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1
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Biringer RG. Migraine signaling pathways: purine metabolites that regulate migraine and predispose migraineurs to headache. Mol Cell Biochem 2023; 478:2813-2848. [PMID: 36947357 DOI: 10.1007/s11010-023-04701-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 03/06/2023] [Indexed: 03/23/2023]
Abstract
Migraine is a debilitating disorder that afflicts over 1 billion people worldwide, involving attacks that result in a throbbing and pulsating headache. Migraine is thought to be a neurovascular event associated with vasoconstriction, vasodilation, and neuronal activation. Understanding signaling in migraine pathology is central to the development of therapeutics for migraine prophylaxis and for mitigation of migraine in the prodrome phase before pain sets in. The fact that both vasoactivity and neural sensitization are involved in migraine indicates that agonists which promote these phenomena may very well be involved in migraine pathology. One such group of agonists is the purines, in particular, adenosine phosphates and their metabolites. This manuscript explores what is known about the relationship between these metabolites and migraine pathology and explores the potential for such relationships through their known signaling pathways. Reported receptor involvement in vasoaction and nociception.
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Affiliation(s)
- Roger Gregory Biringer
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
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2
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Meurer F, Häberlein H, Franken S. Ivy Leaf Dry Extract EA 575 ® Has an Inhibitory Effect on the Signalling Cascade of Adenosine Receptor A 2B. Int J Mol Sci 2023; 24:12373. [PMID: 37569749 PMCID: PMC10418604 DOI: 10.3390/ijms241512373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/26/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Ivy leaf dry extract EA 575® is used to improve complaints of chronic inflammatory bronchial diseases and acute inflammation of the respiratory tract accompanied by coughing. Its mechanism of action has so far been explained by influencing β2-adrenergic signal transduction. In the present study, we investigated a possible influence on adenosine receptor A2B (A2BAR) signalling, as it has been described to play a significant and detrimental role in chronic inflammatory airway diseases. The influence of EA 575® on A2BAR signalling was assessed with measurements of dynamic mass redistribution. Subsequently, the effects on A2BAR-mediated second messenger cAMP levels, β-arrestin 2 recruitment, and cAMP response element (CRE) activation were examined using luciferase-based HEK293 reporter cell lines. Lastly, the impact on A2BAR-mediated IL-6 release in Calu-3 epithelial lung cells was investigated via the Lumit™ Immunoassay. Additionally, the adenosine receptor subtype mediating these effects was specified, and A2BAR was found to be responsible. The present study demonstrates an inhibitory influence of EA 575® on A2BAR-mediated general cellular response, cAMP levels, β-arrestin 2 recruitment, CRE activation, and IL-6 release. Since these EA 575®-mediated effects occur within a time frame of several hours of incubation, its mode of action can be described as indirect. The present data are the first to describe an inhibitory effect of EA 575® on A2BAR signalling. This may offer an explanation for the beneficial clinical effects of the extract in adjuvant asthma therapy.
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Affiliation(s)
| | | | - Sebastian Franken
- Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, 53115 Bonn, Germany; (F.M.); (H.H.)
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Temirak A, Schlegel JG, Voss JH, Vaaßen VJ, Vielmuth C, Claff T, Müller CE. Irreversible Antagonists for the Adenosine A 2B Receptor. Molecules 2022; 27:molecules27123792. [PMID: 35744918 PMCID: PMC9231011 DOI: 10.3390/molecules27123792] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/05/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022] Open
Abstract
Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for the immunotherapy of cancer. In the present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding was confirmed in radioligand binding and bioluminescence resonance energy transfer(BRET)-based Gα15 protein activation assays by performing ligand wash-out and kinetic experiments. p-(1-Propylxanthin-8-yl)benzene sulfonyl fluoride (6a, PSB-21500) was the most potent and selective irreversible A2BAR antagonist of the present series with an apparent Ki value of 10.6 nM at the human A2BAR and >38-fold selectivity versus the other AR subtypes. The corresponding 3-cyclopropyl-substituted xanthine derivative 6c (PSB-21502) was similarly potent, but was non-selective versus A1- and A2AARs. Attachment of a reactive sulfonyl fluoride group to an elongated xanthine 8-substituent (12, Ki 7.37 nM) resulted in a potent, selective, reversibly binding antagonist. Based on previous docking studies, the lysine residue K2697.32 was proposed to react with the covalent antagonists. However, the mutant K269L behaved similarly to the wildtype A2BAR, indicating that 6a and related irreversible A2BAR antagonists do not interact with K2697.32. The new irreversible A2BAR antagonists will be useful tools and have the potential to be further developed as therapeutic drugs.
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Duan L, Sanchez-Guerrero G, Jaeschke H, Ramachandran A. Activation of the adenosine A2B receptor even beyond the therapeutic window of N-acetylcysteine accelerates liver recovery after an acetaminophen overdose. Food Chem Toxicol 2022; 163:112911. [PMID: 35292334 PMCID: PMC9018526 DOI: 10.1016/j.fct.2022.112911] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/25/2022] [Accepted: 03/05/2022] [Indexed: 02/04/2023]
Abstract
Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the USA. The short therapeutic window of the current antidote, N-acetylcysteine (NAC) highlights the need for novel late acting therapeutics. The neuronal guidance cue netrin-1 provides delayed protection against APAP hepatotoxicity through the adenosine A2B receptor (A2BAR). The clinical relevance of this mechanism was investigated here by administration of the A2BAR agonist BAY 60-6583, after an APAP overdose (300 or 600 mg/kg) in fasted male and female C57BL/6J mice with assessment of liver injury 6 or 24 h after APAP in comparison to NAC. BAY 60-6583 treatment 1.5 h after APAP overdose (600 mg/kg) protected against liver injury at 6 h by preserving mitochondrial function despite JNK activation and its mitochondrial translocation. Gender independent protection was sustained when BAY 60-6583 was given 6 h after APAP overdose (300 mg/kg), when NAC administration did not show benefit. This protection was accompanied by enhanced infiltration of macrophages with the reparative anti-inflammatory phenotype by 24 h, accompanied by a decrease in neutrophil infiltration. Thus, our data emphasize the remarkable therapeutic utility of using an A2BAR agonist, which provides delayed protection long after the standard of care NAC ceased to be effective.
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Affiliation(s)
- Luqi Duan
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Giselle Sanchez-Guerrero
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
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Sun D, Shao H, Kaplan HJ. TLR ligand ligation switches adenosine receptor usage of BMDCs leading to augmented Th17 responses in experimental autoimmune uveitis. CURRENT RESEARCH IN IMMUNOLOGY 2022; 3:73-84. [PMID: 36569633 PMCID: PMC9768583 DOI: 10.1016/j.crimmu.2022.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/05/2022] [Accepted: 04/05/2022] [Indexed: 12/27/2022] Open
Abstract
The extracellular level of adenosine increases greatly during inflammation, which modulates immune responses. We have previously reported that adenosine enhances Th17 responses while it suppresses Th1 responses. This study examined whether response of DC to adenosine contributes to the biased effect of adenosine and determined whether adenosine and TLR ligands have counteractive or synergistic effects on DC function. Our results show that adenosine is actively involved in both in vitro and in vivo activation of pathogenic T cells by DCs; however, under adenosine effect DCs' capability of promoting Th1 versus Th17 responses are dissociated. Moreover, activation of A2ARs on DCs inhibits Th1 responses whereas activation of A2BRs on DC enhances Th17 responses. An intriguing observation was that TLR engagement switches the adenosine receptor from A2ARs to A2BRs usage of bone marrow-derived dendritic cells (BMDCs) and adenosine binding to BMDCs via A2BR converts adenosine's anti-to proinflammatory effect. The dual effects of adenosine and TLR ligand on BMDCs synergistically enhances the Th17 responses whereas the dual effect on Th1 responses is antagonistic. The results imply that Th17 responses will gain dominance when inflammatory environment accumulates both TLR ligands and adenosine and the underlying mechanisms include that TLR ligand exposure has a unique effect switching adenosine receptor usage of DCs from A2ARs to A2BRs, via which Th17 responses are promoted. Our observation should improve our understanding on the balance of Th1 and Th17 responses in the pathogenesis of autoimmune and other related diseases.
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Affiliation(s)
- Deming Sun
- Doheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90033, United States
- Corresponding author. Department of Ophthalmology, University of California Los Angeles, Los Angeles, CA, 90033, USA.
| | - Hui Shao
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY, 40202, United States
| | - Henry J. Kaplan
- Saint Louis University (SLU) Eye Institute, SLU School of Medicine, Saint Louis, MO, 63104, United States
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6
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Zarei M, Sahebi Vaighan N, Ziai SA. Purinergic receptor ligands: the cytokine storm attenuators, potential therapeutic agents for the treatment of COVID-19. Immunopharmacol Immunotoxicol 2021; 43:633-643. [PMID: 34647511 PMCID: PMC8544669 DOI: 10.1080/08923973.2021.1988102] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 09/25/2021] [Indexed: 12/13/2022]
Abstract
The coronavirus disease-19 (COVID-19), at first, was reported in Wuhan, China, and then rapidly became pandemic throughout the world. Cytokine storm syndrome (CSS) in COVID-19 patients is associated with high levels of cytokines and chemokines that cause multiple organ failure, systemic inflammation, and hemodynamic instabilities. Acute respiratory distress syndrome (ARDS), a common complication of COVID-19, is a consequence of cytokine storm. In this regard, several drugs have been being investigated to suppress this inflammatory condition. Purinergic signaling receptors comprising of P1 adenosine and P2 purinoceptors play a critical role in inflammation. Therefore, activation or inhibition of some subtypes of these kinds of receptors is most likely to be beneficial to attenuate cytokine storm. This article summarizes suggested therapeutic drugs with potential anti-inflammatory effects through purinergic receptors.
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Affiliation(s)
- Malek Zarei
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Navideh Sahebi Vaighan
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Ali Ziai
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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7
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Abstract
Extracellular nucleosides and nucleotides activate a group of G protein-coupled receptors (GPCRs) known as purinergic receptors, comprising adenosine and P2Y receptors. Furthermore, purinergic P2X ion channels are activated by ATP. These receptors are expressed in liver resident cells and play a critical role in maintaining liver function. In the normal physiology, these receptors regulate hepatic metabolic processes such as insulin responsiveness, glycogen and lipid metabolism, and bile secretion. In disease states, ATP and other nucleotides serve as danger signals and modulate purinergic responses in the cells. Recent studies have demonstrated that purinergic receptors play a significant role in the development of metabolic syndrome associated non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, hepatocellular carcinoma (HCC) and liver inflammation. In this concise review, we dissect the role of purinergic signaling in different liver resident cells involved in maintaining healthy liver function and in the development of the above-mentioned liver pathologies. Moreover, we discuss potential therapeutic strategies for liver diseases by targeting adenosine, P2Y and P2X receptors.
