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1
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Li C, Wang B. Role of P2X7R in Retinal Diseases: A Review. Immun Inflamm Dis 2025; 13:e70203. [PMID: 40396593 DOI: 10.1002/iid3.70203] [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: 01/04/2025] [Revised: 03/16/2025] [Accepted: 04/25/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND P2X purinoceptor 7 receptor (P2X7R) is an ATP-gated ion channel that, upon activation by ATP, triggers the release of inflammatory mediators and induces apoptosis in cells. This channel plays a crucial role in the onset and progression of various diseases. Recently, there has been a growing body of research focused on the function of P2X7R receptors in ophthalmic conditions, particularly concerning retinal diseases such as age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. OBJECTIVE This article is to provide a comprehensive review of the advancements in the study of P2X7R and its association with retinal diseases, elucidating its role in these conditions and identifying potential avenues for future research. METHODS Electronic databases, including PubMed, Web of Science, and Wan fang Data were searched for relevant literature. The following keywords were used: "P2X7R", Age-related macular degeneration", "Diabetic retinopathy", "Retinitis pigmentosa". Both preclinical and clinical studies were included to provide a holistic understanding of P2X7R's role in retinal pathology. RESULTS P2X7R activation exacerbates retinal diseases by promoting inflammation and apoptosis. However, its role in disease progression and homeostasis complicates therapeutic targeting, highlighting the need for selective inhibitors and further research into its context-dependent functions. CONCLUSION P2X7R plays a critical role in the pathogenesis of retinal diseases. At the same time, preclinical studies suggest that P2X7R inhibition holds promise as a therapeutic strategy. Future research should focus on developing selective P2X7R inhibitors, elucidating the receptor's role in different disease stages, and identifying biomarkers to guide personalized treatment. Addressing these challenges will be essential for translating P2X7R-targeted therapies into clinical practice and improving outcomes for patients with retinal diseases.
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Affiliation(s)
- Chunli Li
- Department of Ophthalmology, The Second Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Binsheng Wang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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2
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Olivier E, Rat P. Role of Oxysterols in Ocular Degeneration Mechanisms and Involvement of P2X7 Receptor. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:277-292. [PMID: 38036885 DOI: 10.1007/978-3-031-43883-7_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Ocular degeneration, including cataracts, glaucoma, macular degeneration, and diabetic retinopathy, is a major public health challenge, as it affects the quality of life of millions of people worldwide and, in its advanced stages, leads to blindness. Ocular degeneration, although it can affect different parts of the eye, shares common characteristics such as oxysterols and the P2X7 receptor. Indeed, oxysterols, which are cholesterol derivatives, are associated with ocular degeneration pathogenesis and trigger inflammation and cell death pathways. Activation of the P2X7 receptor is also linked to ocular degeneration and triggers the same pathways. In age-related macular degeneration, these two key players have been associated, but further studies are needed to extrapolate this interrelationship to other ocular degenerations.
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Affiliation(s)
| | - Patrice Rat
- Université Paris Cité, CNRS, CiTCoM, Paris, France
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3
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Elbaz-Hayoun S, Rinsky B, Hagbi-Levi S, Grunin M, Chowers I. CCR1 mediates Müller cell activation and photoreceptor cell death in macular and retinal degeneration. eLife 2023; 12:e81208. [PMID: 37903056 PMCID: PMC10615370 DOI: 10.7554/elife.81208] [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: 06/19/2022] [Accepted: 10/04/2023] [Indexed: 11/01/2023] Open
Abstract
Mononuclear cells are involved in the pathogenesis of retinal diseases, including age-related macular degeneration (AMD). Here, we examined the mechanisms that underlie macrophage-driven retinal cell death. Monocytes were extracted from patients with AMD and differentiated into macrophages (hMdɸs), which were characterized based on proteomics, gene expression, and ex vivo and in vivo properties. Using bioinformatics, we identified the signaling pathway involved in macrophage-driven retinal cell death, and we assessed the therapeutic potential of targeting this pathway. We found that M2a hMdɸs were associated with retinal cell death in retinal explants and following adoptive transfer in a photic injury model. Moreover, M2a hMdɸs express several CCRI (C-C chemokine receptor type 1) ligands. Importantly, CCR1 was upregulated in Müller cells in models of retinal injury and aging, and CCR1 expression was correlated with retinal damage. Lastly, inhibiting CCR1 reduced photic-induced retinal damage, photoreceptor cell apoptosis, and retinal inflammation. These data suggest that hMdɸs, CCR1, and Müller cells work together to drive retinal and macular degeneration, suggesting that CCR1 may serve as a target for treating these sight-threatening conditions.
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Affiliation(s)
- Sarah Elbaz-Hayoun
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
| | - Batya Rinsky
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
| | - Shira Hagbi-Levi
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
| | - Michelle Grunin
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
| | - Itay Chowers
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of JerusalemJerusalemIsrael
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4
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Lepre CC, Russo M, Trotta MC, Petrillo F, D'Agostino FA, Gaudino G, D'Amico G, Campitiello MR, Crisci E, Nicoletti M, Gesualdo C, Simonelli F, D'Amico M, Hermenean A, Rossi S. Inhibition of Galectins and the P2X7 Purinergic Receptor as a Therapeutic Approach in the Neurovascular Inflammation of Diabetic Retinopathy. Int J Mol Sci 2023; 24:ijms24119721. [PMID: 37298672 DOI: 10.3390/ijms24119721] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/30/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023] Open
Abstract
Diabetic retinopathy (DR) is the most frequent microvascular retinal complication of diabetic patients, contributing to loss of vision. Recently, retinal neuroinflammation and neurodegeneration have emerged as key players in DR progression, and therefore, this review examines the neuroinflammatory molecular basis of DR. We focus on four important aspects of retinal neuroinflammation: (i) the exacerbation of endoplasmic reticulum (ER) stress; (ii) the activation of the NLRP3 inflammasome; (iii) the role of galectins; and (iv) the activation of purinergic 2X7 receptor (P2X7R). Moreover, this review proposes the selective inhibition of galectins and the P2X7R as a potential pharmacological approach to prevent the progression of DR.
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Affiliation(s)
- Caterina Claudia Lepre
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 310144 Arad, Romania
| | - Marina Russo
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Francesco Petrillo
- Ph.D. Course in Translational Medicine, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Fabiana Anna D'Agostino
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Gennaro Gaudino
- School of Anesthesia and Intensive Care, University of Foggia, 71122 Foggia, Italy
| | | | - Maria Rosaria Campitiello
- Department of Obstetrics and Gynecology and Physiopathology of Human Reproduction, ASL Salerno, 84124 Salerno, Italy
| | - Erminia Crisci
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Maddalena Nicoletti
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Carlo Gesualdo
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Francesca Simonelli
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Michele D'Amico
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Anca Hermenean
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 310144 Arad, Romania
| | - Settimio Rossi
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
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5
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Martínez-Gil N, Kutsyr O, Noailles A, Fernández-Sánchez L, Vidal L, Sánchez-Sáez X, Sánchez-Castillo C, Lax P, Cuenca N, García AG, Maneu V. Purinergic Receptors P2X7 and P2X4 as Markers of Disease Progression in the rd10 Mouse Model of Inherited Retinal Dystrophy. Int J Mol Sci 2022; 23:ijms232314758. [PMID: 36499084 PMCID: PMC9739106 DOI: 10.3390/ijms232314758] [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: 10/23/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/29/2022] Open
Abstract
The purinergic receptor P2X7 (P2X7R) is implicated in all neurodegenerative diseases of the central nervous system. It is also involved in the retinal degeneration associated with glaucoma, age-related macular degeneration, and diabetic retinopathy, and its overexpression in the retina is evident in these disorders. Retinitis pigmentosa is a progressive degenerative disease that ultimately leads to blindness. Here, we investigated the expression of P2X7R during disease progression in the rd10 mouse model of RP. As the purinergic receptor P2X4 is widely co-expressed with P2X7R, we also studied its expression in the retina of rd10 mice. The expression of P2X7R and P2X4R was examined by immunohistochemistry, flow cytometry, and western blotting. In addition, we analyzed retinal functionality by electroretinographic recordings of visual responses and optomotor tests and retinal morphology. We found that the expression of P2X7R and P2X4R increased in rd10 mice concomitant with disease progression, but with different cellular localization. Our findings suggest that P2X7R and P2X4R might play an important role in RP progression, which should be further analyzed for the pharmacological treatment of inherited retinal dystrophies.
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Affiliation(s)
- Natalia Martínez-Gil
- Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03690 Alicante, Spain
| | - Oksana Kutsyr
- Departamento de Óptica, Farmacología y Anatomía, Universidad de Alicante, 03690 Alicante, Spain
| | - Agustina Noailles
- Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03690 Alicante, Spain
| | - Laura Fernández-Sánchez
- Departamento de Óptica, Farmacología y Anatomía, Universidad de Alicante, 03690 Alicante, Spain
| | - Lorena Vidal
- Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03690 Alicante, Spain
| | - Xavier Sánchez-Sáez
- Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03690 Alicante, Spain
| | - Carla Sánchez-Castillo
- Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03690 Alicante, Spain
| | - Pedro Lax
- Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03690 Alicante, Spain
| | - Nicolás Cuenca
- Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03690 Alicante, Spain
| | - Antonio G. García
- Departamento de Farmacología y Terapéutica, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
- Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, 28006 Madrid, Spain
| | - Victoria Maneu
- Departamento de Óptica, Farmacología y Anatomía, Universidad de Alicante, 03690 Alicante, Spain
- Correspondence:
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6
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MicroRNA-150 (miR-150) and Diabetic Retinopathy: Is miR-150 Only a Biomarker or Does It Contribute to Disease Progression? Int J Mol Sci 2022; 23:ijms232012099. [PMID: 36292956 PMCID: PMC9603433 DOI: 10.3390/ijms232012099] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/05/2022] [Accepted: 10/06/2022] [Indexed: 11/18/2022] Open
Abstract
Diabetic retinopathy (DR) is a chronic disease associated with diabetes mellitus and is a leading cause of visual impairment among the working population in the US. Clinically, DR has been diagnosed and treated as a vascular complication, but it adversely impacts both neural retina and retinal vasculature. Degeneration of retinal neurons and microvasculature manifests in the diabetic retina and early stages of DR. Retinal photoreceptors undergo apoptosis shortly after the onset of diabetes, which contributes to the retinal dysfunction and microvascular complications leading to vision impairment. Chronic inflammation is a hallmark of diabetes and a contributor to cell apoptosis, and retinal photoreceptors are a major source of intraocular inflammation that contributes to vascular abnormalities in diabetes. As the levels of microRNAs (miRs) are changed in the plasma and vitreous of diabetic patients, miRs have been suggested as biomarkers to determine the progression of diabetic ocular diseases, including DR. However, few miRs have been thoroughly investigated as contributors to the pathogenesis of DR. Among these miRs, miR-150 is downregulated in diabetic patients and is an endogenous suppressor of inflammation, apoptosis, and pathological angiogenesis. In this review, how miR-150 and its downstream targets contribute to diabetes-associated retinal degeneration and pathological angiogenesis in DR are discussed. Currently, there is no effective treatment to stop or reverse diabetes-caused neural and vascular degeneration in the retina. Understanding the molecular mechanism of the pathogenesis of DR may shed light for the future development of more effective treatments for DR and other diabetes-associated ocular diseases.
