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1
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Rabbani P, Ramkhelawon B, Cronstein BN. Adenosine metabolism and receptors in aging of the skin, musculoskeletal, immune and cardiovascular systems. Ageing Res Rev 2025; 106:102695. [PMID: 39971100 PMCID: PMC11960428 DOI: 10.1016/j.arr.2025.102695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 11/26/2024] [Accepted: 02/14/2025] [Indexed: 02/21/2025]
Abstract
Aging populations worldwide face an increasing burden of age-related chronic conditions, necessitating a deeper understanding of the underlying mechanisms. Purine metabolism has emerged as a crucial player in the pathophysiology of aging, affecting various tissues and organs. Dysregulation of purine metabolism, particularly alterations in extracellular adenosine levels and adenosine receptor signaling, contributes to age-related musculoskeletal problems, cardiovascular diseases, inflammation, and impaired immune responses. Changes in purine metabolism are associated with diminished tissue repair and regeneration, altered bone density, and impaired muscle regeneration. Mechanistically, age-related alterations in purine metabolism involve reductions in extracellular adenosine production, impaired autocrine signaling, and dysregulated expression of CD73 and CD39. Targeting adenosine receptors, such as A2A and A2B receptors, emerges as a promising therapeutic approach to mitigate age-related conditions, including sarcopenia, obesity, osteoarthritis, and impaired wound healing. Since we cannot reverse time, understanding the intricate molecular interplay between purine metabolism and aging-related pathologies holds significant potential for developing novel therapeutic strategies to improve the health and quality of life of aging populations. In this review, we compile the findings related to purine metabolism during aging in several tissues and organs and provide insights into how these signals can be manipulated to circumvent the deleterious effects of the passage of time on our body.
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Affiliation(s)
- Piul Rabbani
- Hansjorg Wyss Department of Plastic Surgery, New York University Langone Health, New York, NY, USA
| | - Bhama Ramkhelawon
- Division of Vascular Surgery, Department of Surgery, New York University Langone Health, New York, NY, USA; Department of Cell Biology, New York University Langone Health, New York, NY, USA
| | - Bruce N Cronstein
- Department of Medicine, Divisions of Rheumatology and Precision Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA.
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2
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Luo Y, Zheng S, Xiao W, Zhang H, Li Y. Pannexins in the musculoskeletal system: new targets for development and disease progression. Bone Res 2024; 12:26. [PMID: 38705887 PMCID: PMC11070431 DOI: 10.1038/s41413-024-00334-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 03/04/2024] [Accepted: 04/01/2024] [Indexed: 05/07/2024] Open
Abstract
During cell differentiation, growth, and development, cells can respond to extracellular stimuli through communication channels. Pannexin (Panx) family and connexin (Cx) family are two important types of channel-forming proteins. Panx family contains three members (Panx1-3) and is expressed widely in bone, cartilage and muscle. Although there is no sequence homology between Panx family and Cx family, they exhibit similar configurations and functions. Similar to Cxs, the key roles of Panxs in the maintenance of physiological functions of the musculoskeletal system and disease progression were gradually revealed later. Here, we seek to elucidate the structure of Panxs and their roles in regulating processes such as osteogenesis, chondrogenesis, and muscle growth. We also focus on the comparison between Cx and Panx. As a new key target, Panxs expression imbalance and dysfunction in muscle and the therapeutic potentials of Panxs in joint diseases are also discussed.
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Affiliation(s)
- Yan Luo
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Department of Clinical Medicine, Xiangya Medicine School, Central South University, Changsha, Hunan, 410008, China
| | - Shengyuan Zheng
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Department of Clinical Medicine, Xiangya Medicine School, Central South University, Changsha, Hunan, 410008, China
| | - Wenfeng Xiao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hang Zhang
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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Marco-Bonilla M, Herencia R, Fresnadillo M, Huete-Toral F, Carracedo G, Largo R, Herrero-Beaumont G, Mediero A. Dipyridamole activates adenosine A2B receptor and AMPK/cAMP signaling and promotes myogenic differentiation of myoblastic C2C12 cells. Front Pharmacol 2023; 14:1247664. [PMID: 37771723 PMCID: PMC10522837 DOI: 10.3389/fphar.2023.1247664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/28/2023] [Indexed: 09/30/2023] Open
Abstract
Introduction: Sarcopenia is defined as a loss of muscle mass and strength. ATP homeostasis is crucial during myogenesis. We determined how the purinergic system modulates myogenesis using dipyridamole (blocks adenosine taken up by the cells) and tenofovir (inhibits ATP release) in a myoblast cell line. Methods: C2C12 cells were differentiated in the presence/absence of tenofovir/dipyridamole, with/without the A2B selective inhibitor PSB-603. Extra-/intracellular nucleotides were examined via HPLC. The expression of muscle differentiation proteins (Pax7, Mif5, MyoD, MyoG, and MHC), PKA/CREB, adenosine receptors (A1, A2A, A2B, and A3), ATP-channel pannexin-1 and the P2X7 receptor was analyzed via WB and RT-PCR. cAMP and AMPK activation was measured. Results: Tenofovir increased intracellular ATP and reduced extracellular adenosine, decreasing Pax7 expression and increasing MHC expression prematurely. Dipyridamole increased intracellular AMP and extracellular adenosine, counteracting the premature myogenesis promoted by tenofovir. All adenosine receptors were expressed during differentiation with dipyridamole, increasing A2B expression. Tenofovir maintained inactive AMPK and decreased cAMP levels, as well as PKAα and pCREB expression, which were recovered with dipyridamole. Discussion: Adenosine and ATP act as mediators in muscle myogenesis. The blockade of ATP release by tenofovir promotes premature myogenesis, with dipyridamole counteracting the premature differentiation promoted by tenofovir via the adenosine A2B receptor and cAMP/AMPK pathways. Therefore, dipyridamole might be of interest as a therapeutic approach in sarcopenia.
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Affiliation(s)
| | - Raquel Herencia
- Bone and Joint Research Unit, FIIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | - María Fresnadillo
- Bone and Joint Research Unit, FIIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | - Fernando Huete-Toral
- Ocupharm Group Research, Faculty of Optic and Optometry, University Complutense of Madrid, Madrid, Spain
| | - Gonzalo Carracedo
- Ocupharm Group Research, Faculty of Optic and Optometry, University Complutense of Madrid, Madrid, Spain
- Department of Optometry and Vision, Faculty of Optic and Optometry, University Complutense of Madrid, Madrid, Spain
| | - Raquel Largo
- Bone and Joint Research Unit, FIIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | | | - Aránzazu Mediero
- Bone and Joint Research Unit, FIIS-Fundación Jiménez Díaz UAM, Madrid, Spain
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4
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Chen X, Yuan S, Mi L, Long Y, He H. Pannexin1: insight into inflammatory conditions and its potential involvement in multiple organ dysfunction syndrome. Front Immunol 2023; 14:1217366. [PMID: 37711629 PMCID: PMC10498923 DOI: 10.3389/fimmu.2023.1217366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 08/10/2023] [Indexed: 09/16/2023] Open
Abstract
Sepsis represents a global health concern, and patients with severe sepsis are at risk of experiencing MODS (multiple organ dysfunction syndrome), which is associated with elevated mortality rates and a poorer prognosis. The development of sepsis involves hyperactive inflammation, immune disorder, and disrupted microcirculation. It is crucial to identify targets within these processes to develop therapeutic interventions. One such potential target is Panx1 (pannexin-1), a widely expressed transmembrane protein that facilitates the passage of molecules smaller than 1 KDa, such as ATP. Accumulating evidence has implicated the involvement of Panx1 in sepsis-associated MODS. It attracts immune cells via the purinergic signaling pathway, mediates immune responses via the Panx1-IL-33 axis, promotes immune cell apoptosis, regulates blood flow by modulating VSMCs' and vascular endothelial cells' tension, and disrupts microcirculation by elevating endothelial permeability and promoting microthrombosis. At the level of organs, Panx1 contributes to inflammatory injury in multiple organs. Panx1 primarily exacerbates injury and hinders recovery, making it a potential target for sepsis-induced MODS. While no drugs have been developed explicitly against Panx1, some compounds that inhibit Panx1 hemichannels have been used extensively in experiments. However, given that Panx1's role may vary during different phases of sepsis, more investigations are required before interventions against Panx1 can be applied in clinical. Overall, Panx1 may be a promising target for sepsis-induced MODS. Nevertheless, further research is needed to understand its complex role in different stages of sepsis fully and to develop suitable pharmaceutical interventions for clinical use.