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8
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Effendi WI, Nagano T, Kobayashi K, Nishimura Y. Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases. Cells 2020; 9:E785. [PMID: 32213945 PMCID: PMC7140859 DOI: 10.3390/cells9030785] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/21/2020] [Accepted: 03/23/2020] [Indexed: 02/07/2023] Open
Abstract
Adenosine is involved in a range of physiological and pathological effects through membrane-bound receptors linked to G proteins. There are four subtypes of adenosine receptors, described as A1AR, A2AAR, A2BAR, and A3AR, which are the center of cAMP signal pathway-based drug development. Several types of agonists, partial agonists or antagonists, and allosteric substances have been synthesized from these receptors as new therapeutic drug candidates. Research efforts surrounding A1AR and A2AAR are perhaps the most enticing because of their concentration and affinity; however, as a consequence of distressing conditions, both A2BAR and A3AR levels might accumulate. This review focuses on the biological features of each adenosine receptor as the basis of ligand production and describes clinical studies of adenosine receptor-associated pharmaceuticals in human diseases.
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Affiliation(s)
- Wiwin Is Effendi
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan; (W.I.E.); (K.K.); (Y.N.)
- Department of Pulmonology and Respiratory Medicine, Medical Faculty of Airlangga University, Surabaya 60131, Indonesia
| | - Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan; (W.I.E.); (K.K.); (Y.N.)
| | - Kazuyuki Kobayashi
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan; (W.I.E.); (K.K.); (Y.N.)
| | - Yoshihiro Nishimura
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan; (W.I.E.); (K.K.); (Y.N.)
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Abstract
Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein-coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting β 2-agonists are widely used bronchodilators that signal through the activation of the β 2-adrenergic receptor. Short-acting and long-acting antagonists of muscarinic acetylcholine receptors are used to reduce bronchoconstriction by blocking the action of acetylcholine. Leukotriene antagonists that block the signaling of cysteinyl leukotriene receptor 1 are used as an add-on therapy to reduce bronchoconstriction and inflammation induced by cysteinyl leukotrienes. A number of GPCR-targeting asthma drug candidates are also in different stages of development. Among them, antagonists of prostaglandin D2 receptor 2 have advanced into phase III clinical trials. Others, including antagonists of the adenosine A2B receptor and the histamine H4 receptor, are in early stages of clinical investigation. In the past decade, significant research advancements in pharmacology, cell biology, structural biology, and molecular physiology have greatly deepened our understanding of the therapeutic roles of GPCRs in asthma and drug action on these GPCRs. This review summarizes our current understanding of GPCR signaling and pharmacology in the context of asthma treatment. SIGNIFICANCE STATEMENT: Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein-coupled receptors (GPCRs) in asthma therapy, and discusses controversies regarding the use of GPCR drugs and new opportunities in developing GPCR-targeting therapeutics for the treatment of asthma.
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Affiliation(s)
- Stacy Gelhaus Wendell
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)
| | - Hao Fan
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)
| | - Cheng Zhang
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)
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10
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Collum SD, Molina JG, Hanmandlu A, Bi W, Pedroza M, Mertens TCJ, Wareing N, Wei W, Wilson C, Sun W, Rajadas J, Bollyky PL, Philip KM, Ren D, Thandavarayan RA, Bruckner BA, Xia Y, Blackburn MR, Karmouty-Quintana H. Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema. Dis Model Mech 2019; 12:dmm.038711. [PMID: 31036697 PMCID: PMC6550050 DOI: 10.1242/dmm.038711] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 04/10/2019] [Indexed: 01/06/2023] Open
Abstract
Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome that predominantly affects male smokers or ex-smokers and it has a mortality rate of 55% and a median survival of 5 years. Pulmonary hypertension (PH) is a frequently fatal complication of CPFE. Despite this dismal prognosis, no curative therapies exist for patients with CPFE outside of lung transplantation and no therapies are recommended to treat PH. This highlights the need to develop novel treatment approaches for CPFE. Studies from our group have demonstrated that both adenosine and its receptor ADORA2B are elevated in chronic lung diseases. Activation of ADORA2B leads to elevated levels of hyaluronan synthases (HAS) and increased hyaluronan, a glycosaminoglycan that contributes to chronic lung injury. We hypothesize that ADORA2B and hyaluronan contribute to CPFE. Using isolated CPFE lung tissue, we characterized expression levels of ADORA2B and HAS. Next, using a unique mouse model of experimental lung injury that replicates features of CPFE, namely airspace enlargement, PH and fibrotic deposition, we investigated whether 4MU, a HAS inhibitor, was able to inhibit features of CPFE. Increased protein levels of ADORA2B and HAS3 were detected in CPFE and in our experimental model of CPFE. Treatment with 4MU was able to attenuate PH and fibrosis but not airspace enlargement. This was accompanied by a reduction of HAS3-positive macrophages. We have generated pre-clinical data demonstrating the capacity of 4MU, an FDA-approved drug, to attenuate features of CPFE in an experimental model of chronic lung injury. This article has an associated First Person interview with the first author of the paper. Summary: Fibrotic deposition and PH are inhibited by the FDA-approved drug hymecromone, suggesting hyaluronan synthesis inhibition as a potential therapy for CPFE and highlighting a novel mechanism through HAS3-positive macrophages.
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Affiliation(s)
- Scott D Collum
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Jose G Molina
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ankit Hanmandlu
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Weizhen Bi
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Mesias Pedroza
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Tinne C J Mertens
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Nancy Wareing
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Wang Wei
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Cory Wilson
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Wenchao Sun
- Biomaterials and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Jayakumar Rajadas
- Biomaterials and Advanced Drug Delivery Lab, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Paul L Bollyky
- Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Kemly M Philip
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Dewei Ren
- Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | | | - Brian A Bruckner
- Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Yang Xia
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Michael R Blackburn
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Harry Karmouty-Quintana
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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11
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Liu B, Bing Q, Li S, Han B, Lu J, Baiyun R, Zhang X, Lv Y, Wu H, Zhang Z. Role of A 2B adenosine receptor-dependent adenosine signaling in multi-walled carbon nanotube-triggered lung fibrosis in mice. J Nanobiotechnology 2019; 17:45. [PMID: 30922349 PMCID: PMC6440149 DOI: 10.1186/s12951-019-0478-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 03/15/2019] [Indexed: 12/13/2022] Open
Abstract
Background Multi-walled carbon nanotube (MWCNT)-induced lung fibrosis leads to health concerns in human. However, the mechanisms underlying fibrosis pathogenesis remains unclear. The adenosine (ADO) is produced in response to injury and serves a detrimental role in lung fibrosis. In this study, we aimed to explore the ADO signaling in the progression of lung fibrosis induced by MWCNT. Results MWCNT exposure markedly increased A2B adenosine receptor (A2BAR) expression in the lungs and ADO level in bronchoalveolar lavage fluid, combined with elevation of blood neutrophils, collagen fiber deposition, and activation of myeloperoxidase (MPO) activity in the lungs. Furthermore, MWCNT exposure elicited an activation of transforming growth factor (TGF)-β1 and follistatin-like 1 (Fstl1), leading to fibroblasts recruitment and differentiation into myofibroblasts in the lungs in an A2BAR-dependent manner. Conversely, treatment of the selective A2BAR antagonist CVT-6883 exhibited a significant reduction in levels of fibrosis mediators and efficiently decreased cytotoxicity and inflammatory in MWCNT treated mice. Conclusion Our results reveal that accumulation of extracellular ADO promotes the process of the fibroblast-to-myofibroblast transition via A2BAR/TGF-β1/Fstl1 signaling in MWCNT-induced lung fibrosis.
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Affiliation(s)
- Biying Liu
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China.,Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, 600 Changjiang Road, Harbin, 150030, China
| | - Qizheng Bing
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China.,Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, 600 Changjiang Road, Harbin, 150030, China
| | - Siyu Li
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China.,Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, 600 Changjiang Road, Harbin, 150030, China
| | - Bing Han
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China
| | - Jingjing Lu
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China
| | - Ruiqi Baiyun
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China
| | - Xiaoya Zhang
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China
| | - Yueying Lv
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China
| | - Hao Wu
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China
| | - Zhigang Zhang
- College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China. .,Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, 600 Changjiang Road, Harbin, 150030, China.
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12
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Härter M, Kalthof B, Delbeck M, Lustig K, Gerisch M, Schulz S, Kast R, Meibom D, Lindner N. Novel non-xanthine antagonist of the A 2B adenosine receptor: From HTS hit to lead structure. Eur J Med Chem 2018; 163:763-778. [PMID: 30576906 DOI: 10.1016/j.ejmech.2018.11.045] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/16/2018] [Accepted: 11/19/2018] [Indexed: 11/17/2022]
Abstract
The A2B adenosine receptor is a G protein-coupled receptor that belongs to the four member family of adenosine receptors: A1, A2A, A2B, A3. While adenosine-mediated A2B receptor signaling attenuates acute inflammation, facilitates tissue adaptation to hypoxia, and induces increased ischemia tolerance under conditions of an acute insult, persistently elevated adenosine levels and A2B receptor signaling are characteristics of a number of chronic disease states. In this report we describe the discovery of certain thienouracils (thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones) as antagonists of the A2B adenosine receptor by high-throughput screening from our corporate substance collection. The structure optimization of the initial screening hits led to BAY-545, an A2B receptor antagonist that was suitable for in vivo testing. The structure optimization work, SAR that was derived from there, as well as the properties of BAY-545 are also described. In vivo efficacy of BAY-545 was demonstrated in two models of lung fibrosis and data is presented.
