{"title":"Urolithin A alleviates cell senescence by inhibiting ferroptosis and enhances corneal epithelial wound healing.","authors":"Xiao-Xiao Guo, Xue-Jiao Chang, Qi Pu, Ao-Ling Li, Jing Li, Xin-Yu Li","doi":"10.3389/fmed.2024.1441196","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>To analyze the therapeutic effect and mechanism of Urolithin A (UA) on delayed corneal epithelial wound healing.</p><p><strong>Methods: </strong>The C57BL/6 mice were continuously exposed to hyperosmotic stress (HS) for 7 days followed by the removal of central corneal epithelium to establish a delayed corneal epithelial wound healing model <i>in vivo</i>. <i>In vitro</i>, the human corneal epithelial cell line (HCE-T) was also incubated under HS. UA was administered <i>in vivo</i> and <i>in vitro</i> to study its effects on corneal epithelial cells. Senescence-associated β-galactosidase (SA-β-gal) staining was performed to detect the level of cell senescence. Transcriptome sequencing (RNA-seq) was conducted to elucidate the molecular mechanism underlying the effect of UA on corneal epithelial repair. Additionally, the expression of senescence-related and ferroptosis-related genes and the levels of lipid peroxides (LPO) and malondialdehyde (MDA) were measured.</p><p><strong>Results: </strong>Hyperosmotic stress (HS) significantly increased the proportion of SA-β-gal staining positive cells in corneal epithelial cells and upregulated the expression of p16 and p21 (<i>p</i> < 0.0001). Topical application of UA decreased the accumulation of senescent cells in corneal epithelial wounds and promoted epithelial wound healing. The results of RNA-seq of HS-induced corneal epithelial cells showed that the ferroptosis pathway was significantly dysregulated. Further investigation revealed that UA decreased the level of oxidative stress in HCE-T cells, including the levels of LPO and MDA (<i>p</i> < 0.05). Inhibition of ferroptosis significantly prevented cellular senescence in HS-induced HCE-T cells.</p><p><strong>Conclusion: </strong>In this study, UA promoted HS-induced delayed epithelial wound healing by reducing the senescence of corneal epithelial cells through the inhibition of ferroptosis.</p>","PeriodicalId":12488,"journal":{"name":"Frontiers in Medicine","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439666/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fmed.2024.1441196","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: To analyze the therapeutic effect and mechanism of Urolithin A (UA) on delayed corneal epithelial wound healing.
Methods: The C57BL/6 mice were continuously exposed to hyperosmotic stress (HS) for 7 days followed by the removal of central corneal epithelium to establish a delayed corneal epithelial wound healing model in vivo. In vitro, the human corneal epithelial cell line (HCE-T) was also incubated under HS. UA was administered in vivo and in vitro to study its effects on corneal epithelial cells. Senescence-associated β-galactosidase (SA-β-gal) staining was performed to detect the level of cell senescence. Transcriptome sequencing (RNA-seq) was conducted to elucidate the molecular mechanism underlying the effect of UA on corneal epithelial repair. Additionally, the expression of senescence-related and ferroptosis-related genes and the levels of lipid peroxides (LPO) and malondialdehyde (MDA) were measured.
Results: Hyperosmotic stress (HS) significantly increased the proportion of SA-β-gal staining positive cells in corneal epithelial cells and upregulated the expression of p16 and p21 (p < 0.0001). Topical application of UA decreased the accumulation of senescent cells in corneal epithelial wounds and promoted epithelial wound healing. The results of RNA-seq of HS-induced corneal epithelial cells showed that the ferroptosis pathway was significantly dysregulated. Further investigation revealed that UA decreased the level of oxidative stress in HCE-T cells, including the levels of LPO and MDA (p < 0.05). Inhibition of ferroptosis significantly prevented cellular senescence in HS-induced HCE-T cells.
Conclusion: In this study, UA promoted HS-induced delayed epithelial wound healing by reducing the senescence of corneal epithelial cells through the inhibition of ferroptosis.
期刊介绍:
Frontiers in Medicine publishes rigorously peer-reviewed research linking basic research to clinical practice and patient care, as well as translating scientific advances into new therapies and diagnostic tools. Led by an outstanding Editorial Board of international experts, this multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
In addition to papers that provide a link between basic research and clinical practice, a particular emphasis is given to studies that are directly relevant to patient care. In this spirit, the journal publishes the latest research results and medical knowledge that facilitate the translation of scientific advances into new therapies or diagnostic tools. The full listing of the Specialty Sections represented by Frontiers in Medicine is as listed below. As well as the established medical disciplines, Frontiers in Medicine is launching new sections that together will facilitate
- the use of patient-reported outcomes under real world conditions
- the exploitation of big data and the use of novel information and communication tools in the assessment of new medicines
- the scientific bases for guidelines and decisions from regulatory authorities
- access to medicinal products and medical devices worldwide
- addressing the grand health challenges around the world