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Affiliation(s)
| | | | | | - Yun Long
- Department of Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Huaiwu He
- Department of Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
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5
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Van Campenhout R, Caufriez A, Tabernilla A, Maerten A, De Boever S, Sanz-Serrano J, Kadam P, Vinken M. Pannexin1 channels in the liver: an open enemy. Front Cell Dev Biol 2023; 11:1220405. [PMID: 37492223 PMCID: PMC10363690 DOI: 10.3389/fcell.2023.1220405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 06/23/2023] [Indexed: 07/27/2023] Open
Abstract
Pannexin1 proteins form communication channels at the cell plasma membrane surface, which allow the transfer of small molecules and ions between the intracellular compartment and extracellular environment. In this way, pannexin1 channels play an important role in various cellular processes and diseases. Indeed, a plethora of human pathologies is associated with the activation of pannexin1 channels. The present paper reviews and summarizes the structure, life cycle, regulation and (patho)physiological roles of pannexin1 channels, with a particular focus on the relevance of pannexin1 channels in liver diseases.
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6
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Rafii S, Ghouzlani A, Naji O, Ait Ssi S, Kandoussi S, Lakhdar A, Badou A. A 2AR as a Prognostic Marker and a Potential Immunotherapy Target in Human Glioma. Int J Mol Sci 2023; 24:6688. [PMID: 37047660 PMCID: PMC10095519 DOI: 10.3390/ijms24076688] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/05/2023] [Accepted: 03/14/2023] [Indexed: 04/07/2023] Open
Abstract
Gliomas are considered one of the most malignant tumors in the body. The immune system has the ability to control the initiation and development of tumors, including gliomas. Thus, immune cells find themselves controlled by various molecular pathways, inhibiting their activation, such as the immunosuppressive adenosine 2A receptor (A2AR). Our objective was to establish the expression profile and role of A2AR at the transcriptomic level, using real-time RT-PCR in Moroccan glioma patients, in addition to TCGA and CGGA cohorts. The real-time RT-PCR results in Moroccan patients showed that high expression of this gene was associated with poor survival in males. Our study on the CGGA cohort corroborated these results. In addition, there was a positive association of A2AR with T-cell exhaustion genes. A2AR also correlated strongly with genes that are primarily enriched in focal adhesion and extracellular matrix interactions, inducing epithelial mesenchymal transition, angiogenesis, and glioma growth. However, in the TCGA cohort, the A2AR showed results that were different from the two previously examined cohorts. In fact, this gene was instead linked to a good prognosis in patients with the astrocytoma histological type. The correlation and enrichment results reinforced the prognostic role of A2AR in this TCGA cohort, in which its high expression was shown to be related to lymphocyte differentiation and a successful cytolytic response, suggesting a more efficient anti-tumor immune response. Correlations and differential analyses based on A2AR gene expression, to understand the cause of the association of this gene with two different prognoses (CGGA males and TCGA Astrocytoma), showed that the overexpression of A2AR in Chinese male patients could be associated with the overexpression of extracellular adenosine, which binds to A2AR to induce immunosuppression and consequently a poor prognosis. However, in the second group (TCGA astrocytomas), the overexpression of the gene could be associated with an adenosine deficiency, and therefore this receptor does not undergo activation. The absence of A2AR activation in these patients may have protected them from immunosuppression, which could reflect the good prognosis. A2AR can be considered a promising therapeutic target in male CGGA and Moroccan patients with gliomas.
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Affiliation(s)
- Soumaya Rafii
- Immuno-Genetics and Human Pathologies Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca 20000, Morocco
| | - Amina Ghouzlani
- Immuno-Genetics and Human Pathologies Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca 20000, Morocco
| | - Oumayma Naji
- Immuno-Genetics and Human Pathologies Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca 20000, Morocco
| | - Saadia Ait Ssi
- Immuno-Genetics and Human Pathologies Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca 20000, Morocco
| | - Sarah Kandoussi
- Immuno-Genetics and Human Pathologies Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca 20000, Morocco
| | | | - Abdallah Badou
- Immuno-Genetics and Human Pathologies Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca 20000, Morocco
- Mohammed VI Center for Research and Innovation, Rabat, Morocco and Mohammed VI University of Sciences and Health, Casablanca 82403, Morocco
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7
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Larrañaga-Vera A, Toti KS, Flatow JS, Haraczy AJ, Warnick E, Rao H, Gao ZG, Sussman SM, Mediero A, Leucht P, Jacobson KA, Cronstein BN. Novel alendronate-CGS21680 conjugate reduces bone resorption and induces new bone formation in post-menopausal osteoporosis and inflammatory osteolysis mouse models. Arthritis Res Ther 2022; 24:265. [PMID: 36494860 PMCID: PMC9733060 DOI: 10.1186/s13075-022-02961-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/29/2022] [Indexed: 12/13/2022] Open
Abstract
Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements make it unusable in the clinic. We therefore generated a novel alendronate-CGS21680 conjugate (MRS7216), to target the agonist to bone where it remains for long periods thereby diminishing the frequency of administration and curtailing side effects. MRS7216 was synthesized from CGS21680 by sequential activation of the carboxylic acid moiety and reacting with an appropriate amino acid (PEG, alendronic acid) under basic conditions. MRS7216 was tested on C57BL/6J (WT) mice with established osteoporosis (OP) and WT or A2A KO mice with wear particle-induced inflammatory osteolysis (OL). Mice were treated weekly with MRS7216 (10mg/kg). Bone formation was studied after in vivo labeling with calcein/Alizarin Red, and μCT and histology analyses were performed. In addition, human primary osteoblasts and osteoclasts were cultured using bone marrow discarded after hip replacement. Receptor binding studies demonstrate that MRS7216 efficiently binds the A2A adenosine receptor. MRS7216-treated OP and OL mice had significant new bone formation and reduced bone loss compared to vehicle or alendronate-treated mice. Histological analysis showed that MRS7216 treatment significantly reduced osteoclast number and increased osteoblast number in murine models. Interestingly, cultured human osteoclast differentiation was inhibited, and osteoblast differentiation was stimulated by the compound indicating that MRS7216 conjugates represent a novel therapeutic approach to treat osteoporosis and osteolysis.
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Affiliation(s)
- Ane Larrañaga-Vera
- Division of Translational Medicine, Department of Medicine, NYU Langone Health, 550 First Avenue, Medical Science Building, Room, New York, NY, 251, USA
| | - Kiran S Toti
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - James S Flatow
- Division of Translational Medicine, Department of Medicine, NYU Langone Health, 550 First Avenue, Medical Science Building, Room, New York, NY, 251, USA
| | - Alexandra J Haraczy
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Eugene Warnick
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Harsha Rao
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Zhan-Guo Gao
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Sarah M Sussman
- Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Aranzazu Mediero
- Division of Translational Medicine, Department of Medicine, NYU Langone Health, 550 First Avenue, Medical Science Building, Room, New York, NY, 251, USA
- Bone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | - Philipp Leucht
- Department of Orthopedic Surgery, New York University Langone Orthopedic Hospital, New York, USA
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA
| | - Kenneth A Jacobson
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Bruce N Cronstein
- Division of Translational Medicine, Department of Medicine, NYU Langone Health, 550 First Avenue, Medical Science Building, Room, New York, NY, 251, USA.
- Division of Rheumatology, Department of Medicine, NYU Langone Health, New York, NY, USA.