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Affiliation(s)
- Michael Härter
- Small Molecules Innovation, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany.
| | - Bernd Kalthof
- Small Molecules Innovation, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany
| | - Martina Delbeck
- Preclinical Research, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany
| | - Klemens Lustig
- Translational Sciences, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany
| | - Michael Gerisch
- Translational Sciences, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany
| | - Simone Schulz
- Translational Sciences, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany
| | - Raimund Kast
- Preclinical Research, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany
| | - Daniel Meibom
- Small Molecules Innovation, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany
| | - Niels Lindner
- Small Molecules Innovation, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany
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13
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Chepurny OG, Bonaccorso RL, Leech CA, Wöllert T, Langford GM, Schwede F, Roth CL, Doyle RP, Holz GG. Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. Sci Rep 2018; 8:3749. [PMID: 29491394 PMCID: PMC5830615 DOI: 10.1038/s41598-018-22106-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 02/16/2018] [Indexed: 02/07/2023] Open
Abstract
We report the design and target validation of chimeric peptide EP45, a novel 45 amino acid monomeric dual agonist peptide that contains amino acid sequence motifs present within the blood glucose-lowering agent exendin-4 (Ex-4) and the appetite-suppressing agent PYY(3-36). In a new high-throughput FRET assay that provides real-time kinetic information concerning levels of cAMP in living cells, EP45 recapitulates the action of Ex-4 to stimulate cAMP production via the glucagon-like peptide-1 receptor (GLP-1R), while also recapitulating the action of PYY(3-36) to inhibit cAMP production via the neuropeptide Y2 receptor (NPY2R). EP45 fails to activate glucagon or GIP receptors, whereas for cells that co-express NPY2R and adenosine A2B receptors, EP45 acts in an NPY2R-mediated manner to suppress stimulatory effects of adenosine on cAMP production. Collectively, such findings are remarkable in that they suggest a new strategy in which the co-existing metabolic disorders of type 2 diabetes and obesity will be treatable using a single peptide such as EP45 that lowers levels of blood glucose by virtue of its GLP-1R-mediated effect, while simultaneously suppressing appetite by virtue of its NPY2R-mediated effect.
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Affiliation(s)
- Oleg G Chepurny
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, 505 Irving Avenue, Syracuse, NY, 13210, USA
| | - Ron L Bonaccorso
- Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY, 13244, USA
| | - Colin A Leech
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, 505 Irving Avenue, Syracuse, NY, 13210, USA
| | - Torsten Wöllert
- Department of Biology, Syracuse University, Syracuse, NY, 13244, USA
| | - George M Langford
- Department of Biology, Syracuse University, Syracuse, NY, 13244, USA
| | - Frank Schwede
- BIOLOG Life Science Institute, 28199, Bremen, Germany
| | - Christian L Roth
- Center for Integrative Brain Research, Seattle Children's Research Institute, Washington, 98105, USA
- Department of Pediatrics, University of Washington, Seattle, Washington, 98105, USA
| | - Robert P Doyle
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, 505 Irving Avenue, Syracuse, NY, 13210, USA.
- Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY, 13244, USA.
| | - George G Holz
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, 505 Irving Avenue, Syracuse, NY, 13210, USA.
- Department of Pharmacology, State University of New York (SUNY) Upstate Medical University, 505 Irving Avenue, Syracuse, NY, 13210, USA.
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14
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Li H, Lu H, Tang W, Zuo J. Targeting methionine cycle as a potential therapeutic strategy for immune disorders. Expert Opin Ther Targets 2017; 21:1-17. [PMID: 28829212 DOI: 10.1080/14728222.2017.1370454] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Methionine cycle plays an essential role in regulating many cellular events, especially transmethylation reactions, incorporating the methyl donor S-adenosylmethionine (SAM). The transmethylations and substances involved in the cycle have shown complicated effects and mechanisms on immunocytes developments and activations, and exert crucial impacts on the pathological processes in immune disorders. Areas covered: Methionine cycle has been considered as an effective means of drug developments. This review discussed the role of methionine cycle in immune responses and summarized the potential therapeutic strategies based on the cycle, including SAM analogs, methyltransferase inhibitors, S-adenosylhomocysteine hydrolase (SAHH) inhibitors, adenosine receptors specific agonists or antagonists and homocysteine (Hcy)-lowering reagents, in treating human immunodeficiency virus (HIV) infections, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis (SSc) and other immune disorders. Expert opinion: New targets and biomarkers grown out of methionine cycle have developed rapidly in the past decades. However, impacts of epigenetic regulations on immune disorders are unclear and whether the substances in methionine cycle can be clarified as biomarkers remains controversial. Therefore, further elucidation on the role of epigenetic regulations and substances in methionine cycle may contribute to exploring the cycle-derived biomarkers and drugs in immune disorders.
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Affiliation(s)
- Heng Li
- a Laboratory of Immunopharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
- b College of Pharmacy , University of Chinese Academy of Sciences , Beijing , China
| | - Huimin Lu
- a Laboratory of Immunopharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
- b College of Pharmacy , University of Chinese Academy of Sciences , Beijing , China
| | - Wei Tang
- a Laboratory of Immunopharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
- b College of Pharmacy , University of Chinese Academy of Sciences , Beijing , China
| | - Jianping Zuo
- a Laboratory of Immunopharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
- b College of Pharmacy , University of Chinese Academy of Sciences , Beijing , China
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15
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Bahreyni A, Samani SS, Khazaei M, Ryzhikov M, Avan A, Hassanian SM. Therapeutic potentials of adenosine receptors agonists and antagonists in colitis; Current status and perspectives. J Cell Physiol 2017; 233:2733-2740. [DOI: 10.1002/jcp.26073] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 06/28/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Amirhossein Bahreyni
- Faculty of Medicine; Department of Clinical Biochemistry and Immunogenetic Research Center; Mazandaran University of Medical Sciences; Sari Mazandaran Iran
| | - Seyed S. Samani
- Department of Biology; Mashhad Branch; Islamic Azad University; Mashhad Iran
| | - Majid Khazaei
- Faculty of Medicine; Department of Medical Physiology; Mashhad University of Medical Sciences; Mashhad Iran
| | - Mikhail Ryzhikov
- Department of Molecular Microbiology and Immunology; St. Louis University; School of Medicine; Saint Louis Missouri
| | - Amir Avan
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
- Department of Modern Sciences and Technologies; School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Seyed M. Hassanian
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
- Faculty of Medicine; Department of Medical Biochemistry; Mashhad University of Medical Sciences; Mashhad Iran
- Microanatomy Research Center; Mashhad University of Medical Sciences; Mashhad Iran
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16
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Basu S, Barawkar DA, Ramdas V, Patel M, Waman Y, Panmand A, Kumar S, Thorat S, Naykodi M, Goswami A, Reddy BS, Prasad V, Chaturvedi S, Quraishi A, Menon S, Paliwal S, Kulkarni A, Karande V, Ghosh I, Mustafa S, De S, Jain V, Banerjee ER, Rouduri SR, Palle VP, Chugh A, Mookhtiar KA. Design and synthesis of novel xanthine derivatives as potent and selective A 2B adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases. Eur J Med Chem 2017; 134:218-229. [PMID: 28415011 DOI: 10.1016/j.ejmech.2017.04.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 04/01/2017] [Accepted: 04/07/2017] [Indexed: 10/19/2022]
Abstract
Adenosine induces bronchial hyperresponsiveness and inflammation in asthmatics through activation of A2B adenosine receptor (A2BAdoR). Selective antagonists have been shown to attenuate airway reactivity and improve inflammatory conditions in pre-clinical studies. Hence, the identification of novel, potent and selective A2BAdoR antagonist may be beneficial for the potential treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). Towards this effort, we explored several prop-2-ynylated C8-aryl or heteroaryl substitutions on xanthine chemotype and found that 1-prop-2-ynyl-1H-pyrazol-4-yl moiety was better tolerated at the C8 position. Compound 59, exhibited binding affinity (Ki) of 62 nM but was non-selective for A2BAdoR over other AdoRs. Incorporation of substituted phenyl on the terminal acetylene increased the binding affinity (Ki) significantly to <10 nM. Various substitutions on terminal phenyl group and different alkyl substitutions on N-1 and N-3 were explored to improve the potency, selectivity for A2BAdoR and the solubility. In general, compounds with meta-substituted phenyl provided better selectivity for A2BAdoR compared to that of para-substituted analogs. Substitutions such as basic amines like pyrrolidine, piperidine, piperazine or cycloalkyls with polar group were tried on terminal acetylene, keeping in mind the poor solubility of xanthine analogs in general. However, these substitutions led to a decrease in affinity compared to compound 59. Subsequent SAR optimization resulted in identification of compound 46 with high human A2BAdoR affinity (Ki = 13 nM), selectivity against other AdoR subtypes and with good pharmacokinetic properties. It was found to be a potent functional A2BAdoR antagonist with a Ki of 8 nM in cAMP assay in hA2B-HEK293 cells and an IC50 of 107 nM in IL6 assay in NIH-3T3 cells. Docking study was performed to rationalize the observed affinity data. Structure-activity relationship (SAR) studies also led to identification of compound 36 as a potent A2BAdoR antagonist with Ki of 1.8 nM in cAMP assay and good aqueous solubility of 529 μM at neutral pH. Compound 46 was further tested for in vivo efficacy and found to be efficacious in ovalbumin-induced allergic asthma model in mice.
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Affiliation(s)
- Sujay Basu
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
| | - Dinesh A Barawkar
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Vidya Ramdas
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Meena Patel
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Yogesh Waman
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Anil Panmand
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Santosh Kumar
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Sachin Thorat
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Minakshi Naykodi
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Arnab Goswami
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - B Srinivasa Reddy
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Vandna Prasad
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Sandhya Chaturvedi
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Azfar Quraishi
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Suraj Menon
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Shalini Paliwal
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Abhay Kulkarni
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Vikas Karande
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Indraneel Ghosh
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Syed Mustafa
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Siddhartha De
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Vaibhav Jain
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Ena Ray Banerjee
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Sreekanth R Rouduri
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Venkata P Palle
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Anita Chugh
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India
| | - Kasim A Mookhtiar
- Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
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17
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Basu S, Barawkar DA, Ramdas V, Waman Y, Patel M, Panmand A, Kumar S, Thorat S, Bonagiri R, Jadhav D, Mukhopadhyay P, Prasad V, Reddy BS, Goswami A, Chaturvedi S, Menon S, Quraishi A, Ghosh I, Dusange S, Paliwal S, Kulkarni A, Karande V, Thakre R, Bedse G, Rouduri S, Gundu J, Palle VP, Chugh A, Mookhtiar KA. A 2B adenosine receptor antagonists: Design, synthesis and biological evaluation of novel xanthine derivatives. Eur J Med Chem 2016; 127:986-996. [PMID: 27842891 DOI: 10.1016/j.ejmech.2016.11.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 11/03/2016] [Accepted: 11/04/2016] [Indexed: 11/16/2022]
Abstract
A2BAdoR is a low affinity adenosine receptor that functions by Gs mediated elevation of cAMP and subsequent downstream signaling. The receptor has been implicated in lung inflammatory disorders like COPD and asthma. Several potent and selective A2BAdoR antagonists have been reported in literature, however most of the compounds suffer from poor pharmacokinetic profile. Therefore, with the aim to identify novel, potent and selective A2BAdoR antagonists with improved pharmacokinetic properties, we first explored more constrained form of MRS-1754 (4). To improve the metabolic stability, several linker modifications were attempted as replacement of amide linker along with different phenyl or other heteroaryls between C8 position of xanthine head group and terminal phenyl ring. SAR optimization resulted in identification of two novel A2BAdoR antagonists, 8-{1-[5-Oxo-1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-xanthine (31) and 8-(1-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl-xanthine (65), with high binding affinity (Ki = 1 and 1.5 nM, respectively) and selectivity for A2BAdoR with very good functional potency of 0.9 nM and 4 nM, respectively. Compound 31 and 65 also displayed good pharmacokinetic properties in mice with 27% and 65% oral bioavailability respectively. When evaluated in in vivo mice model of asthma, compound 65 also inhibited airway inflammation and airway reactivity in ovalbumin induced allergic asthma at 3 mpk dose.