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7
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Bianca Maria Platania C, Drago F, Bucolo C. The P2X7 receptor as a new pharmacological target for retinal diseases. Biochem Pharmacol 2022; 198:114942. [PMID: 35134386 DOI: 10.1016/j.bcp.2022.114942] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 11/02/2022]
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8
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miRNA signatures in diabetic retinopathy and nephropathy: delineating underlying mechanisms. J Physiol Biochem 2022; 78:19-37. [DOI: 10.1007/s13105-021-00867-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022]
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9
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Mugisho OO, Green CR. The NLRP3 inflammasome in age-related eye disease: Evidence-based connexin hemichannel therapeutics. Exp Eye Res 2021; 215:108911. [PMID: 34958779 DOI: 10.1016/j.exer.2021.108911] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/25/2021] [Accepted: 12/21/2021] [Indexed: 12/21/2022]
Abstract
The inflammasome pathway is a fundamental component of the innate immune system, playing a key role especially in chronic age-related eye diseases (AREDs). The inflammasome is of particular interest because it is a common disease pathway that once instigated, can amplify and perpetuate itself leading to chronic inflammation. With aging, it becomes more difficult to shut down inflammation after an insult but the common pathway means that a shared solution may be feasible that could be effective across multiple disease indications. This review focusses on the NLRP3 inflammasome, the most studied and characterized inflammasome in the eye. It describes the two-step signalling required for NLRP3 inflammasome complex activation, and provides evidence for its role in AREDs. In the final section, the article gives an overview of potential NLRP3 inflammasome targeting therapies, before presenting evidence for connexin hemichannel regulators as upstream blockers of inflammasome activation. These have shown therapeutic efficacy in multiple ocular disease models.
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Affiliation(s)
- Odunayo O Mugisho
- 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, New Zealand
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10
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The P2X7 Receptor: A Promising Pharmacological Target in Diabetic Retinopathy. Int J Mol Sci 2021; 22:ijms22137110. [PMID: 34281162 PMCID: PMC8268192 DOI: 10.3390/ijms22137110] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/25/2021] [Accepted: 06/29/2021] [Indexed: 12/29/2022] Open
Abstract
Diabetes is a worldwide emergency. Its chronic complications impose a heavy burden on patients, health systems, and on society as a whole. Diabetic retinopathy is one of the most common and serious complications of diabetes, and an established risk factor for blindness in adults. Over 15 years of investigation led to the identification of vascular endothelial growth factor (VEGF) as a main pathogenic factor in diabetic retinopathy and to the introduction of highly effective anti-VEGF-based therapies, such as the monoclonal antibody bevacizumab or its fragment ranibizumab, which helped to prevent diabetes-related blindness in millions of patients. Recently, a pathogenic role for uncontrolled increases in the extracellular ATP concentration (eATP) and for overactivation of the purinergic receptor P2X7 (P2X7R) has been suggested. The P2X7R is an eATP-gated plasma membrane channel expressed in multiple tissues and organs, with a pleiotropic function in inflammation, immunity, cancer, and hormone and growth factor release. P2X7R stimulation or overexpression positively regulate the secretion and buildup of VEGF, thus promoting neo-angiogenesis in a wide variety of disease processes. In this review, we explore current evidence that supports the role of P2X7R receptor signaling in the pathogenesis of diabetic retinopathy, as well as the most appealing current therapeutical options for P2X7R targeting.
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11
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Yang K, Liu J, Zhang X, Ren Z, Gao L, Wang Y, Lin W, Ma X, Hao M, Kuang H. H3 Relaxin Alleviates Migration, Apoptosis and Pyroptosis Through P2X7R-Mediated Nucleotide Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation in Retinopathy Induced by Hyperglycemia. Front Pharmacol 2020; 11:603689. [PMID: 33584279 PMCID: PMC7873867 DOI: 10.3389/fphar.2020.603689] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 10/16/2020] [Indexed: 12/11/2022] Open
Abstract
Introduction: P2X7R excitation-interrelated NLRP3 inflammasome activation induced by high glucose contributes to the pathogenesis of diabetic retinopathy (DR). Relaxin-3 is a bioactive peptide with a structure similar to insulin, which has been reported to be effective in diabetic cardiomyopathy models in vivo and in vitro. However, it is not known whether relaxin-3 has a beneficial impact on DR, and the underlying mechanisms of the effect are also remain unknown. Methods and Results: The retinas of male streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats were characterized. Human retinal microvascular endothelial cells (HRMECs) were used to evaluate the anti-inflammatory, antiapoptotic, antipyroptotic and anti-migration effects of H3 relaxin by transmission electron microscopy, wound-healing assay, transwell assay, flow cytometry, cytokine assays and western-blot analysis. After H3 relaxin treatment, changes of the ultrastructure and expression of NLRP3 inflammasome related proteins in the retinas of rats were compared with those in the diabetic group. In vitro, H3 relaxin played a beneficial role that decreased cell inflammation, apoptosis, pyroptosis and migration stimulated by advanced glycation end products (AGEs). Moreover, inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury that similar to the effects of H3 relaxin. H3 relaxin suppressed the stimulation of apoptosis, pyroptosis and migration of HRMECs in response to AGEs mediated by P2X7R activation of the NLRP3 inflammasome. Conclusion: Our findings provide new insights into the mechanisms of the inhibitory effect of H3 relaxin on AGE-induced retinal injury, including migration, apoptosis and pyroptosis, mediated by P2X7R-dependent activation of the NLRP3 inflammasome in HRMECs.
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Affiliation(s)
- Kelaier Yang
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiannan Liu
- The Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaohui Zhang
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ziqi Ren
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lei Gao
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ying Wang
- The Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenjian Lin
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuefei Ma
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ming Hao
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongyu Kuang
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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12
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Calzaferri F, Ruiz-Ruiz C, de Diego AMG, de Pascual R, Méndez-López I, Cano-Abad MF, Maneu V, de Los Ríos C, Gandía L, García AG. The purinergic P2X7 receptor as a potential drug target to combat neuroinflammation in neurodegenerative diseases. Med Res Rev 2020; 40:2427-2465. [PMID: 32677086 DOI: 10.1002/med.21710] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 06/22/2020] [Accepted: 06/27/2020] [Indexed: 12/25/2022]
Abstract
Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD.
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Affiliation(s)
- Francesco Calzaferri
- Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Cristina Ruiz-Ruiz
- Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Antonio M G de Diego
- Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.,Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
| | - Ricardo de Pascual
- Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Iago Méndez-López
- Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - María F Cano-Abad
- Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.,Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
| | - Victoria Maneu
- Departamento de Óptica, Farmacología y Anatomía, Universidad de Alicante, San Vicente del Raspeig, Spain
| | - Cristóbal de Los Ríos
- Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.,Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
| | - Luis Gandía
- Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Antonio G García
- Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.,Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
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13
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Coccurello R, Volonté C. P2X7 Receptor in the Management of Energy Homeostasis: Implications for Obesity, Dyslipidemia, and Insulin Resistance. Front Endocrinol (Lausanne) 2020; 11:199. [PMID: 32528404 PMCID: PMC7247848 DOI: 10.3389/fendo.2020.00199] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/19/2020] [Indexed: 12/15/2022] Open
Abstract
Whole-body energy metabolism entails the highly regulated balance between food intake, nutrient breakdown, energy generation (ATP), and energy storage for the preservation of vital functions and body mass. Purinergic signaling has attracted increasing attention in the regulatory mechanisms not only for the reverse processes of white adipose tissue lipogenesis and lipolysis, but also for brown adipocyte-dependent thermogenesis and leptin production. This regulatory role has remarkable implications in the handling of body's energy expenditure and energy reservoir. Hence, selected purinergic receptors can play a relevant function in lipid metabolism, endocrine activity, glucose uptake, ATP-dependent increased expression of uncoupling protein 1, and browning of adipose tissue. Indeed, purinergic P2 receptors regulate adipogenesis and lipid metabolism and are involved in adipogenic differentiation. In particular, the ionotropic ATP-activated P2X7 subtype is involved in fat distribution, as well as in the modulation of inflammatory pathways in white adipose tissue. Within this context, very recent evidence has established a direct function of P2X7 in energy metabolism. Specifically, either genetic deletion (P2X7 knockout mice) or subchronic pharmacological inhibition of the receptor produces a decrease of whole-body energy expenditure and, concurrently, an increase of carbohydrate oxidation. As further evidence, lipid accumulation, increased fat mass distribution, and weight gain are reported in P2X7-depleted mice. Conversely, the stimulation of P2X7 enhances energy expenditure. Altogether, this knowledge supports the role of P2X7 signaling in the fight against obesity and insulin resistance, as well as in the promotion of adaptive thermogenesis.