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8
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Herman-de-Sousa C, Costa MA, Silva RP, Ferreirinha F, Ribeiro S, Correia-de-Sá P. A2A receptor-induced overexpression of pannexin-1 channels indirectly mediates adenosine fibrogenic actions by favouring ATP release from human subcutaneous fibroblasts. Life Sci 2022; 310:121080. [DOI: 10.1016/j.lfs.2022.121080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 10/09/2022] [Accepted: 10/11/2022] [Indexed: 11/09/2022]
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Ferrari D, Rubini M, Burns JS. The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2. Front Immunol 2022; 13:904419. [PMID: 35784277 PMCID: PMC9248768 DOI: 10.3389/fimmu.2022.904419] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 05/05/2022] [Indexed: 01/18/2023] Open
Abstract
A long-shared evolutionary history is congruent with the multiple roles played by purinergic signaling in viral infection, replication and host responses that can assist or hinder viral functions. An overview of the involvement of purinergic signaling among a range of viruses is compared and contrasted with what is currently understood for SARS-CoV-2. In particular, we focus on the inflammatory and antiviral responses of infected cells mediated by purinergic receptor activation. Although there is considerable variation in a patient's response to SARS-CoV-2 infection, a principle immediate concern in Coronavirus disease (COVID-19) is the possibility of an aberrant inflammatory activation causing diffuse lung oedema and respiratory failure. We discuss the most promising potential interventions modulating purinergic signaling that may attenuate the more serious repercussions of SARS-CoV-2 infection and aspects of their implementation.
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Affiliation(s)
- Davide Ferrari
- Section of Microbiology and Applied Pathology, University of Ferrara, Ferrara, Italy
- Department of Life Science and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Michele Rubini
- Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
| | - Jorge S. Burns
- Department of Life Science and Biotechnology, University of Ferrara, Ferrara, Italy
- Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy
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10
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Caufriez A, Tabernilla A, Van Campenhout R, Cooreman A, Leroy K, Sanz Serrano J, Kadam P, dos Santos Rodrigues B, Lamouroux A, Ballet S, Vinken M. Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels. Int J Mol Sci 2022; 23:ijms23105664. [PMID: 35628472 PMCID: PMC9146942 DOI: 10.3390/ijms23105664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 02/01/2023] Open
Abstract
Although many efforts have been made to elucidate the pathogenesis of COVID-19, the underlying mechanisms are yet to be fully uncovered. However, it is known that a dysfunctional immune response and the accompanying uncontrollable inflammation lead to troublesome outcomes in COVID-19 patients. Pannexin1 channels are put forward as interesting drug targets for the treatment of COVID-19 due to their key role in inflammation and their link to other viral infections. In the present study, we selected a panel of drugs previously tested in clinical trials as potential candidates for the treatment of COVID-19 early on in the pandemic, including hydroxychloroquine, chloroquine, azithromycin, dexamethasone, ribavirin, remdesivir, favipiravir, lopinavir, and ritonavir. The effect of the drugs on pannexin1 channels was assessed at a functional level by means of measurement of extracellular ATP release. Immunoblot analysis and real-time quantitative reversetranscription polymerase chain reaction analysis were used to study the potential of the drugs to alter pannexin1 protein and mRNA expression levels, respectively. Favipiravir, hydroxychloroquine, lopinavir, and the combination of lopinavir with ritonavir were found to inhibit pannexin1 channel activity without affecting pannexin1 protein or mRNA levels. Thusthree new inhibitors of pannexin1 channels were identified that, though currently not being used anymore for the treatment of COVID-19 patients, could be potential drug candidates for other pannexin1-related diseases.
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Affiliation(s)
- Anne Caufriez
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
- Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; (A.L.); (S.B.)
| | - Andrés Tabernilla
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Raf Van Campenhout
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Axelle Cooreman
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Kaat Leroy
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Julen Sanz Serrano
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Prashant Kadam
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Bruna dos Santos Rodrigues
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Arthur Lamouroux
- Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; (A.L.); (S.B.)
| | - Steven Ballet
- Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; (A.L.); (S.B.)
| | - Mathieu Vinken
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
- Correspondence: ; Tel.: +32-2477-4587
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11
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Nadeali Z, Mohammad-Rezaei F, Aria H, Nikpour P. Possible role of pannexin 1 channels and purinergic receptors in the pathogenesis and mechanism of action of SARS-CoV-2 and therapeutic potential of targeting them in COVID-19. Life Sci 2022; 297:120482. [PMID: 35288174 PMCID: PMC8915746 DOI: 10.1016/j.lfs.2022.120482] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 02/28/2022] [Accepted: 03/09/2022] [Indexed: 01/08/2023]
Abstract
Identifying signaling pathways and molecules involved in SARS-CoV-2 pathogenesis is pivotal for developing new effective therapeutic or preventive strategies for COVID-19. Pannexins (PANX) are ATP-release channels in the plasma membrane essential in many physiological and immune responses. Activation of pannexin channels and downstream purinergic receptors play dual roles in viral infection, either by facilitating viral replication and infection or inducing host antiviral defense. The current review provides a hypothesis demonstrating the possible contribution of the PANX1 channel and purinergic receptors in SARS-CoV-2 pathogenesis and mechanism of action. Moreover, we discuss whether targeting these signaling pathways may provide promising preventative therapies and treatments for patients with progressive COVID-19 resulting from excessive pro-inflammatory cytokines and chemokines production. Several inhibitors of this pathway have been developed for the treatment of other viral infections and pathological consequences. Specific PANX1 inhibitors could be potentially included as part of the COVID-19 treatment regimen if, in future, studies demonstrate the role of PANX1 in COVID-19 pathogenesis. Of note, any ATP therapeutic modulation for COVID-19 should be carefully designed and monitored because of the complex role of extracellular ATP in cellular physiology.
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Affiliation(s)
- Zakiye Nadeali
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Mohammad-Rezaei
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Aria
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parvaneh Nikpour
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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12
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Artlett CM. The Mechanism and Regulation of the NLRP3 Inflammasome during Fibrosis. Biomolecules 2022; 12:biom12050634. [PMID: 35625564 PMCID: PMC9138796 DOI: 10.3390/biom12050634] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/29/2022] [Accepted: 03/31/2022] [Indexed: 02/01/2023] Open
Abstract
Fibrosis is often the end result of chronic inflammation. It is characterized by the excessive deposition of extracellular matrix. This leads to structural alterations in the tissue, causing permanent damage and organ dysfunction. Depending on the organ it effects, fibrosis can be a serious threat to human life. The molecular mechanism of fibrosis is still not fully understood, but the NLRP3 (NOD-, LRR- and pyrin–domain–containing protein 3) inflammasome appears to play a significant role in the pathogenesis of fibrotic disease. The NLRP3 inflammasome has been the most extensively studied inflammatory pathway to date. It is a crucial component of the innate immune system, and its activation mediates the secretion of interleukin (IL)-1β and IL-18. NLRP3 activation has been strongly linked with fibrosis and drives the differentiation of fibroblasts into myofibroblasts by the chronic upregulation of IL-1β and IL-18 and subsequent autocrine signaling that maintains an activated inflammasome. Both IL-1β and IL-18 are profibrotic, however IL-1β can have antifibrotic capabilities. NLRP3 responds to a plethora of different signals that have a common but unidentified unifying trigger. Even after 20 years of extensive investigation, regulation of the NLRP3 inflammasome is still not completely understood. However, what is known about NLRP3 is that its regulation and activation is complex and not only driven by various activators but controlled by numerous post-translational modifications. More recently, there has been an intensive attempt to discover NLRP3 inhibitors to treat chronic diseases. This review addresses the role of the NLRP3 inflammasome in fibrotic disorders across many different tissues. It discusses the relationships of various NLRP3 activators to fibrosis and covers different therapeutics that have been developed, or are currently in development, that directly target NLRP3 or its downstream products as treatments for fibrotic disorders.
