxin II (ATX-II) and a large animal model of AF, the right atrium tachypaced pig (A-TP). We evaluated the density of endogenous A2AR in those AF models. Treatment of HL-1 cells with ATX-II reduced cell viability, while the density of A2AR increased significantly, as previously observed in cardiomyocytes with AF. Next, we generated the animal model of AF based on tachypacing pigs. In particular, the density of the key calcium regulatory protein calsequestrin-2 was reduced in A-TP animals, which is consistent with the atrial remodelling shown in humans suffering from AF. Likewise, the density of A2AR in the atrium of the AF pig model increased significantly, as also shown in the biopsies of the right atrium of subjects with AF. Overall, our findings revealed that these two experimental models of AF mimicked the alterations in A2AR density observed in patients with AF, making them attractive models for studying the adenosinergic system in AF. Full article
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