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Affiliation(s)
- Sujay Basu
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India.
| | - Dinesh A Barawkar
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Vidya Ramdas
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Yogesh Waman
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Meena Patel
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Anil Panmand
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Santosh Kumar
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Sachin Thorat
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Rajesh Bonagiri
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Dilip Jadhav
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Partha Mukhopadhyay
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Vandna Prasad
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - B Srinivasa Reddy
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Arnab Goswami
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Sandhya Chaturvedi
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Suraj Menon
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Azfar Quraishi
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Indraneel Ghosh
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Sushant Dusange
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Shalini Paliwal
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Abhay Kulkarni
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Vikas Karande
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Rhishikesh Thakre
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Gaurav Bedse
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Sreekanth Rouduri
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Jayasagar Gundu
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Venkata P Palle
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Anita Chugh
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India
| | - Kasim A Mookhtiar
- Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India.
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18
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Singh J, Shah R, Singh D. Inundation of asthma target research: Untangling asthma riddles. Pulm Pharmacol Ther 2016; 41:60-85. [PMID: 27667568 DOI: 10.1016/j.pupt.2016.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/11/2016] [Accepted: 09/20/2016] [Indexed: 12/31/2022]
Abstract
Asthma is an inveterate inflammatory disorder, delineated by the airway inflammation, bronchial hyperresponsiveness (BHR) and airway wall remodeling. Although, asthma is a vague term, and is recognized as heterogenous entity encompassing different phenotypes. Targeting single mediator or receptor did not prove much clinical significant, as asthma is complex disease involving myriad inflammatory mediators. Asthma may probably involve a large number of different types of molecular and cellular components interacting through complex pathophysiological pathways. This review covers the past, present, and future therapeutic approaches and pathophysiological mechanisms of asthma. Furthermore, review describe importance of targeting several mediators/modulators and receptor antagonists involved in the physiopathology of asthma. Novel targets for asthma research include Galectins, Immunological targets, K + Channels, Kinases and Transcription Factors, Toll-like receptors, Selectins and Transient receptor potential channels. But recent developments in asthma research are very promising, these include Bitter taste receptors (TAS2R) abated airway obstruction in mouse model of asthma and Calcium-sensing receptor obliterate inflammation and in bronchial hyperresponsiveness allergic asthma. All these progresses in asthma targets, and asthma phenotypes exploration are auspicious in untangling of asthma riddles.
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Affiliation(s)
- Jatinder Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India
| | - Ramanpreet Shah
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India
| | - Dhandeep Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India.
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19
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Ju C, Colgan SP, Eltzschig HK. Hypoxia-inducible factors as molecular targets for liver diseases. J Mol Med (Berl) 2016; 94:613-27. [PMID: 27094811 PMCID: PMC4879168 DOI: 10.1007/s00109-016-1408-1] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 03/04/2016] [Accepted: 03/08/2016] [Indexed: 12/11/2022]
Abstract
Liver disease is a growing global health problem, as deaths from end-stage liver cirrhosis and cancer are rising across the world. At present, pharmacologic approaches to effectively treat or prevent liver disease are extremely limited. Hypoxia-inducible factor (HIF) is a transcription factor that regulates diverse signaling pathways enabling adaptive cellular responses to perturbations of the tissue microenvironment. HIF activation through hypoxia-dependent and hypoxia-independent signals have been reported in liver disease of diverse etiologies, from ischemia-reperfusion-induced acute liver injury to chronic liver diseases caused by viral infection, excessive alcohol consumption, or metabolic disorders. This review summarizes the evidence for HIF stabilization in liver disease, discusses the mechanistic involvement of HIFs in disease development, and explores the potential of pharmacological HIF modifiers in the treatment of liver disease.
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MESH Headings
- Animals
- Antineoplastic Agents/therapeutic use
- Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Bevacizumab/therapeutic use
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Clinical Trials as Topic
- Fatty Liver/genetics
- Fatty Liver/metabolism
- Fatty Liver/pathology
- Fatty Liver/therapy
- Gene Expression Regulation
- Hepatitis, Viral, Human/genetics
- Hepatitis, Viral, Human/metabolism
- Hepatitis, Viral, Human/pathology
- Hepatitis, Viral, Human/therapy
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Liver Cirrhosis/genetics
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/pathology
- Liver Cirrhosis/therapy
- Liver Diseases, Alcoholic/genetics
- Liver Diseases, Alcoholic/metabolism
- Liver Diseases, Alcoholic/pathology
- Liver Diseases, Alcoholic/therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Molecular Targeted Therapy
- Oligonucleotides/therapeutic use
- Signal Transduction
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Affiliation(s)
- Cynthia Ju
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado, Auroa, Colorado, 800045, USA.
| | - Sean P Colgan
- Department of Medicine and Mucosal Inflammation Program, School of Medicine, University of Colorado, Auroa, Colorado, 800045, USA
| | - Holger K Eltzschig
- Department of Anesthesiology and Organ Protection Program, School of Medicine, University of Colorado, Auroa, Colorado, 800045, USA
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20
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Tofovic SP, Salah EM, Smits GJ, Whalley ET, Ticho B, Deykin A, Jackson EK. Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction. J Pharmacol Exp Ther 2016; 356:333-40. [PMID: 26585572 PMCID: PMC4727158 DOI: 10.1124/jpet.115.228841] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 11/17/2015] [Indexed: 12/19/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by metabolic syndrome. Current treatment options are limited. Here, we test the hypothesis that combined A1/A2B adenosine receptor blockade is beneficial in obese ZSF1 rats, an animal model of HFpEF with metabolic syndrome. The combined A1/A2B receptor antagonist 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid (BG9928) was administered orally (10 mg/kg/day) to obese ZSF1 rats (n = 10) for 24 weeks (from 20 to 44 weeks of age). Untreated ZSF1 rats (n = 9) served as controls. After 24 weeks of administration, BG9928 significantly lowered plasma triglycerides (in mg/dl: control group, 4351 ± 550; BG9928 group, 2900 ± 551) without adversely affecting plasma cholesterol or activating renin release. BG9928 significantly decreased 24-hour urinary glucose excretion (in mg/kg/day: control group, 823 ± 179; BG9928 group, 196 ± 80) and improved oral glucose tolerance, polydipsia, and polyuria. BG9928 significantly augmented left ventricular diastolic function in association with a reduction in cardiac vasculitis and cardiac necrosis. BG9928 significantly reduced 24-hour urinary protein excretion (in mg/kg/day: control group, 1702 ± 263; BG9928 group, 1076 ± 238), and this was associated with a reduction in focal segmental glomerulosclerosis, tubular atrophy, tubular dilation, and deposition of proteinaceous material in the tubules. These findings show that, in a model of HFpEF with metabolic syndrome, A1/A2B receptor inhibition improves hyperlipidemia, exerts antidiabetic actions, reduces HFpEF, improves cardiac histopathology, and affords renal protection. We conclude that chronic administration of combined A1/A2B receptor antagonists could be beneficial in patients with HFpEF, in particular those with comorbidities such as obesity, diabetes, and dyslipidemias.
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Affiliation(s)
- Stevan P Tofovic
- Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.)
| | - Eman M Salah
- Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.)
| | - Glenn J Smits
- Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.)
| | - Eric T Whalley
- Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.)
| | - Barry Ticho
- Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.)
| | - Aaron Deykin
- Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.)
| | - Edwin K Jackson
- Vascular Medicine Institute (S.P.T.) and the Departments of Medicine (S.P.T., E.K.J.), Pathology (E.M.S.), and Pharmacology and Chemical Biology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Biogen Idec, Inc., Cambridge, Massachusetts (G.J.S., E.T.W., B.T., A.D.)
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21
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Dai T, Li N, Han F, Zhang H, Zhang Y, Liu Q. AMP-guided tumour-specific nanoparticle delivery via adenosine A1 receptor. Biomaterials 2016; 83:37-50. [PMID: 26773664 DOI: 10.1016/j.biomaterials.2016.01.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 12/24/2015] [Accepted: 01/01/2016] [Indexed: 11/19/2022]
Abstract
Active targeting-ligands have been increasingly used to functionalize nanoparticles for tumour-specific clinical applications. Here we utilize nucleotide adenosine 5'-monophosphate (AMP) as a novel ligand to functionalize polymer-based fluorescent nanoparticles (NPs) for tumour-targeted imaging. We demonstrate that AMP-conjugated NPs (NPs-AMP) efficiently bind to and are following internalized into colon cancer cell CW-2 and breast cancer cell MDA-MB-468 in vitro. RNA interference and inhibitor assays reveal that the targeting effects mainly rely on the specific binding of AMP to adenosine A1 receptor (A1R), which is greatly up-regulated in cancer cells than in matched normal cells. More importantly, NPs-AMP specifically accumulate in the tumour site of colon and breast tumour xenografts and are further internalized into the tumour cells in vivo via tail vein injection, confirming that the high in vitro specificity of AMP can be successfully translated into the in vivo efficacy. Furthermore, NPs-AMP exhibit an active tumour-targeting behaviour in various colon and breast cancer cells, which is positively related to the up-regulation level of A1R in cancer cells, suggesting that AMP potentially suits for more extensive A1R-overexpressing cancer models. This work establishes AMP to be a novel tumour-targeting ligand and provides a promising strategy for future diagnostic or therapeutic applications.