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Affiliation(s)
- Carol M Artlett
- Department of Microbiology & Immunology, College of Medicine, Drexel University, Philadelphia, PA 19129, USA
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13
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Lee SW, Kim SM, Hur W, Kang BY, Lee HL, Nam H, Yoo SH, Sung PS, Kwon JH, Jang JW, Kim SJ, Yoon SK. Tenofovir disoproxil fumarate directly ameliorates liver fibrosis by inducing hepatic stellate cell apoptosis via downregulation of PI3K/Akt/mTOR signaling pathway. PLoS One 2021; 16:e0261067. [PMID: 34879114 PMCID: PMC8654182 DOI: 10.1371/journal.pone.0261067] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 11/23/2021] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Antifibrotic agent for the treatment of liver fibrosis has not been developed so far. Long term treatment of chronic hepatitis B patients with antiviral drugs tenofovir disoproxil fumarate (TDF) and entecavir (ETV) results in the regression of liver fibrosis, but the underlying mechanism has not been clarified. Therefore, we aimed to investigate the direct impact of TDF and ETV on liver fibrosis. METHODS Activated hepatic stellate cell (HSC) cell lines were used to evaluate the effects of TDF and ETV. After treatment with each antiviral agent, cell viability, morphology, apoptotic features, autophagy and antifibrosis signalling pathways were examined. Then, collagen deposition, fibrosis markers and activated HSCs were measured in liver tissues of the liver fibrosis model mice. RESULTS After TDF treatment, the viabilities of LX2 and HSC-T6 cells were decreased, and the cells exhibited apoptotic features, but ETV did not induce these effects. Cleavage of PARP and Caspase-3 and the inhibition of the antiapoptotic gene Bcl-xl indicated activated HSC apoptosis following TDF treatment. TDF simultaneously increased autophagy, which also regulated apoptosis through crosstalk. TDF inactivated the PI3K/Akt/mTOR signalling pathway, which was associated with the activation of both apoptosis and autophagy. In the liver fibrosis mouse model, the fibrotic area and activated HSC markers were decreased by TDF but not ETV treatment. Additionally, apoptotic cells were concentrated in the periportal fibrotic area after TDF treatment, which indicated the specific antifibrotic effect of TDF. CONCLUSIONS TDF directly ameliorates liver fibrosis by downregulating the PI3K/Akt/mTOR signalling pathway, which results in the apoptosis of activated HSCs. The antifibrotic effects of TDF indicate that it may be a therapeutic agent for the treatment of liver fibrosis.
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Affiliation(s)
- Sung Won Lee
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Min Kim
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
| | - Wonhee Hur
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
| | - Byung-Yoon Kang
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hae Lim Lee
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Heechul Nam
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sun Hong Yoo
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Pil Soo Sung
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Hyun Kwon
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seong-Jun Kim
- Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
| | - Seung Kew Yoon
- Department of Biomedicine & Health Sciences, The Catholic University Liver Research Centre, POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Llamas-Granda P, Martin-Rodríguez L, Largo R, Herrero-Beaumont G, Mediero A. Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor. Int J Mol Sci 2021; 22:ijms222111490. [PMID: 34768920 PMCID: PMC8583797 DOI: 10.3390/ijms222111490] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 10/20/2021] [Indexed: 12/04/2022] Open
Abstract
Semaphorin 4D (Sema4D) is a neurotrophin that is secreted by osteoclasts and binds to its receptor PlexinB1 on osteoblasts to inhibit their differentiation and function. Adenosine A2A activation inhibits osteoclast Sema4D-mediated secretion, diminishes inflammatory osteolysis and prevents bone loss following tenofovir (one of the most used antivirals in HIV). Therefore, tenofovir might activate Sema4D signaling to alter bone turnover. Female C57Bl/6/A2AKO mice were ovariectomized and treated with saline (control), tenofovir 75 mg/Kg/day, dipyridamole 25 mg/Kg/day or a combination for 5 weeks and long bones were prepared for histology. Primary murine-induced osteoclast/osteoblast were challenged with tenofovir/dipyridamole 1 μM each, and the expression of Sema4D/PlexinB1, RhoA/ROCK/IGF1R was studied by RT-PCR, Western blot and immunostaining. In vivo tenofovir showed an increased expression of Sema4D when compared to control mice, and dipyridamole reverted the expression in an A2A-dependent manner. In vitro, tenofovir increases Sema4D expression and secretion in osteoclast precursors, and pre-treatment with dipyridamole reverted this effect. pRhoA and ROCK1 activation were increased and IRS1/IGF1R expression was diminished by tenofovir in the Vav3/ARHGAP18 mechanism in osteoblast precursors and reverted by dipyridamole in an A2A-dependent manner. This suggests that tenofovir increases bone loss by activation of Sema4D/PlexinB1 signaling, which inhibits osteoblast differentiation. Agents that increase local adenosine concentrations, such as dipyridamole, might prevent bone loss following the inhibition of this pathway.
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15
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Atencio P, Conesa-Buendía FM, Cabello-Ubeda A, Llamas-Granda P, Pérez-Tanoira R, Prieto-Pérez L, Álvarez BÁ, Acosta IC, Arboiro-Pinel R, Díaz-Curiel M, Largo R, Herrero-Beaumont G, Górgolas M, Mediero A. Bone deleterious effects of different nrtis in treatment-naïve HIV patients after 12 and 48 weeks of treatment. Curr HIV Res 2021; 19:434-447. [PMID: 34353266 PMCID: PMC9175084 DOI: 10.2174/1570162x19666210805094434] [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: 03/08/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 11/22/2022]
Abstract
Background Bone alterations have been observed in the course of HIV infection, characterized by a marked decrease in bone mineral density (BMD) and an increase in the frequency of fractures as a result of fragility. We aim to evaluate early changes in bone metabolic profile and the possible association with tenofovir and other nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) in treatment-naïve HIV patients. Methods We conducted a prospective study in naïve HIV-infected adults (under 50 years), separated into three groups according to NRTI therapy: tenofovir disoproxil fumarate (TDF); tenofovir alafenamide (TAF) and abacavir (ABC). BMD and epidemiological, immunological and metabolic bone parameters were evaluated. Bone markers were analyzed in plasma at baseline, 12 and 48 weeks after initiating treatment. Results Average age of patients was 34.8 years (± 9.6). 92.4% of them with CD4 count > 200 cel/μL. At week 12 after starting treatment, both TDF [increase in PN1P (31.7%, p = 0.004), TRAP (11.1%, p = 0.003), OPN (19.3%, p = 0.045) and OC (38.6%, p = 0.001); decrease in OPG (-23.4%, p = 0.003)] and TAF [increase in 42.6% for CTX (p = 0.011), 27.3% for OC (p = 0.001) and 21% for TRAP (p = 0.008); decrease in OPG (-28.8%, p = 0.049)] presented a deep resorption profile compared to ABC, these differences in bone molecular markers, a tendency to equalize at week 48, where no significant differences were observed. Patients treated with TDF showed the greatest decrease in Z-score in both lumbar spine (LS) and femoral neck (FN) at week 48 without statistically significant differences. Conclusion Treatment-naïve HIV patients have a high prevalence of low bone density. Treatment with TDF is associated with greater bone deterioration at 12 and 48 weeks. TAF seems to present similar early bone deterioration at 12 weeks which disappears at 48 weeks.
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Affiliation(s)
- Patricia Atencio
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | | | - Alfonso Cabello-Ubeda
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Patricia Llamas-Granda
- Bone and Joint Research Unit. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Ramón Pérez-Tanoira
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Laura Prieto-Pérez
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Beatriz Álvarez Álvarez
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Irene Carrillo Acosta
- Division of Infectious Diseases. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Rosa Arboiro-Pinel
- Internal Medicine, Bone Disease Department. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Manuel Díaz-Curiel
- Internal Medicine, Bone Disease Department. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Raquel Largo
- Bone and Joint Research Unit. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Gabriel Herrero-Beaumont
- Bone and Joint Research Unit. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Miguel Górgolas
- Internal Medicine, Bone Disease Department. Fundación Jiménez Díaz University Hospital. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
| | - Aránzazu Mediero
- Bone and Joint Research Unit. Research Health Institute, Autónoma de Madrid University (IIS-FJD, UAM). Madrid 28040. Spain
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16
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Acosta ML, Mat Nor MN, Guo CX, Mugisho OO, Coutinho FP, Rupenthal ID, Green CR. Connexin therapeutics: blocking connexin hemichannel pores is distinct from blocking pannexin channels or gap junctions. Neural Regen Res 2021; 16:482-488. [PMID: 32985469 PMCID: PMC7996017 DOI: 10.4103/1673-5374.290097] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Compounds that block the function of connexin and pannexin protein channels have been suggested to be valuable therapeutics for a range of diseases. Some of these compounds are now in clinical trials, but for many of them, the literature is inconclusive about the molecular effect on the tissue, despite evidence of functional recovery. Blocking the different channel types has distinct physiological and pathological implications and this review describes current knowledge of connexin and pannexin protein channels, their function as channels and possible mechanisms of the channel block effect for the latest therapeutic compounds. We summarize the evidence implicating pannexins and connexins in disease, considering their homeostatic versus pathological roles, their contribution to excesive ATP release linked to disease onset and progression.
