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Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis
Retinal ischemia–reperfusion (RIR) injury caused by high intraocular pressure (IOP) is an important risk factor contributing to retinal ganglion cell (RGC) death, eventually causing blindness. A key progressive pathological process in the development of RIR is the death of RGCs. However, the detaile...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295547/ https://www.ncbi.nlm.nih.gov/pubmed/37371903 http://dx.doi.org/10.3390/antiox12061173 |
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author | Zhang, Fan Lin, Bingying Huang, Siyu Wu, Pengsen Zhou, Min Zhao, Jing Hei, Xiangqing Ke, Yu Zhang, Yiting Huang, Danping |
author_facet | Zhang, Fan Lin, Bingying Huang, Siyu Wu, Pengsen Zhou, Min Zhao, Jing Hei, Xiangqing Ke, Yu Zhang, Yiting Huang, Danping |
author_sort | Zhang, Fan |
collection | PubMed |
description | Retinal ischemia–reperfusion (RIR) injury caused by high intraocular pressure (IOP) is an important risk factor contributing to retinal ganglion cell (RGC) death, eventually causing blindness. A key progressive pathological process in the development of RIR is the death of RGCs. However, the detailed mechanisms underlying RGC death caused by RIR have not yet been clearly elucidated, and effective treatments are lacking. Ferroptosis is a recently defined form of programmed cell death that is closely related to organ injury. Melatonin (MT) is a promising neuroprotective agent, but its effects on RIR injury remain unclear. In this study, murine models of acute ocular hypertension and oxygen and glucose deprivation/reoxygenation (OGD/R) model were adopted to simulate retinal ischemia. MT alleviated retinal damage and RGC death in RIR mice, significantly attenuating RIR–induced ferroptosis. Furthermore, MT reduced the expression of p53, a master regulator of ferroptosis pathways, and the upregulation of p53 promoted ferroptosis and largely abolished the neuroprotective effects of MT. Mechanistically, the overexpression (OE) of p53 suppressed the expression of the solute carrier family 7 member 11 (Slc7a11), which was accompanied by increased 12–lipoxygenase (Alox12) expression, triggering retinal ferroptosis. Moreover, MT–ameliorated apoptosis, neuroinflammation and microglial activation were observed. In summary, MT conferred neuroprotection against RIR injury by inhibiting p53–mediated ferroptosis. These findings indicate that MT is a retina–specific ferroptosis inhibitor and a promising therapeutic agent for retinal neuroprotection. |
format | Online Article Text |
id | pubmed-10295547 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102955472023-06-28 Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis Zhang, Fan Lin, Bingying Huang, Siyu Wu, Pengsen Zhou, Min Zhao, Jing Hei, Xiangqing Ke, Yu Zhang, Yiting Huang, Danping Antioxidants (Basel) Article Retinal ischemia–reperfusion (RIR) injury caused by high intraocular pressure (IOP) is an important risk factor contributing to retinal ganglion cell (RGC) death, eventually causing blindness. A key progressive pathological process in the development of RIR is the death of RGCs. However, the detailed mechanisms underlying RGC death caused by RIR have not yet been clearly elucidated, and effective treatments are lacking. Ferroptosis is a recently defined form of programmed cell death that is closely related to organ injury. Melatonin (MT) is a promising neuroprotective agent, but its effects on RIR injury remain unclear. In this study, murine models of acute ocular hypertension and oxygen and glucose deprivation/reoxygenation (OGD/R) model were adopted to simulate retinal ischemia. MT alleviated retinal damage and RGC death in RIR mice, significantly attenuating RIR–induced ferroptosis. Furthermore, MT reduced the expression of p53, a master regulator of ferroptosis pathways, and the upregulation of p53 promoted ferroptosis and largely abolished the neuroprotective effects of MT. Mechanistically, the overexpression (OE) of p53 suppressed the expression of the solute carrier family 7 member 11 (Slc7a11), which was accompanied by increased 12–lipoxygenase (Alox12) expression, triggering retinal ferroptosis. Moreover, MT–ameliorated apoptosis, neuroinflammation and microglial activation were observed. In summary, MT conferred neuroprotection against RIR injury by inhibiting p53–mediated ferroptosis. These findings indicate that MT is a retina–specific ferroptosis inhibitor and a promising therapeutic agent for retinal neuroprotection. MDPI 2023-05-29 /pmc/articles/PMC10295547/ /pubmed/37371903 http://dx.doi.org/10.3390/antiox12061173 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zhang, Fan Lin, Bingying Huang, Siyu Wu, Pengsen Zhou, Min Zhao, Jing Hei, Xiangqing Ke, Yu Zhang, Yiting Huang, Danping Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis |
title | Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis |
title_full | Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis |
title_fullStr | Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis |
title_full_unstemmed | Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis |
title_short | Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis |
title_sort | melatonin alleviates retinal ischemia–reperfusion injury by inhibiting p53–mediated ferroptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295547/ https://www.ncbi.nlm.nih.gov/pubmed/37371903 http://dx.doi.org/10.3390/antiox12061173 |
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