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Affiliation(s)
- Roberto Coccurello
- Institute for Complex System (ISC), National Research Council (CNR), Rome, Italy
- Preclinical Neuroscience, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Rome, Italy
| | - Cinzia Volonté
- Preclinical Neuroscience, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Rome, Italy
- Institute for Systems Analysis and Computer Science, National Research Council (CNR), Rome, Italy
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14
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Puro DG. How goblet cells respond to dry eye: adaptive and pathological roles of voltage-gated calcium channels and P2X 7 purinoceptors. Am J Physiol Cell Physiol 2020; 318:C1305-C1315. [PMID: 32348177 DOI: 10.1152/ajpcell.00086.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Dry eye is a common sight-impairing, painful disorder characterized by disruption of the preocular tear film, whose integrity is required for ~70% of the eye's refractive power. A universal feature of clinical dry eye is hyperosmolarity of the tears resulting from their accelerated evaporation due to dysfunction of tear- and oil-producing ocular glands. A key adaptive response to dryness/hyperosmolarity is release of tear-stabilizing mucin by conjunctival goblet cells. Yet the mechanisms mediating this response to hyperosmolarity remain poorly understood. In this study of freshly excised rat conjunctiva, perforated-patch recordings revealed that during sustained hyperosmolarity, the development of a nonspecific cation (NSC) conductance depolarizes the goblet cells to a near-optimal voltage for the tonic activation of their voltage-gated calcium channels (VGCCs). In turn, as demonstrated by high-resolution membrane capacitance measurements, VGCC activation boosts the exocytotic response of conjunctival goblet cells to neural input. However, over time, VGCC activation also increases the vulnerability of these cells to the lethality of hyperosmolarity. Viability assays further revealed that hyperosmotic-induced goblet cell death is critically dependent on P2X7 receptor channels. Similar to the yin-yang impact of VGCCs on goblet cell physiology and pathobiology, P2X7 activation not only compromises goblet cell viability but also enhances exocytotic activity. Thus, the NSC/VGCC and P2X7 purinoceptor pathways are components of a previously unappreciated high-gain/high-risk adaptive strategy to combat ocular dryness. These pathways boost release of tear-stabilizing mucin at the risk of jeopardizing the viability of the conjunctival goblet cells, whose loss is a histopathological hallmark of irreversible mucin-deficient dry eye.
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Affiliation(s)
- Donald G Puro
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan.,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
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15
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Subauste CS. The CD40-ATP-P2X 7 Receptor Pathway: Cell to Cell Cross-Talk to Promote Inflammation and Programmed Cell Death of Endothelial Cells. Front Immunol 2019; 10:2958. [PMID: 31921199 PMCID: PMC6928124 DOI: 10.3389/fimmu.2019.02958] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 12/02/2019] [Indexed: 12/15/2022] Open
Abstract
Extracellular adenosine 5′-triphosphate (ATP) functions not only as a neurotransmitter but is also released by non-excitable cells and mediates cell–cell communication involving glia. In pathological conditions, extracellular ATP released by astrocytes may act as a “danger” signal that activates microglia and promotes neuroinflammation. This review summarizes in vitro and in vivo studies that identified CD40 as a novel trigger of ATP release and purinergic-induced inflammation. The use of transgenic mice with expression of CD40 restricted to retinal Müller glia and a model of diabetic retinopathy (a disease where the CD40 pathway is activated) established that CD40 induces release of ATP in Müller glia and triggers in microglia/macrophages purinergic receptor-dependent inflammatory responses that drive the development of retinopathy. The CD40-ATP-P2X7 pathway not only amplifies inflammation but also induces death of retinal endothelial cells, an event key to the development of capillary degeneration and retinal ischemia. Taken together, CD40 expressed in non-hematopoietic cells is sufficient to mediate inflammation and tissue pathology as well as cause death of retinal endothelial cells. This process likely contributes to development of degenerate capillaries, a hallmark of diabetic and ischemic retinopathies. Blockade of signaling pathways downstream of CD40 operative in non-hematopoietic cells may offer a novel means of treating diabetic and ischemic retinopathies.
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Affiliation(s)
- Carlos S Subauste
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States.,Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
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16
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Blood-retinal barrier protection against high glucose damage: The role of P2X7 receptor. Biochem Pharmacol 2019; 168:249-258. [PMID: 31302133 DOI: 10.1016/j.bcp.2019.07.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 07/09/2019] [Indexed: 12/13/2022]
Abstract
Blood retinal barrier (BRB) breakdown is a hallmark of diabetic retinopathy, whose occurrence in early or later phases of the disease has not yet been completely clarified. Recent evidence suggests that hyperglycemia induces activation of the P2X7 receptor (P2X7R) leading to pericyte cell death. We herein investigated the role of P2X7R on retinal endothelial cells viability and expression of tight- and adherens-junctions following high glucose (HG) exposure. We found that HG elicited P2X7R activation and expression and release of the pro-inflammatory cytokine IL-1β in human retinal endothelial cells (HRECs). Furthermore, HG exposure caused a decrease in HRECs viability and a damage of the BRB. JNJ47965567, a P2X7R antagonist, protected HRECs from HG-induced damage (LDH release) and preserved the BRB, as shown by transendothelial electrical resistance and cell junction morphology (ZO-1, claudin-5 and VE-cadherin). Moreover, JNJ47965567 treatment significantly decreased IL-1β expression and release, elicited by HG. These data indicate that P2X7R plays an important role to regulate BRB integrity, in particular the block of this receptor was useful to counteract the damage elicited by HG in HRECs, and warranting further clinical evaluation of P2X7R antagonists for the treatment of diabetic macular edema.
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17
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Pérez de Lara MJ, Avilés-Trigueros M, Guzmán-Aránguez A, Valiente-Soriano FJ, de la Villa P, Vidal-Sanz M, Pintor J. Potential role of P2X7 receptor in neurodegenerative processes in a murine model of glaucoma. Brain Res Bull 2019; 150:61-74. [PMID: 31102752 DOI: 10.1016/j.brainresbull.2019.05.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 04/23/2019] [Accepted: 05/10/2019] [Indexed: 12/20/2022]
Abstract
Glaucoma is a common cause of visual impairment and blindness, characterized by retinal ganglion cell (RGC) death. The mechanisms that trigger the development of glaucoma remain unknown and have gained significant relevance in the study of this neurodegenerative disease. P2X7 purinergic receptors (P2X7R) could be involved in the regulation of the synaptic transmission and neuronal death in the retina through different pathways. The aim of this study was to characterize the molecular signals underlying glaucomatous retinal injury. The time-course of functional, morphological, and molecular changes in the glaucomatous retina of the DBA/2J mice were investigated. The expression and localization of P2X7R was analysed in relation with retinal markers. Caspase-3, JNK, and p38 were evaluated in control and glaucomatous mice by immunohistochemical and western-blot analysis. Furthermore, electroretinogram recordings (ERG) were performed to assess inner retina dysfunction. Glaucomatous mice exhibited changes in P2X7R expression as long as the pathology progressed. There was P2X7R overexpression in RGCs, the primary injured neurons, which correlated with the loss of function through ERG measurements. All analyzed MAPK and caspase-3 proteins were upregulated in the DBA/2J retinas suggesting a pro-apoptotic cell death. The increase in P2X7Rs presence may contribute, together with other factors, to the changes in retinal functionality and the concomitant death of RGCs. These findings provide evidence of possible intracellular pathways responsible for apoptosis regulation during glaucomatous degeneration.
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Affiliation(s)
- María J Pérez de Lara
- Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Complutense University of Madrid, c/Arcos de Jalón 118, E-28037, Madrid, Spain
| | - Marcelino Avilés-Trigueros
- Laboratory of Experimental Ophthalmology, Dept. of Ophthalmology, Faculty of Medicine, University of Murcia and Murcia Institute of Bio-Health Research (IMIB), E-30120, El Palmar, Murcia, Spain
| | - Ana Guzmán-Aránguez
- Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Complutense University of Madrid, c/Arcos de Jalón 118, E-28037, Madrid, Spain
| | - F Javier Valiente-Soriano
- Laboratory of Experimental Ophthalmology, Dept. of Ophthalmology, Faculty of Medicine, University of Murcia and Murcia Institute of Bio-Health Research (IMIB), E-30120, El Palmar, Murcia, Spain
| | - Pedro de la Villa
- Systems Biology Department, Faculty of Medicine, University of Alcalá, Alcalá de Henares, Madrid, Spain
| | - Manuel Vidal-Sanz
- Laboratory of Experimental Ophthalmology, Dept. of Ophthalmology, Faculty of Medicine, University of Murcia and Murcia Institute of Bio-Health Research (IMIB), E-30120, El Palmar, Murcia, Spain.
| | - Jesús Pintor
- Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Complutense University of Madrid, c/Arcos de Jalón 118, E-28037, Madrid, Spain
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18
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Xie J, Obiefuna V, Hodgkinson JW, McAllister M, Belosevic M. Teleost antimicrobial peptide hepcidin contributes to host defense of goldfish (Carassius auratus L.) against Trypanosoma carassii. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2019; 94:11-15. [PMID: 30659854 DOI: 10.1016/j.dci.2019.01.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/15/2019] [Accepted: 01/16/2019] [Indexed: 06/09/2023]
Abstract
Hepcidin is an antimicrobial peptide and an iron regulatory protein that prevents the release of excess iron in the blood. There is evidence suggesting that teleost hepcidin is a major player in antimicrobial defense against various bacteria species, but little is known regarding the effects of teleost hepcidin in protozoan parasitic infections. We examined the role of hepcidin during the course of infection of goldfish with Trypanosoma carassii. Quantitative real-time PCR was used to determine the expression of hepcidin in goldfish immune organs during the course of T. carassii infection. During the acute phase of the T. carassii infection, the mRNA levels of hepcidin were up-regulated in liver and kidney. In contrast, an up-regulation of hepcidin mRNA expression in spleen was observed during the chronic phase of the infection. Furthermore, a synthetic goldfish hepcidin peptide induced trypanosome lysis in vitro, and parasite surface disruption was confirmed by scanning electron microscopy (SEM) analysis. These results suggest that, in addition to well-characterized direct antibacterial activities, teleost hepcidin also exhibits trypanocidal activity.