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Affiliation(s)
- Monica L Acosta
- School of Optometry and Vision Science; New Zealand National Eye Centre, University of Auckland; Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland; Brain Research New Zealand-Rangahau Roro Aotearoa, Auckland, New Zealand
| | - Mohd N Mat Nor
- School of Optometry and Vision Science, University of Auckland, Auckland, New Zealand; Faculty of Medicine, Universiti Sultan Zainal Abidin, Terengganu, Malaysia
| | - Cindy X Guo
- School of Optometry and Vision Science, University of Auckland, Auckland, New Zealand
| | - Odunayo O Mugisho
- Department of Ophthalmology, University of Auckland; Buchanan Ocular Therapeutics Unit, Department of Ophthalmology; New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
| | - Frazer P Coutinho
- Department of Ophthalmology, University of Auckland, Auckland, New Zealand
| | - Ilva D Rupenthal
- Department of Ophthalmology, University of Auckland; Buchanan Ocular Therapeutics Unit, Department of Ophthalmology; New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
| | - Colin R Green
- Department of Ophthalmology; New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
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17
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Han H, Desert R, Das S, Song Z, Athavale D, Ge X, Nieto N. Danger signals in liver injury and restoration of homeostasis. J Hepatol 2020; 73:933-951. [PMID: 32371195 PMCID: PMC7502511 DOI: 10.1016/j.jhep.2020.04.033] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/08/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023]
Abstract
Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can also promote inflammation in the context of liver disease. Herein, we provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. In addition, we discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice.
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Affiliation(s)
- Hui Han
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S. Wood St., Suite 1020N, MC 787, Chicago, IL 60612, USA.
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18
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Wang S, Gao S, Zhou D, Qian X, Luan J, Lv X. The role of the CD39-CD73-adenosine pathway in liver disease. J Cell Physiol 2020; 236:851-862. [PMID: 32648591 DOI: 10.1002/jcp.29932] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023]
Abstract
Extracellular adenosine triphosphate (ATP) is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. The ectonucleotidases CD39/ectonucleoside triphosphate diphosphohydrolase-1 and CD73/ecto-5'-nucleotidase are cell-surface enzymes that breakdown extracellular ATP into adenosine. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39-CD73-adenosine pathway changes dynamically with the pathophysiological context in which it is embedded. Accumulating evidence suggests that CD39 and CD73 play important roles in liver disease as critical components of the extracellular adenosinergic pathway. Recent studies have shown that the modification of the CD39-CD73-adenosine pathway alters the liver's response to injury. Moreover, adenosine exerts different effects on the pathophysiology of the liver through different receptors. In this review, we aim to describe the role of the CD39-CD73-adenosine pathway and adenosine receptors in liver disease, highlighting potential therapeutic targets in this pathway, which will facilitate the development of therapeutic strategies for the treatment of liver disease.
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Affiliation(s)
- Sheng Wang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China.,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Institute for Liver Disease, Anhui Medical University, Hefei, Anhui, China
| | - Songsen Gao
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Dexi Zhou
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Xueyi Qian
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Xiongwen Lv
- The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Institute for Liver Disease, Anhui Medical University, Hefei, Anhui, China
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19
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Luo J, Zhang T, Zhu C, Sun J, Zhu W, Ai W, Huang X, Wang X. Asiaticoside might attenuate bleomycin-induced pulmonary fibrosis by activating cAMP and Rap1 signalling pathway assisted by A2AR. J Cell Mol Med 2020; 24:8248-8261. [PMID: 32548952 PMCID: PMC7348182 DOI: 10.1111/jcmm.15505] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/10/2020] [Accepted: 05/24/2020] [Indexed: 12/15/2022] Open
Abstract
Asiaticoside (AS) has been reported to have protective effect on pulmonary fibrosis (PF). In this study, we aimed to explore the potential mechanism of the therapeutic role of AS and its relationship with A2AR in PF. Adenosine 2A receptor gene knockout (A2AR−/−) mice and wild‐type (WT) mice were used to establish bleomycin (BLM)‐induced PF models and were then treated with AS (50 mg/kg/d). Pulmonary inflammation and fibrosis were observed in the PF model with much higher severity in A2AR−/−mice than that in WT mice and AS significantly alleviated lung inflammation and fibrosis; however, it was less effective in A2AR−/− mice than in WT mice via histopathological analysis. Using RNA sequencing analysis, we found up‐regulated differentially expressed genes (DEGs) in BLM group were enriched in immune and inflammation‐associated pathways compared with control group. There were 242 common DEGs between down‐regulated in BLM vs control group and up‐regulated in BLM + AS vs BLM group, which were enriched in cAMP and Rap1 signalling pathways. Furthermore, the expression of five key factors of these two pathways including adenylate cyclase (ADCY1, ADCY5, ADCY8, cAMP and Rap1) were confirmed up‐regulated by AS with the presence of A2AR. Therefore, AS might attenuate BLM‐induced PF by activating cAMP and Rap1 signalling pathways which is assisted by A2AR, making it a promising therapeutic optional for PF.
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Affiliation(s)
- Jing Luo
- Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ting Zhang
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Wenling, Zhenjiang, China
| | - Chengwei Zhu
- Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Junwei Sun
- Division of Pulmonary Medicine, First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, China
| | - Wenjing Zhu
- Division of Pulmonary Medicine, First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, China
| | - Wenxiu Ai
- Division of Pulmonary Medicine, First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, China
| | - Xiaoying Huang
- Division of Pulmonary Medicine, First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, China
| | - Xiaobing Wang
- Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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20
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Swayne LA, Johnstone SR, Ng CS, Sanchez-Arias JC, Good ME, Penuela S, Lohman AW, Wolpe AG, Laubach VE, Koval M, Isakson BE. Consideration of Pannexin 1 channels in COVID-19 pathology and treatment. Am J Physiol Lung Cell Mol Physiol 2020; 319:L121-L125. [PMID: 32519892 PMCID: PMC7347959 DOI: 10.1152/ajplung.00146.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Leigh Anne Swayne
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Scott R Johnstone
- Fralin Biomedical Research Institute at Virginia Tech Carilion Center for Heart and Reparative Medicine Research, Virginia Tech, Roanoke, Virginia.,Department of Biological Sciences, Virginia Tech, Roanoke, Virginia
| | - Chen Seng Ng
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Juan C Sanchez-Arias
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Miranda E Good
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts
| | - Silvia Penuela
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada
| | - Alexander W Lohman
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Abigail G Wolpe
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia.,Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Victor E Laubach
- Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia.,Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Michael Koval
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Brant E Isakson
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia.,Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia
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21
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Ratajczak MZ, Adamiak M, Bujko K, Thapa A, Pensato V, Kucia M, Ratajczak J, Ulrich H. Innate immunity orchestrates the mobilization and homing of hematopoietic stem/progenitor cells by engaging purinergic signaling-an update. Purinergic Signal 2020; 16:153-166. [PMID: 32415576 PMCID: PMC7367963 DOI: 10.1007/s11302-020-09698-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Bone marrow (BM) as an active hematopoietic organ is highly sensitive to changes in body microenvironments and responds to external physical stimuli from the surrounding environment. In particular, BM tissue responds to several cues related to infections, strenuous exercise, tissue/organ damage, circadian rhythms, and physical challenges such as irradiation. These multiple stimuli affect BM cells to a large degree through a coordinated response of the innate immunity network as an important guardian for maintaining homeostasis of the body. In this review, we will foc++us on the role of purinergic signaling and innate immunity in the trafficking of hematopoietic stem/progenitor cells (HSPCs) during their egression from the BM into peripheral blood (PB), as seen along pharmacological mobilization, and in the process of homing and subsequent engraftment into BM after hematopoietic transplantation. Innate immunity mediates these processes by engaging, in addition to certain peptide-based factors, other important non-peptide mediators, including bioactive phosphosphingolipids and extracellular nucleotides, as the main topic of this review. Elucidation of these mechanisms will allow development of more efficient stem cell mobilization protocols to harvest the required number of HSPCs for transplantation and to accelerate hematopoietic reconstitution in transplanted patients.