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Affiliation(s)
- Tongcheng Dai
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Na Li
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Fajun Han
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Hua Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Yuanxing Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai 200237, China
| | - Qin Liu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai 200237, China.
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22
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Eisenstein A, Patterson S, Ravid K. The Many Faces of the A2b Adenosine Receptor in Cardiovascular and Metabolic Diseases. J Cell Physiol 2015; 230:2891-7. [PMID: 25975415 DOI: 10.1002/jcp.25043] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 05/08/2015] [Indexed: 01/09/2023]
Abstract
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. This review will focus on the role of the A2bAR in various cardiovascular and metabolic pathologies in which the receptor is currently being studied. We will illustrate the complexities of A2bAR signaling and highlight areas of research with potential for therapeutic development.
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Affiliation(s)
- Anna Eisenstein
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.,Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Shenia Patterson
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.,Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Katya Ravid
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.,Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.,Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.,Evans Center for Interdisciplinary Biomedical Research, Boston University School of Medicine, Boston, Massachusetts
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23
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Loftfield E, Shiels MS, Graubard BI, Katki HA, Chaturvedi AK, Trabert B, Pinto LA, Kemp TJ, Shebl FM, Mayne ST, Wentzensen N, Purdue MP, Hildesheim A, Sinha R, Freedman ND. Associations of Coffee Drinking with Systemic Immune and Inflammatory Markers. Cancer Epidemiol Biomarkers Prev 2015; 24:1052-60. [PMID: 25999212 DOI: 10.1158/1055-9965.epi-15-0038-t] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 04/28/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Coffee drinking has been inversely associated with mortality as well as cancers of the endometrium, colon, skin, prostate, and liver. Improved insulin sensitivity and reduced inflammation are among the hypothesized mechanisms by which coffee drinking may affect cancer risk; however, associations between coffee drinking and systemic levels of immune and inflammatory markers have not been well characterized. METHODS We used Luminex bead-based assays to measure serum levels of 77 immune and inflammatory markers in 1,728 older non-Hispanic Whites. Usual coffee intake was self-reported using a food frequency questionnaire. We used weighted multivariable logistic regression models to examine associations between coffee and dichotomized marker levels. We conducted statistical trend tests by modeling the median value of each coffee category and applied a 20% false discovery rate criterion to P values. RESULTS Ten of the 77 markers were nominally associated (P trend < 0.05) with coffee drinking. Five markers withstood correction for multiple comparisons and included aspects of the host response namely chemotaxis of monocytes/macrophages (IFNγ, CX3CL1/fractalkine, CCL4/MIP-1β), proinflammatory cytokines (sTNFRII), and regulators of cell growth (FGF-2). Heavy coffee drinkers had lower circulating levels of IFNγ [odds ratios (OR), 0.35; 95% confidence intervals (CI), 0.16-0.75], CX3CL1/fractalkine (OR, 0.25; 95% CI, 0.10-0.64), CCL4/MIP-1β (OR, 0.48; 95% CI, 0.24-0.99), FGF-2 (OR, 0.62; 95% CI, 0.28-1.38), and sTNFRII (OR, 0.34; 95% CI, 0.15-0.79) than non-coffee drinkers. CONCLUSIONS Lower circulating levels of inflammatory markers among coffee drinkers may partially mediate previously observed associations of coffee with cancer and other chronic diseases. IMPACT Validation studies, ideally controlled feeding trials, are needed to confirm these associations.
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Affiliation(s)
- Erikka Loftfield
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
| | - Meredith S Shiels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Barry I Graubard
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Hormuzd A Katki
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Anil K Chaturvedi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Britton Trabert
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Ligia A Pinto
- HPV Immunology Laboratory, Leidos Biomedical Research, Inc., SAIC-Frederick/NCI-Frederick, Frederick, Maryland
| | - Troy J Kemp
- HPV Immunology Laboratory, Leidos Biomedical Research, Inc., SAIC-Frederick/NCI-Frederick, Frederick, Maryland
| | - Fatma M Shebl
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut. Yale Cancer Center, New Haven, Connecticut
| | - Susan T Mayne
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut. Yale Cancer Center, New Haven, Connecticut
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Mark P Purdue
- Ontario Institute for Cancer Research, Toronto, Canada
| | - Allan Hildesheim
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Rashmi Sinha
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Neal D Freedman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
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24
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Antonioli L, Csóka B, Fornai M, Colucci R, Kókai E, Blandizzi C, Haskó G. Adenosine and inflammation: what's new on the horizon? Drug Discov Today 2014; 19:1051-68. [DOI: 10.1016/j.drudis.2014.02.010] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 02/06/2014] [Accepted: 02/25/2014] [Indexed: 12/18/2022]
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25
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Mansourian M, Fassihi A, Saghaie L, Madadkar-Sobhani A, Mahnam K, Abbasi M. QSAR and docking analysis of A2B adenosine receptor antagonists based on non-xanthine scaffold. Med Chem Res 2014. [DOI: 10.1007/s00044-014-1133-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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26
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Tilley S, Volmer J, Picher M. Therapeutic applications. Subcell Biochem 2014; 55:235-76. [PMID: 21560050 PMCID: PMC7120595 DOI: 10.1007/978-94-007-1217-1_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
The current treatments offered to patients with chronic respiratory diseases are being re-evaluated based on the loss of potency during long-term treatments or because they only provide significant clinical benefits to a subset of the patient population. For instance, glucocorticoids are considered the most effective anti-inflammatory therapies for chronic inflammatory and immune diseases, such as asthma. But they are relatively ineffective in asthmatic smokers, and patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). As such, the pharmaceutical industry is exploring new therapeutic approaches to address all major respiratory diseases. The previous chapters demonstrated the widespread influence of purinergic signaling on all pulmonary functions and defense mechanisms. In Chap. 8, we described animal studies which highlighted the critical role of aberrant purinergic activities in the development and maintenance of chronic airway diseases. This last chapter covers all clinical and pharmaceutical applications currently developed based on purinergic receptor agonists and antagonists. We use the information acquired in the previous chapters on purinergic signaling and lung functions to scrutinize the preclinical and clinical data, and to realign the efforts of the pharmaceutical industry.
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Affiliation(s)
- Stephen Tilley
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, 29799, USA,
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27
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Lee IA, Kamba A, Low D, Mizoguchi E. Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease. World J Gastroenterol 2014; 20:1127-38. [PMID: 24574789 PMCID: PMC3921497 DOI: 10.3748/wjg.v20.i5.1127] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/26/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Family 18 chitinases have a binding capacity with chitin, a polymer of N-acetylglucosamine. Recent studies strongly suggested that chitinase 3-like 1 (CHI3L1, also known as YKL-40) and acidic mammalian chitinase, the two major members of family 18 chitinases, play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD), bronchial asthma and several other inflammatory disorders. Based on the data from high-throughput screening, it has been found that three methylxanthine derivatives, caffeine, theophylline, and pentoxifylline, have competitive inhibitory effects against a fungal family 18 chitinase by specifically interacting with conserved tryptophans in the active site of this protein. Methylxanthine derivatives are also known as adenosine receptor antagonists, phosphodiesterase inhibitors and histone deacetylase inducers. Anti-inflammatory effects of methylxanthine derivatives have been well-documented in the literature. For example, a beneficial link between coffee or caffeine consumption and type 2 diabetes as well as liver cirrhosis has been reported. Furthermore, theophylline has a long history of being used as a bronchodilator in asthma therapy, and pentoxifylline has an immuno-modulating effect for peripheral vascular disease. However, it is still largely unknown whether these methylxanthine derivative-mediated anti-inflammatory effects are associated with the inhibition of CHI3L1-induced cytoplasmic signaling cascades in epithelial cells. In this review article we will examine the above possibility and summarize the biological significance of methylxanthine derivatives in intestinal epithelial cells. We hope that this study will provide a rationale for the development of methylxanthine derivatives, in particular caffeine, -based anti-inflammatory therapeutics in the field of IBD and IBD-associated carcinogenesis.
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Pejman L, Omrani H, Mirzamohammadi Z, Shahbazfar AA, Khalili M, Keyhanmanesh R. The Effect of Adenosine A2A and A2B Antagonists on Tracheal Responsiveness, Serum Levels of Cytokines and Lung Inflammation in Guinea Pig Model of Asthma. Adv Pharm Bull 2013; 4:131-8. [PMID: 24511476 DOI: 10.5681/apb.2014.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 08/14/2013] [Accepted: 09/01/2013] [Indexed: 11/17/2022] Open
Abstract
PURPOSE Nowadays adenosine is specified as an important factor in the pathophysiology of asthma. For determining the effect of different A2 receptors, in this investigation the effect of single dose of selective adenosine A2A and A2B antagonists (ZM241385 and MRS1706) on different inflammatory parameters; tracheal responsiveness to methacholine and ovalbumin, total and differential cell count in bronchoalveolar lavage (BAL), blood levels of IL-4 and IFN-γ and lung pathology of guinea pig model of asthma were assessed. METHODS All mentioned parameters were evaluated in two sensitized groups of guinea pigs pretreated with A2A and A2B antagonists (S+Anta A2A, S+Anta A2B) compared with sensitized (S) and control (C) groups. RESULTS The tracheal responsiveness to methacholine and OA, total cell and eosinophil and basophil count in BAL, blood IL-4 level and pathological changes in pre-treated group with MRS1706 (S+Anta A2B) was significantly lower than those of sensitized group (p<0.01 to p<0.05). In pretreated group with Anta A2A(S+Anta A2A), all the above changes were reversed. CONCLUSION These results showed a preventive effect of A2B antagonist (MRS1706) on tracheal responsiveness to methacholine and OA, total and differential cell count in bronchoalveolar lavage, blood cytokines and pathological changes. Administration of ZM241385, selective A2A antagonist, deteriorated the induction effect of ovalbumin.