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Affiliation(s)
- Jiasong Xie
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Victory Obiefuna
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Jordan W Hodgkinson
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Mark McAllister
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Miodrag Belosevic
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
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Pavlou S, Augustine J, Cunning R, Harkin K, Stitt AW, Xu H, Chen M. Attenuating Diabetic Vascular and Neuronal Defects by Targeting P2rx7. Int J Mol Sci 2019; 20:ijms20092101. [PMID: 31035433 PMCID: PMC6540042 DOI: 10.3390/ijms20092101] [Citation(s) in RCA: 12] [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: 03/29/2019] [Revised: 04/23/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023] Open
Abstract
Retinal vascular and neuronal degeneration are established pathological features of diabetic retinopathy. Data suggest that defects in the neuroglial network precede the clinically recognisable vascular lesions in the retina. Therefore, new treatments that target early-onset neurodegeneration would be expected to have great value in preventing the early stages of diabetic retinopathy. Here, we show that the nucleoside reverse transcriptase inhibitor lamivudine (3TC), a newly discovered P2rx7 inhibitor, can attenuate progression of both neuronal and vascular pathology in diabetic retinopathy. We found that the expression of P2rx7 was increased in the murine retina as early as one month following diabetes induction. Compared to non-diabetic controls, diabetic mice treated with 3TC were protected against the formation of acellular capillaries in the retina. This occurred concomitantly with a maintenance in neuroglial function, as shown by improved a- and b-wave amplitude, as well as oscillatory potentials. An improvement in the number of GABAergic amacrine cells and the synaptophysin-positive area was also observed in the inner retina of 3TC-treated diabetic mice. Our data suggest that 3TC has therapeutic potential since it can target both neuronal and vascular defects caused by diabetes.
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Affiliation(s)
- Sofia Pavlou
- Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
| | - Josy Augustine
- Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
| | - Rónán Cunning
- Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
| | - Kevin Harkin
- Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
| | - Alan W Stitt
- Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
| | - Heping Xu
- Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
| | - Mei Chen
- Centre for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
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20
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Cheng J, Korte N, Nortley R, Sethi H, Tang Y, Attwell D. Targeting pericytes for therapeutic approaches to neurological disorders. Acta Neuropathol 2018; 136:507-523. [PMID: 30097696 PMCID: PMC6132947 DOI: 10.1007/s00401-018-1893-0] [Citation(s) in RCA: 167] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/30/2018] [Accepted: 07/31/2018] [Indexed: 12/13/2022]
Abstract
Many central nervous system diseases currently lack effective treatment and are often associated with defects in microvascular function, including a failure to match the energy supplied by the blood to the energy used on neuronal computation, or a breakdown of the blood–brain barrier. Pericytes, an under-studied cell type located on capillaries, are of crucial importance in regulating diverse microvascular functions, such as angiogenesis, the blood–brain barrier, capillary blood flow and the movement of immune cells into the brain. They also form part of the “glial” scar isolating damaged parts of the CNS, and may have stem cell-like properties. Recent studies have suggested that pericytes play a crucial role in neurological diseases, and are thus a therapeutic target in disorders as diverse as stroke, traumatic brain injury, migraine, epilepsy, spinal cord injury, diabetes, Huntington’s disease, Alzheimer’s disease, diabetes, multiple sclerosis, glioma, radiation necrosis and amyotrophic lateral sclerosis. Here we report recent advances in our understanding of pericyte biology and discuss how pericytes could be targeted to develop novel therapeutic approaches to neurological disorders, by increasing blood flow, preserving blood–brain barrier function, regulating immune cell entry to the CNS, and modulating formation of blood vessels in, and the glial scar around, damaged regions.
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Affiliation(s)
- Jinping Cheng
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Rd, Guangzhou, 510120, People's Republic of China
| | - Nils Korte
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Ross Nortley
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Huma Sethi
- Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
| | - Yamei Tang
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Rd, Guangzhou, 510120, People's Republic of China.
| | - David Attwell
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
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Sugiyama T. Special Issue for Purinergic Receptors, Particularly P2X 7 Receptor, in the Eye. Vision (Basel) 2018; 2:E30. [PMID: 31735893 PMCID: PMC6835916 DOI: 10.3390/vision2030030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 07/23/2018] [Indexed: 11/16/2022] Open
Affiliation(s)
- Tetsuya Sugiyama
- Nakano Eye Clinic of Kyoto Medical Co-operative, Kyoto 604-8404, Japan; ; Tel.: +81-75-801-4151
- Department of Ophthalmology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
- Department of Ophthalmology, Toho University Sakura Medical Center, Sakura, Chiba 285-8741, Japan
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22
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Purinergic Vasotoxicity: Role of the Pore/Oxidant/K ATP Channel/Ca 2+ Pathway in P2X 7-Induced Cell Death in Retinal Capillaries. Vision (Basel) 2018; 2. [PMID: 30288454 PMCID: PMC6166475 DOI: 10.3390/vision2030025] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
P2X7 receptor/channels in the retinal microvasculature not only regulate vasomotor activity, but can also trigger cells in the capillaries to die. While it is known that this purinergic vasotoxicity is dependent on the transmembrane pores that form during P2X7 activation, events linking pore formation with cell death remain uncertain. To better understand this pathophysiological process, we used YO-PRO-1 uptake, dichlorofluorescein fluorescence, perforated-patch recordings, fura-2 imaging and trypan blue dye exclusion to assess the effects of the P2X7 agonist, benzoylbenzoyl-ATP (BzATP), on pore formation, oxidant production, ion channel activation, [Ca2+]i and cell viability. Experiments demonstrated that exposure of retinal microvessels to BzATP increases capillary cell oxidants via a mechanism dependent on pore formation and the enzyme, NADPH oxidase. Indicative that oxidation plays a key role in purinergic vasotoxicity, an inhibitor of this enzyme completely prevented BzATP-induced death. We further discovered that vasotoxicity was boosted 4-fold by a pathway involving the oxidation-driven activation of hyperpolarizing KATP channels and the resulting increase in calcium influx. Our findings revealed that the previously unappreciated pore/oxidant/KATP channel/Ca2+ pathway accounts for 75% of the capillary cell death triggered by sustained activation of P2X7 receptor/channels. Elucidation of this pathway is of potential therapeutic importance since purinergic vasotoxicity may play a role in sight-threatening disorders such as diabetic retinopathy.
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Chen Z, He L, Li L, Chen L. The P2X7 purinergic receptor: An emerging therapeutic target in cardiovascular diseases. Clin Chim Acta 2018; 479:196-207. [PMID: 29366837 DOI: 10.1016/j.cca.2018.01.032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/19/2018] [Accepted: 01/19/2018] [Indexed: 10/24/2022]
Abstract
The P2X7 purinergic receptor, a calcium permeable cationic channel, is activated by extracellular ATP. Most studies show that P2X7 receptor plays an important role in the nervous system diseases, immune response, osteoporosis and cancer. Mounting evidence indicates that P2X7 receptor is also associated with cardiovascular disease. For example, the P2X7 receptor activated by ATP can attenuate myocardial ischemia-reperfusion injury. By contrast, inhibition of P2X7 receptor decreases arrhythmia after myocardial infarction, prolongs cardiac survival after a long term heart transplant, alleviates the dilated cardiomyopathy and the autoimmune myocarditis process. The P2X7 receptor also mitigates vascular diseases including atherosclerosis, hypertension, thrombosis and diabetic retinopathy. This review focuses on the latest research on the role and therapeutic potential of P2X7 receptor in cardiovascular diseases.
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Affiliation(s)
- Zhe Chen
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China
| | - Lu He
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China
| | - Lanfang Li
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China.
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China.
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24
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Mancini JE, Ortiz G, Potilinstki C, Salica JP, Lopez ES, Croxatto JO, Gallo JE. Possible neuroprotective role of P2X2 in the retina of diabetic rats. Diabetol Metab Syndr 2018; 10:31. [PMID: 29682007 PMCID: PMC5898034 DOI: 10.1186/s13098-018-0332-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 04/04/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Purinergic receptors are expressed in different tissues including the retina. These receptors are involved in processes like cell growth, proliferation, activation and survival. ATP is the major activator of P2 receptors. In diabetes, there is a constant ATP production and this rise of ATP leads to a persistent activation of purinergic receptors. Antagonists of these receptors are used to evaluate their inhibition effects. Recently, the P2X2 has been reported to have a neuroprotective role. METHODS We carried out a study in groups of diabetic and non-diabetic rats (N = 5) treated with intraperitoneal injections of PPADS, at 9 and 24 weeks of diabetes. Control group received only the buffer. Animals were euthanized at 34 weeks of diabetes or at a matching age. Rat retinas were analyzed with immunohistochemistry and western blot using antibodies against GFAP, P2X2, P2Y2 and VEGF-A. RESULTS Diabetic animals treated with PPADS disclosed a much more extended staining of VEGF-A than diabetics without treatment. A lower protein expression of VEGF-A was found at the retina of diabetic animals without treatment of purinergic antagonists compared to diabetics with the antagonist treatment. Inhibition of P2X2 receptor by PPADS decreases cell death in the diabetic rat retina. CONCLUSION Results might be useful for better understanding the pathophysiology of diabetic retinopathy.
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Affiliation(s)
- Jorge E. Mancini
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Gustavo Ortiz
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Constanza Potilinstki
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Juan P. Salica
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Emiliano S. Lopez
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - J. Oscar Croxatto
- Department of Ocular Pathology, Fundación Oftalmlógica Argentina “Jorge Malbran”, Buenos Aires, Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
| | - Juan E. Gallo
- Department of Ophthalmology, Nanomedicine & Vision Group, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Juan D. Perón 1500, B1629AHJ Pilar, Buenos Aires Argentina
- Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas (UA-CONICET), Pilar, Buenos Aires, Argentina
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Fan C, Qiao Y, Tang M. Notoginsenoside R1 attenuates high glucose-induced endothelial damage in rat retinal capillary endothelial cells by modulating the intracellular redox state. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:3343-3354. [PMID: 29200830 PMCID: PMC5703151 DOI: 10.2147/dddt.s149700] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The aim of this study was to examine whether Notoginsenoside R1 (NR1) attenuates high glucose-induced cell damage in rat retinal capillary endothelial cells (RCECs) and to explore the mechanisms involved. The exposure of rat RCECs to high concentration of glucose (30 mM) for 72 h led to significant cytotoxicity, including decreased cell viability, reduced mitochondrial DNA copy number, increased lactate dehydrogenase release and elevated apoptosis. NR1, when present in the culture medium, markedly attenuated the high glucose-induced cytotoxicity in rat RCECs. Moreover, high glucose also induced a significant increase in intracellular reactive oxygen species and subsequently increased the activity of NADPH oxidase and poly-ADP (ribose) polymerase, whereas the activity of catalase decreased. The addition of NR1 to the medium significantly reduced the generation of reactive oxygen species, inhibited NADPH oxidase and poly-ADP (ribose) polymerase activities and increased catalase activity in RCECs, accompanied by a reduced cellular nitrotyrosine level. To explore the underlying mechanisms involved, the cellular redox status was monitored. Both the cellular NAD+ and NADPH levels decreased significantly in high glucose medium, which resulted in a marked decrease in the NAD+/NADH and NADPH/NADP+ ratios. High glucose stimulation also enhanced the accumulation of GSSG, maintaining the GSH/GSSG ratio lower than that in the control group with 5.5 mM glucose. When treated with NR1, the cellular NAD+, NADPH and GSH concentrations increased, and the ratios of NAD+/NADH, NADPH/NADP+ and GSH/GSSG increased, similar to the control group. These results demonstrate that NR1 attenuates high glucose-induced cell damage in RCECs. Therefore, NR1 may exert its protective effects via mechanisms that involve changes in the cellular redox state.