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Affiliation(s)
- Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine Medical, University of Warsaw, Warsaw, Poland.
| | - Mateusz Adamiak
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine Medical, University of Warsaw, Warsaw, Poland
| | - Kamila Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
| | - Arjun Thapa
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
| | - Valentina Pensato
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
| | - Magda Kucia
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
- Center for Preclinical Studies and Technology, Department of Regenerative Medicine Medical, University of Warsaw, Warsaw, Poland
| | - Janina Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Professor Lineu Prestes 748, Sao Paulo, SP, 05508-000, Brazil.
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22
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Adenosine Deaminase as a Biomarker of Tenofovir Mediated Inflammation in Naïve HIV Patients. Int J Mol Sci 2020; 21:ijms21103590. [PMID: 32438744 PMCID: PMC7278965 DOI: 10.3390/ijms21103590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/15/2020] [Accepted: 05/18/2020] [Indexed: 01/04/2023] Open
Abstract
Plasma levels of adenosine deaminase (ADA), an enzyme that deaminates adenosine to inosine, are increased during inflammation. An increase in ADA activity occurs with lower human immunodeficiency virus (HIV) viral load and higher CD4+ T cell counts. We aimed to investigate the role of plasma ADA as a biomarker of inflammation in treatment-naïve HIV patients who received tenofovir or another nucleoside analog for comparison. Ninety-two treatment-naïve patients were included in the study and grouped by treatment, i.e., tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) or Triumeq. ADA activity was measured in plasma and cytokines were analyzed by MILLIPLEX® MAP-Luminex® Technology. Plasma concentration of monocytes and neutrophils was measured at 0, 3, and 12 months post-treatment. Treatment-naïve HIV patients had increased ADA concentrations (over 15 U/L) that decreased after treatment with TAF and Triumeq, though this did not occur in TDF-treated patients. However, all groups exhibited a pro-inflammatory systemic profile at 12 months of treatment. Plasma GM-CSF levels decreased after 12 months of treatment in the TDF group, with a concomitant decrease in blood monocyte count, and a negative correlation with ADA values was found. In conclusion, ADA levels may be modulated by antiretroviral therapy in HIV patients, possibly affecting inflammatory status.
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23
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de Leve S, Wirsdörfer F, Jendrossek V. The CD73/Ado System-A New Player in RT Induced Adverse Late Effects. Cancers (Basel) 2019; 11:cancers11101578. [PMID: 31623231 PMCID: PMC6827091 DOI: 10.3390/cancers11101578] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 10/11/2019] [Accepted: 10/12/2019] [Indexed: 02/06/2023] Open
Abstract
Radiotherapy (RT) is a central component of standard treatment for many cancer patients. RT alone or in multimodal treatment strategies has a documented contribution to enhanced local control and overall survival of cancer patients, and cancer cure. Clinical RT aims at maximizing tumor control, while minimizing the risk for RT-induced adverse late effects. However, acute and late toxicities of IR in normal tissues are still important biological barriers to successful RT: While curative RT may not be tolerable, sub-optimal tolerable RT doses will lead to fatal outcomes by local recurrence or metastatic disease, even when accepting adverse normal tissue effects that decrease the quality of life of irradiated cancer patients. Technical improvements in treatment planning and the increasing use of particle therapy have allowed for a more accurate delivery of IR to the tumor volume and have thereby helped to improve the safety profile of RT for many solid tumors. With these technical and physical strategies reaching their natural limits, current research for improving the therapeutic gain of RT focuses on innovative biological concepts that either selectively limit the adverse effects of RT in normal tissues without protecting the tumor or specifically increase the radiosensitivity of the tumor tissue without enhancing the risk of normal tissue complications. The biology-based optimization of RT requires the identification of biological factors that are linked to differential radiosensitivity of normal or tumor tissues, and are amenable to therapeutic targeting. Extracellular adenosine is an endogenous mediator critical to the maintenance of homeostasis in various tissues. Adenosine is either released from stressed or injured cells or generated from extracellular adenine nucleotides by the concerted action of the ectoenzymes ectoapyrase (CD39) and 5′ ectonucleotidase (NT5E, CD73) that catabolize ATP to adenosine. Recent work revealed a role of the immunoregulatory CD73/adenosine system in radiation-induced fibrotic disease in normal tissues suggesting a potential use as novel therapeutic target for normal tissue protection. The present review summarizes relevant findings on the pathologic roles of CD73 and adenosine in radiation-induced fibrosis in different organs (lung, skin, gut, and kidney) that have been obtained in preclinical models and proposes a refined model of radiation-induced normal tissue toxicity including the disease-promoting effects of radiation-induced activation of CD73/adenosine signaling in the irradiated tissue environment. However, expression and activity of the CD73/adenosine system in the tumor environment has also been linked to increased tumor growth and tumor immune escape, at least in preclinical models. Therefore, we will discuss the use of pharmacologic inhibition of CD73/adenosine-signaling as a promising strategy for improving the therapeutic gain of RT by targeting both, malignant tumor growth and adverse late effects of RT with a focus on fibrotic disease. The consideration of the therapeutic window is particularly important in view of the increasing use of RT in combination with various molecularly targeted agents and immunotherapy to enhance the tumor radiation response, as such combinations may result in increased or novel toxicities, as well as the increasing number of cancer survivors.
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Affiliation(s)
- Simone de Leve
- Institute of Cell Biology (Cancer Research), University Hospital Essen, 45122 Essen, Germany.
| | - Florian Wirsdörfer
- Institute of Cell Biology (Cancer Research), University Hospital Essen, 45122 Essen, Germany.
| | - Verena Jendrossek
- Institute of Cell Biology (Cancer Research), University Hospital Essen, 45122 Essen, Germany.
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24
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Li L, Zhao J, Zhou L, Chen J, Ma Y, Yu Y, Cheng J. Tenofovir alafenamide fumarate attenuates bleomycin-induced pulmonary fibrosis by upregulating the NS5ATP9 and TGF-β1/Smad3 signaling pathway. Respir Res 2019; 20:163. [PMID: 31331325 PMCID: PMC6647111 DOI: 10.1186/s12931-019-1102-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 06/18/2019] [Indexed: 02/06/2023] Open
Abstract
Background Pulmonary fibrosis is a progressive and irreversible disease for which therapeutic options are currently limited. A recent in vivo study showed that tenofovir, a nucleotide analogue reverse transcriptase inhibitor, had direct antifibrotic effects on skin and liver fibrosis. Another study in vitro revealed that NS5ATP9 inhibited the activation of human hepatic stellate cells. Because of the similarity of fibrotic diseases, we hypothesized that tenofovir alafenamide fumarate (TAF), the prodrug of tenofovir, and NS5ATP9, is related to and plays a role in the suppression of pulmonary fibrosis. Methods We investigated the influence of NS5ATP9 on fibrosis in vitro. Human lung fibroblasts (HFL1) were transfected with short interfering RNAs or overexpression plasmids of NS5ATP9 before stimulation by human recombinant transforming growth factor-β1. The effect of TAF was evaluated in a bleomycin-induced fibrosis murine model. Male C57BL/6 mice were treated with bleomycin on day 0 by intratracheal injection and intragastrically administered TAF or vehicle. Left lung sections were fixed for histological analysis, while homogenates of the right lung sections and HFL1 cells were analyzed by western blotting and quantitative reverse transcription polymerase chain reaction. Results NS5ATP9 suppressed the activation of lung fibroblasts. Upregulation of collagen type 3 (α 1 chain) and α-smooth muscle actin was observed in HFL1 cells when NS5ATP9 was silenced, and vice-versa. TAF also showed anti-fibrotic effects in mice, as demonstrated by histological analysis of fibrosis and expression of extracellular matrix components in the lung sections. Additionally, TAF inhibited transforming growth factor-β1 and phosphorylated-Smad3 synthesis in HFL1 cells and the murine model, which was accompanied by upregulation of NS5ATP9. Conclusions Our results suggest that NS5ATP9 forms a negative feedback pathway in pulmonary fibrosis and TAF has anti-fibrotic properties as it upregulates the expression level of NS5ATP9. As TAF has been shown to be safe and well-tolerated in humans, TAF and NS5ATP9 may be useful for developing novel therapeutics for pulmonary fibrosis. Electronic supplementary material The online version of this article (10.1186/s12931-019-1102-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lingxia Li
- Department of Infectious Diseases, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing, 100034, China.,Peking University Ditan Teaching Hospital, Beijing 100015, China; Beijing; Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Jing Zhao
- Peking University Ditan Teaching Hospital, Beijing 100015, China; Beijing; Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Li Zhou
- Peking University Ditan Teaching Hospital, Beijing 100015, China; Beijing; Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China.,Department of Infectious Disease, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Jie Chen
- Peking University Ditan Teaching Hospital, Beijing 100015, China; Beijing; Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China.,Department of Infectious Disease, First Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Yuanyuan Ma
- Laboratory Animal Center, Peking University First Hospital, Beijing, 100034, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing, 100034, China.