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Affiliation(s)
- Laleh Pejman
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hasan Omrani
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Mirzamohammadi
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Ali Shahbazfar
- Department of Pathology, Faculty of Veterinary Medicine, Tabriz University, Tabriz, Iran
| | - Majid Khalili
- Tuberculosis and Lung Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rana Keyhanmanesh
- Tuberculosis and Lung Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Caruso M, Alamo A, Crisafulli E, Raciti C, Fisichella A, Polosa R. Adenosine signaling pathways as potential therapeutic targets in respiratory disease. Expert Opin Ther Targets 2013; 17:761-72. [PMID: 23642090 DOI: 10.1517/14728222.2013.795220] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Adenosine receptors (ARs) and their differential pattern of expression modulate a series of pleiotropic activities that are known to contribute to the control of inflammation, remodeling, and tissue repair. Consequently, pharmacological manipulation of adenosine signaling pathway is of great interest and is currently exploited as a therapeutic target for a number of respiratory diseases with several molecules with agonist and antagonist activities against known ARs being developed for the treatment of different conditions of the respiratory system. AREAS COVERED Herein, we will review the rational basis leading to the development of novel therapies for asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cystic fibrosis. Their most recent clinical development will be also discussed. EXPERT OPINION Advances in our understanding of the pathogenetic role of adenosine in respiratory diseases may be soon translated into effective treatment options. In consideration of the complex interplay driven by the different pattern of receptor distribution and/or affinity of the four known AR subtypes in specific cell types at different stages of the disease, it is likely that combination of selective antagonist/agonists for different AR subtypes will be required to obtain reasonable clinical efficacy. Alternatively, controlling the factors involved in driving adenosine concentrations in the tissue may be also of great significance.
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Affiliation(s)
- Massimo Caruso
- University of Catania-AOU Policlinico-V. Emanuele, Institute of Internal Medicine and Clinical Immunology, Department of Clinical and Molecular Bio-Medicine, Catania, Italy.
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Khan MA. Inflammation signals airway smooth muscle cell proliferation in asthma pathogenesis. Multidiscip Respir Med 2013; 8:11. [PMID: 23388501 PMCID: PMC3568740 DOI: 10.1186/2049-6958-8-11] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 01/03/2013] [Indexed: 01/07/2023] Open
Abstract
Background Airway inflammation stimulates proliferation of airway smooth muscle cell, which contributes to the development of hyperplasia and hypertrophy of smooth muscle cell. The increase in airway smooth muscle cell mass is believed to be due to an up-regulation of inflammatory mediators in the airway. It is now well recognized that chronic inflammation as well as airway hyper-responsiveness and remodeling of airway during inflammation, are crucial to asthma. Airway hyper-responsiveness is caused by increased cell proliferation or by hypertrophy of airway smooth muscle cell depending on the nature of the inflammatory stimulation. Airway smooth muscle cell proliferation in asthma is regulated by the proinflammatory cytokines including IL-1β and TNF-α. These proinflammatory cytokines have been shown to influence human airway smooth muscle cell proliferation in vitro, which is due to cyclooxygenase-2 expression, production of prostaglandin E2, and increased cAMP levels. Conclusions This review highlights the role of different proinflammatory cytokines in regulating airway smooth muscle cell growth and also focuses on regulation of differential gene expression in airway smooth muscle cell by growth factors and cytokines, also to bestow unique insight into the effects of conventional asthma therapies on airway smooth muscle cell proliferation and development of new therapeutic strategies to control asthma.
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Affiliation(s)
- Mohammad Afzal Khan
- Department of Medicine, Stanford University, VAPAHCS, 3801 Miranda Avenue, Building 101, Room B4-105, Palo Alto, California, 94304, USA.
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Karmouty-Quintana H, Xia Y, Blackburn MR. Adenosine signaling during acute and chronic disease states. J Mol Med (Berl) 2013; 91:173-81. [PMID: 23340998 DOI: 10.1007/s00109-013-0997-1] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 01/04/2013] [Accepted: 01/08/2013] [Indexed: 12/18/2022]
Abstract
Adenosine is a signaling nucleoside that is produced following tissue injury, particularly injury involving ischemia and hypoxia. The production of extracellular adenosine and its subsequent signaling through adenosine receptors plays an important role in orchestrating injury responses in multiple organs. There are four adenosine receptors that are widely distributed on immune, epithelial, endothelial, neuronal,and stromal cells throughout the body. Interestingly, these receptors are subject to altered regulation following injury. Studies in mouse models and human cells and tissues have identified that the production of adenosine and its subsequent signaling through its receptors plays largely beneficial roles in acute disease states, with the exception of brain injury. In contrast, if elevated adenosine levels are sustained beyond the acute injury phase, adenosine responses can become detrimental by activating pathways that promote tissue injury and fibrosis. Understanding when during the course of disease adenosine signaling is beneficial as opposed to detrimental and defining the mechanisms involved will be critical for the advancement of adenosine-based therapies for acute and chronic diseases. The purpose of this review is to discuss key observations that define the beneficial and detrimental aspects of adenosine signaling during acute and chronic disease states with an emphasis on cellular processes, such as inflammatory cell regulation, vascular barrier function, and tissue fibrosis.
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Affiliation(s)
- Harry Karmouty-Quintana
- Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, 6431 Fannin Blvd, Suite 6.200, Houston, TX 77030, USA
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Toldo S, Zhong H, Mezzaroma E, Van Tassell BW, Kannan H, Zeng D, Belardinelli L, Voelkel NF, Abbate A. GS-6201, a selective blocker of the A2B adenosine receptor, attenuates cardiac remodeling after acute myocardial infarction in the mouse. J Pharmacol Exp Ther 2012; 343:587-95. [PMID: 22923737 PMCID: PMC11047795 DOI: 10.1124/jpet.111.191288] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Accepted: 08/23/2012] [Indexed: 01/18/2023] Open
Abstract
Adenosine (Ado) is released in response to tissue injury, promotes hyperemia, and modulates inflammation. The proinflammatory effects of Ado, which are mediated by the A(2B) Ado receptor (AdoR), may exacerbate tissue damage. We hypothesized that selective blockade of the A(2B) AdoR with 3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione (GS-6201) during acute myocardial infarction (AMI) would reduce adverse cardiac remodeling. Male ICR mice underwent coronary artery ligation or sham surgery (n = 10-12 per group). The selective A(2B) AdoR antagonist GS-6201 (4 mg/kg) was given intraperitoneally twice daily starting immediately after surgery and continuing for 14 days. Transthoracic echocardiography was performed before surgery and after 7, 14, and 28 days. A subgroup of mice was killed 72 h after surgery, and the activity of caspase-1, a key proinflammatory mediator, was measured in the cardiac tissue. All sham-operated mice were alive at 4 weeks, whereas 50% of vehicle-treated mice and 75% of GS-6201-treated mice were alive at 4 weeks after surgery. Compared with vehicle, treatment with GS-6201 prevented caspase-1 activation in the heart at 72 h after AMI (P < 0.001) and significantly limited the increase in left ventricular (LV) end-diastolic diameter by 40% (P < 0.001), the decrease in LV ejection fraction by 18% (P < 0.01) and the changes in the myocardial performance index by 88% (P < 0.001) at 28 days after AMI. Selective blockade of A(2B) AdoR with GS-6201 reduces caspase-1 activity in the heart and leads to a more favorable cardiac remodeling after AMI in the mouse.
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Affiliation(s)
- Stefano Toldo
- Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, VA, USA
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Abstract
Evidence for a significant role and impact of purinergic signaling in normal and diseased airways is now beyond dispute. The present review intends to provide the current state of knowledge of the involvement of purinergic pathways in the upper and lower airways and lungs, thereby differentiating the involvement of different tissues, such as the epithelial lining, immune cells, airway smooth muscle, vasculature, peripheral and central innervation, and neuroendocrine system. In addition to the vast number of well illustrated functions for purinergic signaling in the healthy respiratory tract, increasing data pointing to enhanced levels of ATP and/or adenosine in airway secretions of patients with airway damage and respiratory diseases corroborates the emerging view that purines act as clinically important mediators resulting in either proinflammatory or protective responses. Purinergic signaling has been implicated in lung injury and in the pathogenesis of a wide range of respiratory disorders and diseases, including asthma, chronic obstructive pulmonary disease, inflammation, cystic fibrosis, lung cancer, and pulmonary hypertension. These ostensibly enigmatic actions are based on widely different mechanisms, which are influenced by the cellular microenvironment, but especially the subtypes of purine receptors involved and the activity of distinct members of the ectonucleotidase family, the latter being potential protein targets for therapeutic implementation.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Royal Free Campus, London, UK.
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Les effets pléiotropes d’un inhibiteur réversible de récepteurs P2Y12. ARCHIVES OF CARDIOVASCULAR DISEASES SUPPLEMENTS 2012. [DOI: 10.1016/s1878-6480(12)70832-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Kumral A, Tuzun F, Yesilirmak DC, Duman N, Ozkan H. Genetic basis of apnoea of prematurity and caffeine treatment response: role of adenosine receptor polymorphisms: genetic basis of apnoea of prematurity. Acta Paediatr 2012; 101:e299-303. [PMID: 22462821 DOI: 10.1111/j.1651-2227.2012.02664.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
AIM Caffeine treatment reduces the frequency of apnoea of prematurity (AOP) and eliminates the need for mechanical ventilation by acting as a nonspecific inhibitor of adenosine A1 and adenosine 2A receptors. Patients with AOP have demonstrated variant responses to caffeine therapy. We proposed to investigate the role of A1 and 2A polymorphisms in the development of AOP and individual differences in caffeine response. Secondly, we aimed to determine whether these polymorphisms have any effect on bronchopulmonary dysplasia (BPD) development. METHODS Cord blood samples were collected from infants born with gestational ages between 24 and 34 weeks. Two groups were defined: patients without apnoea (n = 60) and patients with apnoea (n = 55). Patients with apnoea were divided into two subgroups: a caffeine-responsive group (n = 30) and an unresponsive group (n = 25). Six single-nucleotide polymorphisms were chosen for genotyping. RESULTS Patients with apnoea over 28 weeks of gestational age who responded to the caffeine treatment were found to carry the rs16851030 C/C genotype rather than the C/T or T/T genotype. Logistic regression analysis showed a significant correlation between rs35320474-C/T and T/T genotypes and apnoea and BPD development. CONCLUSION Our results indicate a role for adenosine receptor gene polymorphisms in susceptibility to AOP and BPD and in interindividual variability to caffeine response.