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Affiliation(s)
- Chunlan Fan
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Yuan Qiao
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Minke Tang
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China
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Subauste CS. CD40, a Novel Inducer of Purinergic Signaling: Implications to the Pathogenesis of Experimental Diabetic Retinopathy. Vision (Basel) 2017; 1:vision1030020. [PMID: 31740645 PMCID: PMC6835793 DOI: 10.3390/vision1030020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 08/08/2017] [Accepted: 08/09/2017] [Indexed: 11/16/2022] Open
Abstract
Diabetic retinopathy is a leading complication of diabetes. Death of capillary cells with resulting capillary degeneration is a central feature of this disease. Chronic low-grade inflammation has been linked to the development of retinal capillary degeneration in diabetes. CD40 is an upstream inducer of a broad range of inflammatory responses in the diabetic retina and is required for death of retinal capillary cells. Recent studies uncovered CD40 as a novel inducer of purinergic signaling and identified the CD40-ATP-P2X7 pathway as having a key role in the induction of inflammation in the diabetic retina and programmed cell death of retinal endothelial cells.
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Affiliation(s)
- Carlos S. Subauste
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; ; Tel.: +1-216-368-2785
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
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The Role of the P2X7 Receptor in Ocular Stresses: A Potential Therapeutic Target. Vision (Basel) 2017; 1:vision1020014. [PMID: 31740640 PMCID: PMC6835678 DOI: 10.3390/vision1020014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/10/2017] [Accepted: 05/14/2017] [Indexed: 01/30/2023] Open
Abstract
The P2X7 receptor is expressed in both anterior and posterior segments of the eyeball. In the ocular surface, the P2X7 receptor is activated in case of external aggressions: preservatives and surfactants induce the activation of P2X7 receptors, leading to either apoptosis, inflammation, or cell proliferation. In the retina, the key endogenous actors of age-related macular degeneration, diabetic retinopathy, and glaucoma act through P2X7 receptors’ activation and/or upregulation of P2X7 receptors’ expression. Different therapeutic strategies aimed at the P2X7 receptor exist. P2X7 receptor antagonists, such as divalent cations and Brilliant Blue G (BBG) could be used to target either the ocular surface or the retina, as long as polyunsaturated fatty acids may exert their effects through the disruption of plasma membrane lipid rafts or saffron that reduces the response evoked by P2X7 receptor stimulation. Treatments against P2X7 receptor activation are proposed by using either eye drops or food supplements.
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Platania CBM, Giurdanella G, Di Paola L, Leggio GM, Drago F, Salomone S, Bucolo C. P2X7 receptor antagonism: Implications in diabetic retinopathy. Biochem Pharmacol 2017; 138:130-139. [PMID: 28479300 DOI: 10.1016/j.bcp.2017.05.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 05/02/2017] [Indexed: 12/13/2022]
Abstract
Diabetic retinopathy (DR) is the most frequent complication of diabetes and one of leading causes of blindness worldwide. Early phases of DR are characterized by retinal pericyte loss mainly related to concurrent inflammatory process. Recently, an important link between P2X7 receptor (P2X7R) and inflammation has been demonstrated indicating this receptor as potential pharmacological target in DR. Here we first carried out an in silico molecular modeling study in order to characterize the allosteric pocket in P2X7R, and identify a suitable P2X7R antagonist through molecular docking. JNJ47965567 was identified as the hit compound in docking calculations, as well as for its absorption, distribution, metabolism and excretion (ADME) profile. As an in vitro model of early diabetic retinopathy, human retinal pericytes were exposed to high glucose (25mM, 48h) that caused a significant (p<0.05) release of IL-1β and LDH. The block of P2X7R by JNJ47965567 significantly (p<0.05) reverted the damage elicited by high glucose, detected as IL-1β and LDH release. Overall, our findings suggest that the P2X7R represents an attractive pharmacological target to manage the early phase of diabetic retinopathy, and the compound JNJ47965567 is a good template to discover other P2X7R selective antagonists.
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Affiliation(s)
- Chiara Bianca Maria Platania
- Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Giovanni Giurdanella
- Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Luisa Di Paola
- School of Engineering, University Campus BioMedico, Roma, Italy
| | - Gian Marco Leggio
- Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy; Center for Research in Ocular Pharmacology - CERFO, University of Catania, Catania, Italy
| | - Filippo Drago
- Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy; Center for Research in Ocular Pharmacology - CERFO, University of Catania, Catania, Italy
| | - Salvatore Salomone
- Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy; Center for Research in Ocular Pharmacology - CERFO, University of Catania, Catania, Italy
| | - Claudio Bucolo
- Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy; Center for Research in Ocular Pharmacology - CERFO, University of Catania, Catania, Italy.
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Portillo JAC, Lopez Corcino Y, Dubyak GR, Kern TS, Matsuyama S, Subauste CS. Ligation of CD40 in Human Müller Cells Induces P2X7 Receptor-Dependent Death of Retinal Endothelial Cells. Invest Ophthalmol Vis Sci 2016; 57:6278-6286. [PMID: 27893093 PMCID: PMC5119488 DOI: 10.1167/iovs.16-20301] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 10/12/2016] [Indexed: 02/06/2023] Open
Abstract
Purpose Cluster of differentiation 40 (CD40) is required for retinal capillary degeneration in diabetic mice, a process mediated by the retinal endothelial cells (REC) death. However, CD40 activates prosurvival signals in endothelial cells. The purpose of this study was to identify a mechanism by which CD40 triggers programmed cell death (PCD) of RECs and address this paradox. Methods Human RECs and Müller cells were incubated with CD154 and L-N6-(1-Iminoethyl)lysine (L-Nil, nitric oxide synthase 2 inhibitor), α-lipoic acid (inhibitor of oxidative stress), anti-Fas ligand antibody, or A-438079 (P2X7 adenosine triphosphate [ATP] receptor inhibitor). Programmed cell death was analyzed by fluorescence-activated cell sorting (FACS) or Hoechst/propidium iodide staining. Release of ATP was measured using a luciferase-based assay. Mice were made diabetic with streptozotocin. Expression of P2X7 was assessed by FACS, quantitative PCR, or immunohistochemistry. Results Ligation of CD40 in primary RECs did not induce PCD. In contrast, in the presence of primary CD40+ Müller cells, CD40 stimulation caused PCD of RECs that was not impaired by L-Nil, α-lipoic acid, or anti-Fas ligand antibody. We found CD40 did not trigger TNF-α or IL-1β secretion. Primary Müller cells released extracellular ATP in response to CD40 ligation. Inhibition of P2X7 (A-438079) impaired PCD of RECs; CD40 upregulated P2X7 in RECs, making them susceptible to ATP/P2X7-mediated PCD. Diabetic mice upregulated P2X7 in the retina and RECs in a CD40-dependent manner. Conclusions Cluster of differentiation 40 induces PCD of RECs through a dual mechanism: ATP release by Müller cells and P2X7 upregulation in RECs. These findings are likely of in vivo relevance since CD40 upregulates P2X7 in RECs in diabetic mice and CD40 is known to be required for retinal capillary degeneration.
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Affiliation(s)
- Jose-Andres C. Portillo
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Yalitza Lopez Corcino
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States
| | - George R. Dubyak
- Department of Biophysics, Case Western Reserve University, Cleveland, Ohio, United States
| | - Timothy S. Kern
- Division of Molecular Endocrinology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States
- Veterans Administration Medical Center, Research Service 151, Cleveland, Ohio, United States
| | - Shigemi Matsuyama
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States
| | - Carlos S. Subauste
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States
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Ho T, Aplin FP, Jobling AI, Phipps JA, de Iongh RU, Greferath U, Vessey KA, Fletcher EL. Localization and Possible Function of P2X Receptors in Normal and Diseased Retinae. J Ocul Pharmacol Ther 2016; 32:509-517. [DOI: 10.1089/jop.2015.0158] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Tracy Ho
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia
| | - Felix P. Aplin
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia
| | - Andrew I. Jobling
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia
| | - Joanna A. Phipps
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia
| | - Robb U. de Iongh
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia
| | - Ursula Greferath
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia
| | - Kirstan A. Vessey
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia
| | - Erica L. Fletcher
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia
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Riis-Vestergaard MJ, Bek T. Purinergic mechanisms and prostaglandin E receptors involved in ATP-induced relaxation of porcine retinal arterioles in vitro. Ophthalmic Res 2015; 54:135-42. [PMID: 26376245 DOI: 10.1159/000438905] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 07/22/2015] [Indexed: 11/19/2022]
Abstract
PURPOSE Adenosine triphosphate (ATP) is involved in the tone regulation of retinal arterioles, and the effect may be direct, through ATP degradation or mediated by cyclo-oxygenase products. However, the relative contribution of these mechanisms and the extent to which the mechanisms are active in the retinal vascular wall or depend on the perivascular retinal tissue are unknown. METHODS Porcine retinal arterioles with perivascular retinal tissue were mounted in a wire myograph for isometric tone recordings. The relaxing effects of ATP and the non-degradable analogue ATP-x03B3;S were studied in the presence of antagonists to ATP, adenosine and prostaglandin E (EP) receptors. The experiments were repeated after removal of the perivascular retinal tissue. RESULTS ATP induced a significant concentration-dependent relaxation of retinal arterioles (p < 0.05) which was reduced after removal of perivascular retinal tissue. The effect was due to non-degraded ATP and a degradation product of ATP acting via adenosine receptors. Relaxation was reduced by ibuprofen and blocking of EP1 receptors. CONCLUSION ATP-induced relaxation of retinal arterioles is mediated by ATP, ATP degradation products and by stimulation of EP1 receptors, involving both the perivascular retina and the vascular wall. The findings emphasize the complexity of purinergic effects in the regulation of retinal vascular tone.