| | - Jun Cheng
- Peking University Ditan Teaching Hospital, Beijing 100015, China; Beijing; Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China. .,Department of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, No.8 East Jingshun Street, Chaoyang District, Beijing, 100015, China.
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25
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Conesa-Buendía FM, Llamas-Granda P, Larrañaga-Vera A, Wilder T, Largo R, Herrero-Beaumont G, Cronstein B, Mediero A. Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice. J Bone Miner Res 2019; 34:923-938. [PMID: 30645771 DOI: 10.1002/jbmr.3665] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 12/04/2018] [Accepted: 01/05/2019] [Indexed: 12/19/2022]
Abstract
Osteopenia and fragility fractures have been associated with human immunodeficiency virus (HIV) infection. Tenofovir, a common antiviral in HIV treatment, also leads to increases in bone catabolism markers and decreased BMD in children and young adults. In murine models and human cell lines, tenofovir inhibits adenosine triphosphate release and decreases extracellular adenosine levels. Adenosine and adenosine A2A receptor inhibit osteoclast formation, and increase local adenosine concentration with dipyridamole, an agent that blocks adenosine cellular uptake and stimulates new bone formation as well as bone morphogenic protein 2. We hypothesized that tenofovir regulates bone resorption by diminishing endogenous adenosine levels and questioned whether dipyridamole may be a useful treatment to counteract the deleterous bone effects of tenofovir. Primary murine osteoclasts were induced by M-CSF/RANKL, and the number of TRAP-positive-cells was studied after challenge with tenofovir alone or in combination with dipyridamole. Differentiation markers were studied by RT-PCR and MAPK/NFkB expression by Western blot. Male C57Bl/6 mice were treated as follows: saline 0.9% (control), tenofovir 75 mg/kg/day, dipyridamole 25 mg/kg/day, combination tenofovir/dipyridamole (n = 10, 4 weeks). Calcein/Alizarin Red-labeling of newly formed bone was used, and long bones were prepared for micro-computed tomography (μCT)/histology. Tenofovir produced a dose-dependent increase in osteoclast differentiation (EC50 = 44.5nM) that was reversed by dipyridamole (IC50 = 0.3 μM). Tenofovir increased cathepsin K and NFATc1 mRNA levels and dipyridamole reversed the effect. Dipyridamole reversed the effect of tenofovir on pERK1/2, pp38, and NFkB nuclear translocation. Mice treated with tenofovir lost nearly 10% of their body weight (p < 0.001). μCT revealed decreased BMD and altered trabecular bone in tenofovir-treated mice, reversed by dipyridamole. TRAP-staining showed increased osteoclasts in tenofovir-treated mice (p < 0.005), an effect reversed by dipyridamole. Similar results were obtained for cathepsin K and CD68. RANKL-positive cells were increased in tenofovir-treated mice, whereas osteoprotegerin-positive cells were decreased; both effects were reversed by dipyridamole. These results suggest that treatment with agents that increase local adenosine concentrations, like dipyridamole, might prevent bone loss following tenofovir treatment. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
| | | | - Ane Larrañaga-Vera
- Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, NY, USA
| | - Tuere Wilder
- Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, NY, USA
| | - Raquel Largo
- Bone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | | | - Bruce Cronstein
- Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, NY, USA
| | - Aránzazu Mediero
- Bone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain.,Division of Translational Medicine, Department of Medicine, NYU School of Medicine, New York, NY, USA
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26
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Hernández-Guerra M, Hadjihambi A, Jalan R. Gap junctions in liver disease: Implications for pathogenesis and therapy. J Hepatol 2019; 70:759-772. [PMID: 30599172 DOI: 10.1016/j.jhep.2018.12.023] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 12/03/2018] [Accepted: 12/12/2018] [Indexed: 02/07/2023]
Abstract
In the normal liver, cells interact closely through gap junctions. By providing a pathway for the trafficking of low molecular mass molecules, these channels contribute to tissue homeostasis and maintenance of hepatic function. Thus, dysfunction of gap junctions affects a wide variety of liver processes, such as differentiation, cell death, inflammation and fibrosis. In fact, dysfunctional gap junctions have been implicated, for more than a decade, in cholestatic disease, hepatic cancer and cirrhosis. Additionally, in recent years there is an increasing body of evidence that these channels are also involved in other relevant and prevalent liver pathological processes, such as non-alcoholic fatty liver disease, acute liver injury and portal hypertension. In parallel to these new clinical implications the available data include controversial observations. Thus, a comprehensive overview is required to better understand the functional complexity of these pores. This paper will review the most recent knowledge concerning gap junction dysfunction, with a special focus on the role of these channels in the pathogenesis of relevant clinical entities and on potential therapeutic targets that are amenable to modification by drugs.
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Affiliation(s)
| | | | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Royal Free Medical School, London, UK
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27
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Temelkova I, Patterson JW, Tchernev G. Scleromyxedema (Arndt - Gottron Syndrome) Developing Under Tenofovir Treatment for Hepatitis B: Unique Presentation in a Bulgarian Patient! Open Access Maced J Med Sci 2019; 7:782-785. [PMID: 30962839 PMCID: PMC6447340 DOI: 10.3889/oamjms.2019.181] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/17/2019] [Accepted: 02/18/2019] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND: Scleromyxedema, also referred to as the Arndt-Gottron (S-AG) syndrome or the systemic form of Lichen myxedematosus (LM), is a cutaneous mucinosis with a chronic course and high lethality from systemic involvement of other organs and systems. Interesting in several aspects is the association between scleromyxedema and viral hepatitis about: 1) hepatitis virus infection as a possible etiological factor for the development of scleromyxedema, 2) antiretroviral therapy for the treatment of hepatitis as a method of reversing scleromyxedema and 3) antiviral drugs as inducers of scleromyxedema. CASE REPORT: We present a 53-year old patient who for nine months had been on tenofovir disoproxil 245 mg (0-0-1) therapy for chronic hepatitis B. Three months after the start of antiviral therapy (i.e. for a period of 6 months), the patient observed swelling, itching and hardening of the skin on the face, ears and hands, which subsequently spread throughout the trunk. Subsequent histological study of a skin biopsy revealed changes of scleromyxedema at an advanced stage, though immunoelectrophoresis of serum and urine excluded the presence of paraproteinaemia or para proteinuria. Systemic antihistamine and topical corticosteroid therapy were instituted. Bone involvement with possible plasmacytoma was excluded, and a myelogram showed evidence of an erythroblastic reaction of bone marrow. CONCLUSION: We believe that drug-induced scleromyxedema is a rare but possible phenomenon. We describe the first case of tenofovir-induced scleromyxedema within the framework of chronic hepatitis B treatment.