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Affiliation(s)
- Abdullah Kumral
- Department of Pediatrics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
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Rudich N, Ravid K, Sagi-Eisenberg R. Mast cell adenosine receptors function: a focus on the a3 adenosine receptor and inflammation. Front Immunol 2012; 3:134. [PMID: 22675325 PMCID: PMC3366457 DOI: 10.3389/fimmu.2012.00134] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Accepted: 05/09/2012] [Indexed: 12/13/2022] Open
Abstract
Adenosine is a metabolite, which has long been implicated in a variety of inflammatory processes. Inhaled adenosine provokes bronchoconstriction in asthmatics or chronic obstructive pulmonary disease patients, but not in non-asthmatics. This hyper responsiveness to adenosine appears to be mediated by mast cell activation. These observations have marked the receptor that mediates the bronchoconstrictor effect of adenosine on mast cells (MCs), as an attractive drug candidate. Four subtypes (A1, A2a, A2b, and A3) of adenosine receptors have been cloned and shown to display distinct tissue distributions and functions. Animal models have firmly established the ultimate role of the A3 adenosine receptor (A3R) in mediating hyper responsiveness to adenosine in MCs, although the influence of the A2b adenosine receptor was confirmed as well. In contrast, studies of the A3R in humans have been controversial. In this review, we summarize data on the role of different adenosine receptors in mast cell regulation of inflammation and pathology, with a focus on the common and distinct functions of the A3R in rodent and human MCs. The relevance of mouse studies to the human is discussed.
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Affiliation(s)
- Noam Rudich
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University Tel Aviv, Israel
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Ehrentraut H, Westrich JA, Eltzschig HK, Clambey ET. Adora2b adenosine receptor engagement enhances regulatory T cell abundance during endotoxin-induced pulmonary inflammation. PLoS One 2012; 7:e32416. [PMID: 22389701 PMCID: PMC3289657 DOI: 10.1371/journal.pone.0032416] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Accepted: 01/30/2012] [Indexed: 01/01/2023] Open
Abstract
Anti-inflammatory signals play an essential role in constraining the magnitude of an inflammatory response. Extracellular adenosine is a critical tissue-protective factor, limiting the extent of inflammation. Given the potent anti-inflammatory effects of extracellular adenosine, we sought to investigate how extracellular adenosine regulates T cell activation and differentiation. Adenosine receptor activation by a pan adenosine-receptor agonist enhanced the abundance of murine regulatory T cells (Tregs), a cell type critical in constraining inflammation. Gene expression studies in both naïve CD4 T cells and Tregs revealed that these cells expressed multiple adenosine receptors. Based on recent studies implicating the Adora2b in endogenous anti-inflammatory responses during acute inflammation, we used a pharmacologic approach to specifically activate Adora2b. Indeed, these studies revealed robust enhancement of Treg differentiation in wild-type mice, but not in Adora2b−/− T cells. Finally, when we subjected Adora2b-deficient mice to endotoxin-induced pulmonary inflammation, we found that these mice experienced more severe inflammation, characterized by increased cell recruitment and increased fluid leakage into the airways. Notably, Adora2b-deficient mice failed to induce Tregs after endotoxin-induced inflammation and instead had an enhanced recruitment of pro-inflammatory effector T cells. In total, these data indicate that the Adora2b adenosine receptor serves a potent anti-inflammatory role, functioning at least in part through the enhancement of Tregs, to limit inflammation.
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Affiliation(s)
| | | | | | - Eric T. Clambey
- Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, United States of America
- * E-mail:
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Rittiner JE, Korboukh I, Hull-Ryde EA, Jin J, Janzen WP, Frye SV, Zylka MJ. AMP is an adenosine A1 receptor agonist. J Biol Chem 2012; 287:5301-9. [PMID: 22215671 DOI: 10.1074/jbc.m111.291666] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.
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Affiliation(s)
- Joseph E Rittiner
- Department of Cell and Molecular Physiology, University of North Carolina Neuroscience Center, Chapel Hill, North Carolina 27599, USA
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Abstract
Over the past 20 years, the growing awareness that purinergic signaling events literally shape the immune and inflammatory responses to infection and allergic reactions warranted the development of animal models to assess their importance in vivo in acute lung injury and chronic airway diseases. The pioneer work conducted with the adenosine deaminase (ADA)-deficient mouse provided irrefutable evidence that excess adenosine (ADO) accumulating in the lungs of asthmatic patients, constitutes a powerful mediator of disease severity. These original studies launched the development of murine strains for the two major ectonucleotidases responsible for the generation of airway ADO from ATP release: CD39 and CD73. The dramatic acute lung injury and chronic lung complications, manifested by these knockout mice in response to allergens and endotoxin, demonstrated the critical importance of regulating the availability of ATP and ADO for their receptors. Therapeutic targets are currently evaluated using knockout mice and agonists/antagonists for each ADO receptor (A(1)R, A(2A)R, A(2B)R, and A(3)R) and the predominant ATP receptors (P2Y(2)R and P2X(7)R). This chapter provides an in-depth description of each in vivo study, and a critical view of the therapeutic potentials for the treatment of airway diseases.
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Affiliation(s)
- Maryse Picher
- and Treatment Center, Cystic Fibrosis Pulmonary Research and T, University of North Carolina, Chapel Hill,, 27599 North Carolina USA
| | - Richard C. Boucher
- University of North Carolina, - Cystic Fibrosis Pulmonary Research and, Thurston-Bowles building - 7011, CHAPEL HILL, 27599 North Carolina USA
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Discovery of benzothiazole-based adenosine A2B receptor antagonists with improved A2A selectivity. Bioorg Med Chem Lett 2011; 21:1933-6. [DOI: 10.1016/j.bmcl.2011.02.053] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 02/05/2011] [Accepted: 02/14/2011] [Indexed: 11/17/2022]
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Feoktistov I, Biaggioni I. Role of adenosine A(2B) receptors in inflammation. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2011; 61:115-44. [PMID: 21586358 PMCID: PMC3748596 DOI: 10.1016/b978-0-12-385526-8.00005-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent progress in our understanding of the unique role of A(2B) receptors in the regulation of inflammation, immunity, and tissue repair was considerably facilitated with the introduction of new pharmacological and genetic tools. However, it also led to seemingly conflicting conclusions on the role of A(2B) adenosine receptors in inflammation with some publications indicating proinflammatory effects and others suggesting the opposite. This chapter reviews the functions of A(2B) receptors in various cell types related to inflammation and integrated effects of A(2B) receptor modulation in several animal models of inflammation. It is argued that translation of current findings into novel therapies would require a better understanding of A(2B) receptor functions in diverse types of inflammatory responses in various tissues and at different points of their progression.
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Affiliation(s)
- Igor Feoktistov
- Department of Medicine, Vanderbilt University, Division of Cardiovascular Medicine, Nashville, Tennessee, USA
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Abstract
Both caffeine and theophylline have a variety of roles in regulating inflammatory responses. At pharmacologically relevant concentrations most of the effects of these commonly used methylxanthines are attributable to adenosine receptor blockade and histone deacetylase activation. In addition, at higher concentrations methylxanthines can suppress inflammation by inhibiting phosphodiesterases, thereby elevating intracellular cyclic adenosine monophosphate levels. In summary, methylxanthines regulate inflammation by multiple mechanisms.
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Affiliation(s)
- György Haskó
- Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA
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Zhao Y, LaPar DJ, Steidle J, Emaminia A, Kron IL, Ailawadi G, Linden J, Lau CL. Adenosine signaling via the adenosine 2B receptor is involved in bronchiolitis obliterans development. J Heart Lung Transplant 2010; 29:1405-14. [PMID: 20920842 PMCID: PMC3100202 DOI: 10.1016/j.healun.2010.07.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2010] [Revised: 06/10/2010] [Accepted: 07/02/2010] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Adenosine is produced in response to ischemia or inflammation and protects tissues from injury. Four adenosine receptors are critical in the physiologic negative-feedback mechanism for limitation and termination of tissue-specific and systemic inflammatory responses. Accumulating evidence has focused on the anti-inflammatory and immunosuppressive role of the adenosine 2A receptor (A(2A)R), and we have previously reported on its role in the development of bronchiolitis obliterans (BO) after lung transplantation. Few studies, however, have reported the role of the adenosine 2B receptor (A(2B)R) in BO. Data suggests that the A(2B)R has pro-inflammatory and pro-fibrotic roles. We hypothesized that adenosine signaling through A(2B)R is involved in the development of BO. METHODS A murine heterotopic tracheal model across a total alloantigenic mismatch was used to study A(2B)R signaling in BO. Tracheal transplants consisted of Balb/c donor tracheas transplanted into wild-type or A(2B)R knockout (KO) C57BL/6 recipients. Transplanted tracheas were removed 3, 7, 12, and 21 days after transplantation. The luminal obliteration was evaluated through hematoxylin and eosin staining, and the cellular infiltration (macrophage, neutrophil, CD3+ and Foxp3+ regulatory T cell) was detected by immunohistochemical staining. RESULTS Compared with allografts in wild-type recipients, tracheas transplanted into A(2B)R KO mice displayed less BO development on Day 21. A(2B)R KO mice had an increase in CD3+ T cells and CD4+/CD25+/Foxp3+ regulatory T cells than did wild-type mice on Day 7. By Day 12, more CD3+ T cells were present in the wild-type trachea compared with the A(2B)R KO, but the percentage of CD4+/CD25+/Foxp3+ regulatory T cells remained higher in the tracheas of A(2B)R KO mice. CONCLUSIONS A(2B)R stimulation may promote the development of BO by inhibiting CD4+/CD25+/Foxp3+ regulatory T-cell infiltration.