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Granado M, Amor S, Montoya JJ, Monge L, Fernández N, García-Villalón ÁL. Altered expression of P2Y2 and P2X7 purinergic receptors in the isolated rat heart mediates ischemia-reperfusion injury. Vascul Pharmacol 2015; 73:96-103. [PMID: 26070527 DOI: 10.1016/j.vph.2015.06.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 05/26/2015] [Accepted: 06/08/2015] [Indexed: 11/17/2022]
Abstract
The aim of this study is to analyze the expression of purinergic receptors in the heart after ischemia-reperfusion, and their possible role in ischemia-reperfusion injury. Rat hearts were perfused according to the Langendorff technique and subjected to 30 min ischemia followed by 15 min reperfusion. Ischemia-reperfusion reduced the gene expression and protein content of purinergic receptors of the P2Y2 subtype, and increased the gene expression and protein content of the P2X7 subtype. Treatment with the agonist of the P2Y2 subtype 2-thio-UTP and with the antagonist of the P2X7 subtype Brilliant Blue improved myocardial function parameters, reduced cell death and increased the myocardial expression of antiapoptotic markers after ischemia-reperfusion. These results suggest that the myocardial expression of the protective P2Y2 subtype of purinergic receptors is reduced, whereas that of the harmful subtype P2X7 subtype is increased during coronary ischemia-reperfusion. This may contribute to myocardial injury in this condition.
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Affiliation(s)
- Miriam Granado
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma, 28029 Madrid, Spain
| | - Sara Amor
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma, 28029 Madrid, Spain
| | - Juan José Montoya
- Universidad Alfonso X el Sabio, Villanueva de la Cañada, 28691 Madrid, Spain
| | - Luis Monge
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma, 28029 Madrid, Spain
| | - Nuria Fernández
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma, 28029 Madrid, Spain
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Reichenbach A, Bringmann A. Purinergic signaling in retinal degeneration and regeneration. Neuropharmacology 2015; 104:194-211. [PMID: 25998275 DOI: 10.1016/j.neuropharm.2015.05.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 05/07/2015] [Accepted: 05/07/2015] [Indexed: 02/01/2023]
Abstract
Purinergic signaling is centrally involved in mediating the degeneration of the injured and diseased retina, the induction of retinal gliosis, and the protection of the retinal tissue from degeneration. Dysregulated calcium signaling triggered by overactivation of P2X7 receptors is a crucial step in the induction of neuronal and microvascular cell death under pathogenic conditions like ischemia-hypoxia, elevated intraocular pressure, and diabetes, respectively. Overactivation of P2X7 plays also a pathogenic role in inherited and age-related photoreceptor cell death and in the age-related dysfunction and degeneration of the retinal pigment epithelium. Gliosis of micro- and macroglial cells, which is induced and/or modulated by purinergic signaling and associated with an impaired homeostatic support to neurons, and the ATP-mediated propagation of retinal gliosis from a focal injury into the surrounding noninjured tissue are involved in inducing secondary cell death in the retina. On the other hand, alterations in the glial metabolism of extracellular nucleotides, resulting in a decreased level of ATP and an increased level of adenosine, may be neuroprotective in the diseased retina. Purinergic signals stimulate the proliferation of retinal glial cells which contributes to glial scarring which has protective effects on retinal degeneration and adverse effects on retinal regeneration. Pharmacological modulation of purinergic receptors, e.g., inhibition of P2X and activation of adenosine receptors, may have clinical importance for the prevention of photoreceptor, neuronal, and microvascular cell death in diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, and glaucoma, respectively, for the clearance of retinal edema, and the inhibition of dysregulated cell proliferation in proliferative retinopathies. This article is part of a Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.
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Affiliation(s)
- Andreas Reichenbach
- Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig, Germany.
| | - Andreas Bringmann
- Department of Ophthalmology and Eye Hospital, University of Leipzig, Leipzig, Germany
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Sathanoori R, Swärd K, Olde B, Erlinge D. The ATP Receptors P2X7 and P2X4 Modulate High Glucose and Palmitate-Induced Inflammatory Responses in Endothelial Cells. PLoS One 2015; 10:e0125111. [PMID: 25938443 PMCID: PMC4418812 DOI: 10.1371/journal.pone.0125111] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 03/20/2015] [Indexed: 12/20/2022] Open
Abstract
Endothelial cells lining the blood vessels are principal players in vascular inflammatory responses. Dysregulation of endothelial cell function caused by hyperglycemia, dyslipidemia, and hyperinsulinemia often result in impaired vasoregulation, oxidative stress, inflammation, and altered barrier function. Various stressors including high glucose stimulate the release of nucleotides thus initiating signaling via purinergic receptors. However, purinergic modulation of inflammatory responses in endothelial cells caused by high glucose and palmitate remains unclear. In the present study, we investigated whether the effect of high glucose and palmitate is mediated by P2X7 and P2X4 and if they play a role in endothelial cell dysfunction. Transcript and protein levels of inflammatory genes as well as reactive oxygen species production, endothelial-leukocyte adhesion, and cell permeability were investigated in human umbilical vein endothelial cells exposed to high glucose and palmitate. We report high glucose and palmitate to increase levels of extracellular ATP, expression of P2X7 and P2X4, and inflammatory markers. Both P2X7 and P2X4 antagonists inhibited high glucose and palmitate-induced interleukin-6 levels with the former having a significant effect on interleukin-8 and cyclooxygenase-2. The effect of the antagonists was confirmed with siRNA knockdown of the receptors. In addition, P2X7 mediated both high glucose and palmitate-induced increase in reactive oxygen species levels and decrease in endothelial nitric oxide synthase. Blocking P2X7 inhibited high glucose and palmitate-induced expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as well as leukocyte-endothelial cell adhesion. Interestingly, high glucose and palmitate enhanced endothelial cell permeability that was dependent on both P2X7 and P2X4. Furthermore, antagonizing the P2X7 inhibited high glucose and palmitate-mediated activation of p38-mitogen activated protein kinase. These findings support a novel role for P2X7 and P2X4 coupled to induction of inflammatory molecules in modulating high glucose and palmitate-induced endothelial cell activation and dysfunction.
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Affiliation(s)
- Ramasri Sathanoori
- Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden
- * E-mail:
| | - Karl Swärd
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Björn Olde
- Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden
| | - David Erlinge
- Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden
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Loukovaara S, Sahanne S, Jalkanen S, Yegutkin GG. Increased intravitreal adenosine 5'-triphosphate, adenosine 5'-diphosphate and adenosine 5'-monophosphate levels in patients with proliferative diabetic retinopathy. Acta Ophthalmol 2015; 93:67-73. [PMID: 25079888 DOI: 10.1111/aos.12507] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 06/04/2014] [Indexed: 12/28/2022]
Abstract
PURPOSE Extracellular purines play important role in ocular physiology, diabetes, vascular remodelling and adaptation to inflammation. This study was aimed to evaluate intravitreal purine levels in patients with diabetic retinopathy (DR) and other non-vascular vitreoretinal eye diseases. METHODS Vitreous samples were collected at the start of the three-port pars plana vitrectomy. Study group comprised 55 eyes operated due to sight-threatening forms of DR, including eyes of 24 patients with proliferative DR. Of the 143 non-diabetic controls, 112 had rhegmatogenous retinal detachment and 31 macular hole or pucker. Intravitreal purine concentrations were determined using a combination of bioluminescent [adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP)] and fluorometric [adenosine 5'-monophosphate (AMP), adenosine, inosine] enzyme-coupled sensing assays. RESULTS Compared with non-diabetic controls, DR eyes contained significantly higher (p < 0.01) concentrations of ATP (4.2 ± 0.6 versus 34.5 ± 13.7 nm; mean ± SEM), ADP (19.5 ± 2.7 versus 43.7 ± 14.5 nm) and AMP (1290 ± 115 versus 1876 ± 190 nm). Intravitreal adenosine and inosine levels varied within submicromolar to low micromolar range, and their concentrations did not differ between the groups studied. CONCLUSIONS High concentrations of intravitreal nucleotides ATP, ADP and AMP may be related to the pathogenesis of sight-threatening forms of DR.
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Affiliation(s)
- Sirpa Loukovaara
- Unit of Vitreoretinal Surgery; Department of Ophthalmology; Helsinki University Central Hospital; Helsinki Finland
| | - Sari Sahanne
- Unit of Anesthesiology and Intensive Care Medicine; Eye-ENT Hospital; Helsinki University Central Hospital; Helsinki Finland
| | - Sirpa Jalkanen
- MediCity Research Laboratory; University of Turku and Turku University Hospital; Turku Finland
- National Institute for Health and Welfare; Turku Finland
| | - Gennady G. Yegutkin
- MediCity Research Laboratory; University of Turku and Turku University Hospital; Turku Finland
- National Institute for Health and Welfare; Turku Finland
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Sugiyama T. Role of P2X 7 receptors in the development of diabetic retinopathy. World J Diabetes 2014; 5:141-145. [PMID: 24748927 PMCID: PMC3990313 DOI: 10.4239/wjd.v5.i2.141] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 12/04/2013] [Accepted: 01/06/2014] [Indexed: 02/05/2023] Open
Abstract
The P2X7 receptor is one of the members of the family of purinoceptors which are ligand-gated membrane ion channels activated by extracellular adenosine 5’-triphosphate. A unique feature of the P2X7 receptor is that its activation can result in the formation of large plasma membrane pores that allow not only the flux of ions but also of hydrophilic molecules of up to 900 Da. Recent studies indicate that P2X7-mediated signaling can trigger apoptotic cell death after ischemia and during the course of certain neurodegenerative disorders. Expression of the P2X7 receptor has been demonstrated in most types of cells in the retina. This purinoceptor mediates the contraction of pericytes and regulates the spatial and temporal dynamics of the vasomotor response through cell-to-cell electrotonic transmission within the microvascular networks. Of potential clinical significance, investigators have found that diabetes markedly boosts the vulnerability of retinal microvessels to the lethal effect of P2X7 receptor activation. This purinergic vasotoxicity may result in reduced retinal blood flow and disrupted vascular function in the diabetic retina. With recent reports indicating an association between P2X7 receptor activation and inflammatory cytokine expression in the retina, this receptor may also exacerbate the development of diabetic retinopathy by a mechanism involving inflammation.