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Affiliation(s)
- Ivanka Temelkova
- Medical Institute of Ministry of Interior (MVR), Department of Dermatology, Venereology and Dermatologic Surgery, General Skobelev 79, 1606 Sofia, Bulgaria.,Onkoderma - Clinic for Dermatology, Venereology and Dermatologic Surgery, General Skobelev 26, 1606 Sofia, Bulgaria
| | - James W Patterson
- Department of Pathology, University of Virginia Health System, 1215 Lee Street, Box 800214, Charlottesville, VA 22908, Virginia, United States
| | - Georgi Tchernev
- Medical Institute of Ministry of Interior (MVR), Department of Dermatology, Venereology and Dermatologic Surgery, General Skobelev 79, 1606 Sofia, Bulgaria.,Onkoderma - Clinic for Dermatology, Venereology and Dermatologic Surgery, General Skobelev 26, 1606 Sofia, Bulgaria
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28
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Cooreman A, Van Campenhout R, Ballet S, Annaert P, Van Den Bossche B, Colle I, Cogliati B, Vinken M. Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease. Hepatology 2019; 69:1317-1323. [PMID: 30300925 DOI: 10.1002/hep.30306] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 09/17/2018] [Indexed: 12/20/2022]
Abstract
Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin-like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin-based and pannexin-based channels in noncancerous liver disease.
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Affiliation(s)
- Axelle Cooreman
- Department of Toxicology, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Steven Ballet
- Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Pieter Annaert
- Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium
| | - Bert Van Den Bossche
- Department of Abdominal Surgery and Hepato-Pancreatico-Biliary Surgery, Algemeen Stedelijk Ziekenhuis Campus Aalst, Aalst, Belgium
| | - Isabelle Colle
- Department of Hepatology and Gastroenterology, Algemeen Stedelijk Ziekenhuis Campus Aalst, Aalst, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Mathieu Vinken
- Department of Toxicology, Vrije Universiteit Brussel, Brussels, Belgium
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29
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Liu Z, Li C, Kang N, Malhi H, Shah VH, Maiers JL. Transforming growth factor β (TGFβ) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation. J Biol Chem 2019; 294:3137-3151. [PMID: 30610118 PMCID: PMC6398135 DOI: 10.1074/jbc.ra118.005761] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 01/02/2019] [Indexed: 12/13/2022] Open
Abstract
Transforming growth factor β (TGFβ) potently activates hepatic stellate cells (HSCs), which promotes production and secretion of extracellular matrix (ECM) proteins and hepatic fibrogenesis. Increased ECM synthesis and secretion in response to TGFβ is associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). TGFβ and UPR signaling pathways are tightly intertwined during HSC activation, but the regulatory mechanism that connects these two pathways is poorly understood. Here, we found that TGFβ treatment of immortalized HSCs (i.e. LX-2 cells) induces phosphorylation of the UPR sensor inositol-requiring enzyme 1α (IRE1α) in a SMAD2/3-procollagen I-dependent manner. We further show that IRE1α mediates HSC activation downstream of TGFβ and that its role depends on activation of a signaling cascade involving apoptosis signaling kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK). ASK1-JNK signaling promoted phosphorylation of the UPR-associated transcription factor CCAAT/enhancer binding protein β (C/EBPβ), which is crucial for TGFβ- or IRE1α-mediated LX-2 activation. Pharmacological inhibition of C/EBPβ expression with the antiviral drug adefovir dipivoxil attenuated TGFβ-mediated activation of LX-2 or primary rat HSCs in vitro and hepatic fibrogenesis in vivo Finally, we identified a critical relationship between C/EBPβ and the transcriptional regulator p300 during HSC activation. p300 knockdown disrupted TGFβ- or UPR-induced HSC activation, and pharmacological inhibition of the C/EBPβ-p300 complex decreased TGFβ-induced HSC activation. These results indicate that TGFβ-induced IRE1α signaling is critical for HSC activation through a C/EBPβ-p300-dependent mechanism and suggest C/EBPβ as a druggable target for managing fibrosis.
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Affiliation(s)
- Zhikui Liu
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
| | - Chao Li
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
| | - Ningling Kang
- Tumor Microenvironment and Metastasis, Hormel Institute, University of Minnesota, Austin, Minnesota 55912
| | - Harmeet Malhi
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
| | - Vijay H Shah
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
| | - Jessica L Maiers
- From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 and
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30
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Cerrone M, van Opbergen CJM, Malkani K, Irrera N, Zhang M, Van Veen TAB, Cronstein B, Delmar M. Blockade of the Adenosine 2A Receptor Mitigates the Cardiomyopathy Induced by Loss of Plakophilin-2 Expression. Front Physiol 2018; 9:1750. [PMID: 30568602 PMCID: PMC6290386 DOI: 10.3389/fphys.2018.01750] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 11/20/2018] [Indexed: 12/13/2022] Open
Abstract
Background: Mutations in plakophilin-2 (PKP2) are the most common cause of familial Arrhythmogenic Right Ventricular Cardiomyopathy, a disease characterized by ventricular arrhythmias, sudden death, and progressive fibrofatty cardiomyopathy. The relation between loss of PKP2 expression and structural cardiomyopathy remains under study, though paracrine activation of pro-fibrotic intracellular signaling cascades is a likely event. Previous studies have indicated that ATP release into the intracellular space, and activation of adenosine receptors, can regulate fibrosis in various tissues. However, the role of this mechanism in the heart, and in the specific case of a PKP2-initiated cardiomyopathy, remains unexplored. Objectives: To investigate the role of ATP/adenosine in the progression of a PKP2-associated cardiomyopathy. Methods: HL1 cells were used to study PKP2- and Connexin43 (Cx43)-dependent ATP release. A cardiac-specific, tamoxifen-activated PKP2 knock-out murine model (PKP2cKO) was used to define the effect of adenosine receptor blockade on the progression of a PKP2-dependent cardiomyopathy. Results: HL1 cells silenced for PKP2 showed increased ATP release compared to control. Knockout of Cx43 in the same cells blunted the effect. PKP2cKO transcriptomic data revealed overexpression of genes involved in adenosine-receptor cascades. Istradefylline (an adenosine 2A receptor blocker) tempered the progression of fibrosis and mechanical failure observed in PKP2cKO mice. In contrast, PSB115, a blocker of the 2B adenosine receptor, showed opposite effects. Conclusion: Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2. Given the limitations of the animal model, translation to the case of patients with PKP2 deficiency needs to be done with caution.
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Affiliation(s)
- Marina Cerrone
- Leon H. Charney Division of Cardiology, NYU School of Medicine, New York, NY, United States
| | - Chantal J M van Opbergen
- Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands
| | - Kabir Malkani
- Leon H. Charney Division of Cardiology, NYU School of Medicine, New York, NY, United States
| | - Natasha Irrera
- Division of Translational Medicine, NYU School of Medicine, New York, NY, United States.,Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Mingliang Zhang
- Leon H. Charney Division of Cardiology, NYU School of Medicine, New York, NY, United States
| | - Toon A B Van Veen
- Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands
| | - Bruce Cronstein
- Division of Translational Medicine, NYU School of Medicine, New York, NY, United States
| | - Mario Delmar
- Leon H. Charney Division of Cardiology, NYU School of Medicine, New York, NY, United States
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ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract. Int J Mol Sci 2018; 19:ijms19082371. [PMID: 30103545 PMCID: PMC6121306 DOI: 10.3390/ijms19082371] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 08/02/2018] [Accepted: 08/06/2018] [Indexed: 12/12/2022] Open
Abstract
Extracellular nucleotides, such as adenosine triphosphate (ATP), are released from host cells including nerve termini, immune cells, injured or dead cells, and the commensal bacteria that reside in the gut lumen. Extracellular ATP interacts with the host through purinergic receptors, and promotes intercellular and bacteria-host communication to maintain the tissue homeostasis. However, the release of massive concentrations of ATP into extracellular compartments initiates acute and chronic inflammatory responses through the activation of immunocompetent cells (e.g., T cells, macrophages, and mast cells). In this review, we focus on the functions of ATP as a pathophysiologic mediator that is required for the induction and resolution of inflammation and inter-species communication.
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