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Affiliation(s)
- Yunge Zhao
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Damien J. LaPar
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - John Steidle
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Abbas Emaminia
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Irving L. Kron
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Gorav Ailawadi
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Joel Linden
- Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
| | - Christine L. Lau
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia
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Adenosine receptor subtypes in airways responses of sensitized guinea-pigs to inhaled ovalbumin. Pulm Pharmacol Ther 2010; 23:355-64. [DOI: 10.1016/j.pupt.2010.03.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2009] [Revised: 03/05/2010] [Accepted: 03/30/2010] [Indexed: 11/23/2022]
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Ohtsuka T, Changelian PS, Bouïs D, Noon K, Harada H, Lama VN, Pinsky DJ. Ecto-5'-nucleotidase (CD73) attenuates allograft airway rejection through adenosine 2A receptor stimulation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 185:1321-9. [PMID: 20548026 PMCID: PMC3014992 DOI: 10.4049/jimmunol.0901847] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
There are multiple drivers of leukocyte recruitment in lung allografts that contribute to lymphocytic bronchitis (LB) and bronchiolitis obliterans (BO). The innate mechanisms driving (or inhibiting) leukocyte trafficking to allografts remain incompletely understood. This study tested the hypothesis that CD73 (ecto-5'nucleotidase), an enzyme that catalyzes the conversion of AMP to adenosine, is a critical negative regulator of LB and BO. Implantation of tracheal allografts from wild type (WT) mice into CD73(-/-) recipients revealed a striking increase in airway luminal obliteration at 7 d (62 +/- 4% and 47 +/- 5% for CD73(-/-) and WT allograft recipients, respectively; p = 0.046). There was also a concordant increase in CD3(+) lymphocytic infiltration (523 +/- 41 cells and 313 +/- 43 cells for CD73(-/-) and WT allograft recipients, respectively; p = 0.013). Because real-time PCR revealed a 43-fold upregulation of mRNA for the adenosine A2A receptor (A2AR) in WT allografts compared with WT isografts (p = 0.032), additional experiments were performed to determine whether the protective effect of CD73 was due to generation of adenosine and its stimulation of the A2AR. Treatment of WT recipients with an A2AR agonist significantly reduced CD3(+) lymphocyte infiltration and airway luminal obliteration; similar treatment of CD73(-/-) recipients rescued them from LB and airway obliteration. These data implicate CD73 acting through adenosine generation and its stimulation of the A2AR as a critical negative modulator of lymphocyte recruitment into airway allografts. The CD73/adenosine axis might be a new therapeutic target to prevent BO.
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Affiliation(s)
- Takashi Ohtsuka
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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Cheung AWH, Brinkman J, Firooznia F, Flohr A, Grimsby J, Gubler ML, Guertin K, Hamid R, Marcopulos N, Norcross RD, Qi L, Ramsey G, Tan J, Wen Y, Sarabu R. 4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists. Bioorg Med Chem Lett 2010; 20:4140-6. [PMID: 20541935 DOI: 10.1016/j.bmcl.2010.05.056] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Revised: 05/13/2010] [Accepted: 05/14/2010] [Indexed: 10/19/2022]
Abstract
7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.
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Ponnoth DS, Nadeem A, Tilley S, Mustafa SJ. Involvement of A1 adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma. Am J Physiol Heart Circ Physiol 2010; 299:H81-7. [PMID: 20400685 DOI: 10.1152/ajpheart.01090.2009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Poor lung function and respiratory disorders like asthma have a positive correlation with the development of adverse cardiovascular events. Increased adenosine levels are associated with lung inflammation that could lead to altered vascular responses and systemic inflammation. We hypothesized that asthmatic lung inflammation has systemic effects through A(1) adenosine receptors (A(1)AR) and investigated the effects of aerosolized adenosine on vascular reactivity and inflammation, using A(1)AR knockout (A(1)KO) and corresponding wild-type (A(1)WT) mice that were divided into three experimental groups each: control (CON), allergen sensitized and challenged (SEN), and SEN + aerosolized adenosine (SEN + AD). Animals were sensitized with ragweed (200 microg ip; days 1 and 6), followed by 1% ragweed aerosol challenges (days 11 to 13). On day 14, the SEN + AD groups received one adenosine aerosol challenge (6 mg/ml) for 2 min, and aortae were collected on day 15. 5'-N-ethylcarboxamidoadenosine (NECA; nonselective adenosine analog) induced concentration-dependent aortic relaxation in the A(1)WT CON group, which was impaired in the A(1)WT SEN and SEN + AD groups. All groups of A(1)KO mice showed similar (no significant difference) concentration-dependent relaxation to NECA. The A(1)WT SEN and SEN + AD groups had a significantly higher contraction to selective A(1) agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) compared with the CON group. Western blot data showed that aortic A(1)AR expression was significantly increased in WT SEN and SEN + AD mice compared with CON mice. Gene expression of ICAM-1 and IL-5 was significantly increased in allergic A(1)WT aorta and were undetected in the A(1)KO groups. A(1)WT allergic mice had significantly higher airway hyperresponsiveness (enhanced pause) to NECA, with adenosine aerosol further enhancing it. In conclusion, allergic A(1)WT mice showed altered vascular reactivity, increased airway hyperresponsiveness, and systemic inflammation. These data suggest that A(1)AR is proinflammatory systemically in this model of allergic asthma.
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Affiliation(s)
- Dovenia S Ponnoth
- Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA
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Fernandez-Rodriguez S, Broadley KJ, Ford WR, Kidd EJ. Increased muscarinic receptor activity of airway smooth muscle isolated from a mouse model of allergic asthma. Pulm Pharmacol Ther 2010; 23:300-7. [PMID: 20347047 DOI: 10.1016/j.pupt.2010.03.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2009] [Revised: 02/19/2010] [Accepted: 03/04/2010] [Indexed: 12/22/2022]
Abstract
The mechanisms leading to airway hyper-responsiveness (AHR) in asthma are still not fully understood. AHR could be produced by hypersensitivity of the airway smooth muscle or hyperreactivity of the airways. This study was conducted to ascertain whether AHR in a murine model of asthma is produced by changes at the level of the airway smooth muscle. Airway smooth muscle responses were characterised in vitro in isolated trachea spirals from naive mice and from an acute ovalbumin (OVA) challenge model of allergic asthma. AHR was investigated in vivo in conscious, freely moving mice. Inflammatory cell influx into the lungs and antibody responses to the antigen were also measured. In vitro study of tracheal airway smooth muscle from naïve mice demonstrated concentration-related contractions to methacholine and 5-HT, but no responses to histamine or adenosine or its stable analogue, 5'-N-ethyl-carboxamidoadenosine. The contractions to 5-HT were inhibited by ketanserin and alosetron indicating involvement of 5-HT(2A) and 5-HT(3) receptors, respectively. In an acute model of allergic asthma, OVA-treated mice were shown to be atopic by inflammatory cell influx to the lungs after OVA challenge, increases in total IgE and OVA-specific IgG levels and contractions to OVA in isolated trachea. In the asthmatic model, AHR to methacholine was demonstrated in conscious, freely moving mice in vivo and in isolated trachea in vitro 24 and 72h after OVA challenge. No AHR in vitro was seen for 5-HT, histamine or adenosine. These results suggest that, in our mouse model of asthma, changes occur at the level of the muscarinic receptor transduction pathway of coupling to airway smooth muscle contraction. These changes are maintained when tissues are removed from the inflammatory environment and for at least 3 days.
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Affiliation(s)
- Sofia Fernandez-Rodriguez
- Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cathays Park, Cardiff CF10 3NB, UK.
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Michael S, Warstat C, Michel F, Yan L, Müller CE, Nieber K. Adenosine A(2A) agonist and A(2B) antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation. Purinergic Signal 2009; 6:117-24. [PMID: 20020217 DOI: 10.1007/s11302-009-9174-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2009] [Accepted: 12/01/2009] [Indexed: 12/22/2022] Open
Abstract
Adenosine can show anti-inflammatory as well as pro-inflammatory activities. The contribution of the specific adenosine receptor subtypes in various cells, tissues and organs is complex. In this study, we examined the effect of the adenosine A(2A) receptor agonist CGS 21680 and the A(2B)R antagonist PSB-1115 on acute inflammation induced experimentally by 2,4,6-trinitrobenzenesulfonic acid (TNBS) on rat ileum/jejunum preparations. Pre-incubation of the ileum/jejunum segments with TNBS for 30 min resulted in a concentration-dependent inhibition of acetylcholine (ACh)-induced contractions. Pharmacological activation of the A(2A)R with CGS 21680 (0.1-10 microM) pre-incubated simultaneously with TNBS (10 mM) prevented concentration-dependently the TNBS-induced inhibition of the ACh contractions. Stimulation of A(2B)R with the selective agonist BAY 60-6583 (10 microM) did neither result in an increase nor in a further decrease of ACh-induced contractions compared to the TNBS-induced inhibition. The simultaneous pre-incubation of the ileum/jejunum segments with TNBS (10 mM) and the selective A(2B)R antagonist PSB-1115 (100 microM) inhibited the contraction-decreasing effect of TNBS. The effects of the A(2A)R agonist and the A(2B)R antagonist were in the same range as the effect induced by 1 microM methotrexate. The combination of the A(2A)R agonist CGS 21680 and the A(2B)R antagonist PSB-1115 at subthreshold concentrations of both agents found a significant amelioration of the TNBS-diminished contractility. Our results demonstrate that the activation of A(2A) receptors or the blockade of the A(2B) receptors can prevent the inflammation-induced disturbance of the ACh-induced contraction in TNBS pre-treated small intestinal preparations. The combination of both may be useful for the treatment of inflammatory bowel diseases.
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Ohta A, Ohta A, Madasu M, Kini R, Subramanian M, Goel N, Sitkovsky M. A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. THE JOURNAL OF IMMUNOLOGY 2009; 183:5487-93. [PMID: 19843934 DOI: 10.4049/jimmunol.0901247] [Citation(s) in RCA: 161] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Immunosuppressive signaling via the A2A adenosine receptor (A2AR) provokes a mechanism that protects inflamed tissues from excessive damage by immune cells. This mechanism is desirable not only for preventing uncontrolled tissue destruction by overactive immune responses, but also for protecting tumor tissues from antitumor immune responses. In aforementioned circumstances, T cell priming may occur in an environment containing high concentrations of extracellular adenosine. To examine qualitative changes in T cells activated in the presence of adenosine, we asked whether different functional responses of T cells are equally susceptible to A2AR agonists. In this study, we demonstrate that A2AR signaling during T cell activation strongly inhibited development of cytotoxicity and cytokine-producing activity in T cells, whereas the inhibition of T cell proliferation was only marginal. Both CD8(+) and CD4(+) T cells proliferated well in the presence of A2AR agonists, but their IFN-gamma-producing activities were susceptible to inhibition by cAMP-elevating A2AR. Importantly, the impaired effector functions were maintained in T cells even after removal of the A2AR agonist, reflecting T cell memory of the immunoregulatory effect of adenosine. Thus, although the adenosine-rich environment may allow for the expansion of T cells, the functional activation of T cells may be critically impaired. This physiological mechanism could explain the inefficiency of antitumor T cells in the tumor microenvironment.
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Affiliation(s)
- Akio Ohta
- New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 113 Mugar Health Sciences Building, Boston, MA 02115, USA.
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