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Abcouwer SF, Gardner TW. Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment. Ann N Y Acad Sci 2014; 1311:174-90. [PMID: 24673341 DOI: 10.1111/nyas.12412] [Citation(s) in RCA: 174] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Diabetic retinopathy (DR) impairs vision of patients with type 1 and type 2 diabetes, associated with vascular dysfunction and occlusion, retinal edema, hemorrhage, and inappropriate growth of new blood vessels. The recent success of biologic treatments targeting vascular endothelial growth factor (VEGF) demonstrates that treating the vascular aspects in the later stages of the disease can preserve vision in many patients. It would also be highly desirable to prevent the onset of the disease or arrest its progression at a stage preceding the appearance of overt microvascular pathologies. The progression of DR is not necessarily linear but may follow a series of steps that evolve over the course of multiple years. Abundant data suggest that diabetes affects the entire neurovascular unit of the retina, with an early loss of neurovascular coupling, gradual neurodegeneration, gliosis, and neuroinflammation occurring before observable vascular pathologies. In this article, we consider the pathology of DR from the point of view that diabetes causes measurable dysfunctions in the complex integral network of cell types that produce and maintain human vision.
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Affiliation(s)
- Steven F Abcouwer
- Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, Michigan
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Burnstock G. Introduction and perspective, historical note. Front Cell Neurosci 2013; 7:227. [PMID: 24312014 PMCID: PMC3836022 DOI: 10.3389/fncel.2013.00227] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Accepted: 11/04/2013] [Indexed: 12/11/2022] Open
Abstract
P2 nucleotide receptors were proposed to consist of two subfamilies based on pharmacology in 1985, named P2X and P2Y receptors. Later, this was confirmed following cloning of the receptors for nucleotides and studies of transduction mechanisms in the early 1990s. P2X receptors are ion channels and seven subtypes are recognized that form trimeric homomultimers or heteromultimers. P2X receptors are involved in neuromuscular and synaptic neurotransmission and neuromodulation. They are also expressed on many types of non-neuronal cells to mediate smooth muscle contraction, secretion, and immune modulation. The emphasis in this review will be on the pathophysiology of P2X receptors and therapeutic potential of P2X receptor agonists and antagonists for neurodegenerative and inflammatory disorders, visceral and neuropathic pain, irritable bowel syndrome, diabetes, kidney failure, bladder incontinence and cancer, as well as disorders if the special senses, airways, skin, cardiovascular, and musculoskeletal systems.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical SchoolLondon, UK
- Department of Pharmacology, The University of MelbourneMelbourne, VIC, Australia
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Birch RE, Schwiebert EM, Peppiatt-Wildman CM, Wildman SS. Emerging key roles for P2X receptors in the kidney. Front Physiol 2013; 4:262. [PMID: 24098285 PMCID: PMC3785026 DOI: 10.3389/fphys.2013.00262] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 09/05/2013] [Indexed: 12/29/2022] Open
Abstract
P2X ionotropic non-selective cation channels are expressed throughout the kidney and are activated in a paracrine or autocrine manner following the binding of extracellular ATP and related extracellular nucleotides. Whilst there is a wealth of literature describing a regulatory role of P2 receptors (P2R) in the kidney, there are significantly less data on the regulatory role of P2X receptors (P2XR) compared with that described for metabotropic P2Y. Much of the historical literature describing a role for P2XR in the kidney has focused heavily on the role of P2X1R in the autoregulation of renal blood flow. More recently, however, there has been a plethora of manuscripts providing compelling evidence for additional roles for P2XR in both kidney health and disease. This review summarizes the current evidence for the involvement of P2XR in the regulation of renal tubular and vascular function, and highlights the novel data describing their putative roles in regulating physiological and pathophysiological processes in the kidney.
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Affiliation(s)
- R. E. Birch
- Medway School of Pharmacy, The Universities of Kent and GreenwichKent, UK
| | | | | | - S. S. Wildman
- Medway School of Pharmacy, The Universities of Kent and GreenwichKent, UK
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Abstract
The pancreas is an organ with a central role in nutrient breakdown, nutrient sensing and release of hormones regulating whole body nutrient homeostasis. In diabetes mellitus, the balance is broken-cells can be starving in the midst of plenty. There are indications that the incidence of diabetes type 1 and 2, and possibly pancreatogenic diabetes, is rising globally. Events leading to insulin secretion and action are complex, but there is emerging evidence that intracellular nucleotides and nucleotides are not only important as intracellular energy molecules but also as extracellular signalling molecules in purinergic signalling cascades. This signalling takes place at the level of the pancreas, where the close apposition of various cells-endocrine, exocrine, stromal and immune cells-contributes to the integrated function. Following an introduction to diabetes, the pancreas and purinergic signalling, we will focus on the role of purinergic signalling and its changes associated with diabetes in the pancreas and selected tissues/organ systems affected by hyperglycaemia and other stress molecules of diabetes. Since this is the first review of this kind, a comprehensive historical angle is taken, and common and divergent roles of receptors for nucleotides and nucleosides in different organ systems will be given. This integrated picture will aid our understanding of the challenges of the potential and currently used drugs targeted to specific organ/cells or disorders associated with diabetes.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF UK
- Department of Pharmacology, Melbourne University, Melbourne, Australia
| | - Ivana Novak
- Molecular and Integrative Physiology, Department of Biology, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100 Copenhagen Ø, Denmark
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Bek T, Al-Mashhadi RH, Misfeldt M, Riis-Vestergaard MJ, Bentzon JF, Pedersen SMM. Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL-receptor deficiency and diabetes mellitus. Exp Eye Res 2013; 115:79-86. [PMID: 23806330 DOI: 10.1016/j.exer.2013.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Revised: 06/03/2013] [Accepted: 06/10/2013] [Indexed: 10/26/2022]
Abstract
Metabolic disturbances in diabetes mellitus include changes in the type and concentration of lipids in the blood plasma which may contribute to the development of diabetic retinopathy. This disease is characterized by changes in retinal blood flow secondary to changes in the tone of retinal arterioles which is regulated by compounds such as adenosine, adenosine triphosphate (ATP), the glutamate agonist N-methyl-d-aspartate (NMDA) and prostaglandin E2 (PGE2). However, the relation between increased plasma low density lipoprotein (LDL) and tone regulation in retinal resistance vessels has not been studied in detail. Twelve male and nine female Yucatan minipigs overexpressing a gain-of-function mutant (D374Y) of the human gene PCSK9 that blocks LDL transport into the liver and twelve wild-type males were studied. The animals were fed a cholesterol rich diet from the age of 60 days, followed by induction of diabetes mellitus in twelve of the transgenic animals. The animals were sacrificed at a mean age of 51 weeks (range 26-60 weeks), followed by inspection and histological examination of retinal vessels, and examination of the changes in vascular tone induced by adenosine, ATP, NMDA and PGE2. In the transgenic pigs without diabetes mellitus ATP-induced relaxation was reduced in isolated arterioles, and a whitish infiltration in an arteriole was observed in 4/8 (50%) of the animals, whereas these changes were not found in the other groups. Histological examination of one of the infiltrations showed staining with Oil Red O representing foamy cells sub-endothelially in the vascular wall indicating atheromatosis. Adenosine, ATP and PGE2 induced a significant concentration-dependent relaxation of retinal arterioles in all groups. The presence of perivascular retinal tissue had no effect on the relaxing effect of adenosine, but increased the relaxing effect of ATP and PGE2 in the two transgenic animal groups, whereas NMDA had no significant effect on vascular tone in any of the groups. Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL-receptor deficiency and diabetes mellitus. This suggests that transgenic animal models are suitable for studying the influence of systemic diseases on retinal vascular function.
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Affiliation(s)
- Toke Bek
- Department of Ophthalmology, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark.
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Guzman-Aranguez A, Santano C, Martin-Gil A, Fonseca B, Pintor J. Nucleotides in the eye: focus on functional aspects and therapeutic perspectives. J Pharmacol Exp Ther 2013; 345:331-41. [PMID: 23504005 DOI: 10.1124/jpet.112.202473] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The presence and activity of nucleotides and dinucleotides in the physiology of most, if not all, organisms, from bacteria to humans, have been recognized by the scientific community, and the eye is no exception. Nucleotides in the dynamic fluids interact with many ocular structures, such as the tears and aqueous humor. Moreover, high concentrations of nucleotides in these secretions may reflect disease states such as dry eye and glaucoma. Apart from the nucleotide concentration in these fluids, P2 purinergic receptors have been described on the ocular surface (cornea and conjunctiva), anterior pole (ciliary body, trabecular meshwork), and posterior pole (retina). P2X and P2Y purinergic receptors are essential in maintaining the homeostasis of ocular processes, such as tear secretion, aqueous humor production, or retinal modulation. When they are functioning properly, they allow the eye to do its job (to see), but in some cases, a lack or an excess of nucleotides or a malfunction in the corresponding purinergic receptors leads to disease. This Perspective is focused on the nucleotides and dinucleotides and the P2 purinergic receptors in the eye and how they contribute to normal and disease states. We also emphasize the action of nucleotides and their receptors and antagonists as potential therapeutic agents.
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Affiliation(s)
- Ana Guzman-Aranguez
- Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, Universidad Complutense Madrid, C/Arcos de Jalón 118, 28037 Madrid, Spain
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Abstract
Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRβ)(+) and CD105(+) stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRβ(+) stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.
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45
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Puro DG. Retinovascular physiology and pathophysiology: new experimental approach/new insights. Prog Retin Eye Res 2012; 31:258-70. [PMID: 22333041 DOI: 10.1016/j.preteyeres.2012.01.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 01/28/2012] [Accepted: 01/31/2012] [Indexed: 01/09/2023]
Abstract
An important challenge in visual neuroscience is to understand the physiology and pathophysiology of the intra-retinal vasculature, whose function is required for ophthalmoception by humans and most other mammals. In the quest to learn more about this highly specialized portion of the circulatory system, a newly developed method for isolating vast microvascular complexes from the rodent retina has opened the way for using techniques such as patch-clamping, fluorescence imaging and time-lapse photography to elucidate the functional organization of a capillary network and its pre-capillary arteriole. For example, the ability to obtain dual perforated-patch recordings from well-defined sites within an isolated microvascular complex permitted the first characterization of the electrotonic architecture of a capillary/arteriole unit. This analysis revealed that this operational unit is not simply a homogenous synctium, but has a complex functional organization that is dynamically modulated by extracellular signals such as angiotensin II. Another recent discovery is that a capillary and its pre-capillary arteriole have distinct physiological differences; capillaries have an abundance of ATP-sensitive potassium (K(ATP)) channels and a dearth of voltage-dependent calcium channels (VDCCs) while the converse is true for arterioles. In addition, voltage transmission between abluminal cells and the endothelium is more efficient in the capillaries. Thus, the capillary network is well-equipped to generate and transmit voltages, and the pre-capillary arteriole is well-adapted to transduce a capillary-generated voltage into a change in abluminal cell calcium and thereby, a vasomotor response. Use of microvessels isolated from the diabetic retina has led to new insights concerning retinal vascular pathophysiology. For example, soon after the onset of diabetes, the efficacy of voltage transmission through the endothelium is diminished; arteriolar VDCCs are inhibited, and there is increased vulnerability to purinergic vasotoxicity, which is a newly identified pathobiological mechanism. Other recent studies reveal that K(ATP) channels not only have an essential physiological role in generating vasomotor responses, but their activation substantially boosts the lethality of hypoxia. Thus, the pathophysiology of the retinal microvasculature is closely linked with its physiology.
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Affiliation(s)
- Donald G Puro
- Department of Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
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Barber AJ, Gardner TW, Abcouwer SF. The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy. Invest Ophthalmol Vis Sci 2011; 52:1156-63. [PMID: 21357409 DOI: 10.1167/iovs.10-6293] [Citation(s) in RCA: 317] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The most striking features of diabetic retinopathy are the vascular abnormalities that are apparent by fundus examination. There is also strong evidence that diabetes causes apoptosis of neural and vascular cells in the retina. Thus, there is good reason to define diabetic retinopathy as a form of chronic neurovascular degeneration. In keeping with the gradual onset of retinopathy in humans, the rate of cell loss in the animal models is insidious, even in uncontrolled diabetes. This is not surprising given that a sustained high rate of cell loss without regeneration would soon lead to catastrophic tissue destruction. The consequences of ongoing cell death are difficult to detect, and even the quantification of cumulative cell loss requires painstaking histology and microscopy. This subtle cell loss raises the issue of the relevance of the phenomenon to the progression of diabetic retinopathy and the ultimate loss of vision. Neuronal function may be compromised in advance of apoptosis, contributing to an early deterioration of vision. Here we review some of the evidence supporting apoptotic cell death as a contributing mechanism of diabetic retinopathy, explore some of the potential causes, and discuss the potential links between apoptosis and loss of visual function in diabetic retinopathy.
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Affiliation(s)
- Alistair J Barber
- Department of Ophthalmology, Penn State Hershey Eye Center, Penn State Hershey College of Medicine, Hershey, Pennsylvania 17033, USA.
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47
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Burnstock G, Kennedy C. P2X receptors in health and disease. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2011; 61:333-372. [PMID: 21586364 DOI: 10.1016/b978-0-12-385526-8.00011-4] [Citation(s) in RCA: 160] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Seven P2X receptor subunits have been cloned which form functional homo- and heterotrimers. These are cation-selective channels, equally permeable to Na(+) and K(+) and with significant Ca(2+) permeability. The three-dimensional structure of the P2X receptor is described. The channel pore is formed by the α-helical transmembrane spanning region 2 of each subunit. When ATP binds to a P2X receptor, the pore opens within milliseconds, allowing the cations to flow. P2X receptors are expressed on both central and peripheral neurons, where they are involved in neuromuscular and synaptic neurotransmission and neuromodulation. They are also expressed in most types of nonneuronal cells and mediate a wide range of actions, such as contraction of smooth muscle, secretion, and immunomodulation. Changes in the expression of P2X receptors have been characterized in many pathological conditions of the cardiovascular, gastrointestinal, respiratory, and urinogenital systems and in the brain and special senses. The therapeutic potential of P2X receptor agonists and antagonists is currently being investigated in a range of disorders, including chronic neuropathic and inflammatory pain, depression, cystic fibrosis, dry eye, irritable bowel syndrome, interstitial cystitis, dysfunctional urinary bladder, and cancer.
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Affiliation(s)
- G Burnstock
- Autonomic Neuroscience Centre, University College Medical School, London, United Kingdom
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Charles BA, Conley YP, Chen G, Miller RG, Dorman JS, Gorin MB, Ferrell RE, Sereika SM, Rotimi CN, Orchard TJ. Variants of the adenosine A(2A) receptor gene are protective against proliferative diabetic retinopathy in patients with type 1 diabetes. Ophthalmic Res 2010; 46:1-8. [PMID: 21088442 PMCID: PMC2997447 DOI: 10.1159/000317057] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Accepted: 06/09/2010] [Indexed: 11/19/2022]
Abstract
AIMS The adenosine A(2A) receptor (ADORA(2A)) may ameliorate deleterious physiologic effects associated with tissue injury in individuals with diabetes. We explored associations between variants of the ADORA(2A) gene and proliferative diabetic retinopathy (PDR) in a cohort of patients with type 1 diabetes (T1D). METHODS The participants were from the Pittsburgh Epidemiology of Diabetes Complications prospective study of childhood-onset T1D. Stereoscopic photographs of the retinal fundus taken at baseline, then biennially, for 10 years were used to define PDR according to the modified Airlie House system. Two tagging single nucleotide polymorphisms (tSNPs; rs2236624-C/T and rs4822489-G/T) in the ADORA(2A) gene were selected using the HapMap (haplotype map) reference database. RESULTS A significant association was observed between SNP rs2236624 and PDR in the recessive genetic model. Participants homozygous for the T allele displayed a decreased risk of developing prevalent PDR (odds ratio, OR = 0.36; p = 0.04) and incident PDR (hazard ratio = 0.156; p = 0.009), and for all cases of PDR combined (OR = 0.23; p = 0.001). The protective effect of T allele homozygosity remained after adjusting for covariates. Similarly, for SNP rs4822489, an association between PDR and T allele homozygosity was observed following covariate adjustment (OR = 0.55; 95% CI: 0.31-0.92; p = 0.04). CONCLUSION Genetic variants of ADORA(2A) offer statistically significant protection against PDR development in patients with T1D.
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Affiliation(s)
- Bashira A Charles
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-5635, USA.
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Extracellular high dosages of adenosine triphosphate induce inflammatory response and insulin resistance in rat adipocytes. Biochem Biophys Res Commun 2010; 402:455-60. [PMID: 20946888 DOI: 10.1016/j.bbrc.2010.10.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2010] [Accepted: 10/06/2010] [Indexed: 01/24/2023]
Abstract
Adenosine triphosphate (ATP), an important signaling molecule, participates in various pathophysiological processes via the activation of purinergic-receptors. Recent studies have shown that the expression and function of purinergic-receptors (P2-receptors) could be altered in diabetic or hyperinsulinemia conditions. To characterize the effect of ATP on insulin signaling, we treated primary rat adipocytes with varied concentrations of ATP. The pre-treatment led to impaired insulin signaling, i.e., blunted phosphorylation in Insulin Receptor Substrate-1 (IRS-1) tyrosine and Protein Kinase B (PKB) Ser473 in response to insulin treatment, when ATP concentration reached 1mM. We then observed that ATP dose-dependently reduced the level of IκB, a negative regulator of inflammatory response. Consistently, IRS-1 Ser307 phosphorylation in response to insulin treatment, a site for inflammatory pathway to interfere insulin signaling, was enhanced by ATP. Furthermore, effects of ATP on insulin signaling and IκB content were blocked by P2-receptor inhibition. Finally, insulin-stimulated glucose uptake was impaired by ATP in adipocytes but not in the L6 muscle cells. This study therefore shows for the first time the involvement of ATP-evoked P2-receptor activation in mediating the inflammatory response and the generation of insulin resistance in adipocytes.
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Yego ECK, Mohr S. siah-1 Protein is necessary for high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation and cell death in Muller cells. J Biol Chem 2010; 285:3181-90. [PMID: 19940145 PMCID: PMC2823464 DOI: 10.1074/jbc.m109.083907] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Indexed: 11/06/2022] Open
Abstract
The translocation and accumulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the nucleus has closely been associated with cell death induction. However, the mechanism of this process has not been completely understood. The E3 ubiquitin ligase siah-1 (seven in absentia homolog 1) has recently been identified as a potential shuttle protein to transport GAPDH from the cytosol to the nucleus. Previously, we have demonstrated that elevated glucose levels induce GAPDH nuclear accumulation in retinal Müller cells. Therefore, this study investigated the role of siah-1 in high glucose-induced GAPDH nuclear translocation and subsequent cell death in retinal Müller cells. High glucose significantly increased siah-1 expression within 12 h. Under hyperglycemic conditions, siah-1 formed a complex with GAPDH and was predominantly localized in the nucleus of Müller cells. siah-1 knockdown using 50 nm siah-1 small interfering RNA significantly decreased high glucose-induced GAPDH nuclear accumulation at 24 h by 43.8 +/- 4.0%. Further, knockdown of siah-1 prevented high glucose-induced cell death of Müller cells potentially by inhibiting p53 phosphorylation consistent with previous observations, indicating that nuclear GAPDH induces cell death via p53 activation. Therefore, inhibition of GAPDH nuclear translocation and accumulation by targeting siah-1 promotes Müller cell survival under hyperglycemic conditions.
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Affiliation(s)
- E. Chepchumba K. Yego
- From the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 and
| | - Susanne Mohr
- From the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 and
- the Department of Physiology, Michigan State University, East Lansing, Michigan 48824
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