Cited by 26Ocular Surface and Contact LensAdvanced Drug Delivery SystemsCircadian rhythm and melatonin

Copolymer micelle-administered melatonin ameliorates hyperosmolarity-induced ocular surface damage through regulating PINK1-mediated mitophagy

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Xu, Jing, Chen, Peng, Zhao, Guangfen, Wei, Susu, Li, Qiqi, Guo, Chuanlong, Cao, Qilong, Wu, Xianggen +1 more·2022·Current Eye Research

Abstract

Purpose To investigate the role and mechanism of melatonin-loaded polymer polyvinyl caprolactam–polyvinyl acetate–polyethyleneglycol graft copolymer micelles (Mel-Mic) in dry eye disease (DED).Methods In vitro, the apoptosis and reactive oxygen species (ROS) generation in human corneal epithelial cells (HCECs) were analyzed by immunostaining and flow cytometry. The effect of Mel-Mic on autophagy and mitophagy was evaluated by immunostaining and western blots. PINK1 knockdown was analyzed by small interfering RNA. In vivo, sodium fluorescein staining, tear secretion test, and periodic acid-Schiff staining were used to determine whether Mel-Mic can alleviate the severity of DED. Small molecule antagonists were pretreated to investigate whether melatonin type 1 and/or 2 receptors (MT1/MT2) mediate the effects of Mel-Mic.Results Mel-Mic improved the solubility and biological activities of Mel in aqueous solutions. Treatment with Mel-Mic decreased the apoptosis of HCECs exposed to hyperosmotic medium, accompanied by downregulation of cleaved Caspase-3 and upregulation of Bcl-2. In addition, Mel-Mic application suppressed ROS overproduction, rescued mitochondrial function, and decreased the level of oxidative stress associated biomarkers (COX-2 and 4-HNE) in HCECs. Interestingly, HCECs treated with Mel-Mic exhibited increased levels of mitophagy markers (PINK1, PARKIN, Beclin 1, and LC3B) and restored impaired mitophagic flux under hyperosmolarity. While PINK1 knockdown largely abolished its protective effects. In vivo, compared to vehicle group, topical Mel-Mic-solution-treated mice showed significantly improved clinical parameters, increased tear production, and decreased goblet cells loss in a dose-dependent manner. Also, transmission electron microscopic assay revealed increased autophagosome number in the corneal epithelium of Mel-Mic group. Moreover, luzindole, a nonselective MT1/MT2 antagonist, but not 4-P-PDOT, a selective MT2 antagonist, blocked the protective effect of Mel-Mic.Conclusions Our findings demonstrated that Mel-Mic ameliorates hyperosmolarity-induced ocular surface damage via PINK1-mediated mitophagy and may represent an effective treatment for DED possibly through acting MT1 receptor.

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Crossref · 10.1080/02713683.2021.2022163

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  • Mice treated with Mel-Mic solution exhibited markedly improved clinical parameters including enhanced tear production and reduced loss of goblet cells in a dose-dependent manner.

    “In vivo studies revealed that mice treated with Mel-Mic solution exhibited markedly improved clinical parameters including enhanced tear production and reduced loss of goblet cells in a dose-dependent manner [129].”
  • Mel-Mic improved solubility of melatonin in aqueous solutions and decreased the apoptosis rate of human corneal epithelial cells.

    “the Melatonin-loaded polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer micelles (Mel-Mic) were fabricated to improve the solubility of Mel in aqueous solutions and decrease the apoptosis rate of human corneal epithelial cells (HCECs).”

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Authors
Xu, J., Chen, P., Zhao, G., Wei, S., Li, Q., Guo, C., Cao, Q., Wu, X., & Di, G.
Affiliations
  • Qingdao University (CN)
  • Department of Medicine, The Liaocheng Third People’s Hospital, Liaocheng, China
  • Qingdao University of Science and Technology (CN)
  • Haier Group (China) (CN)
Corresponding author
Di, Guohu
Venue
Current Eye Research
Published
2022-03-07
Volume
47
Issue
5
Pages
688-703
ISSN
  • 0271-3683 (ISSN-L)
  • 1460-2202
OpenAlex
W4213072722
Cited by
26
References
56
Citations by year
2026: 4 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 5
FWCI
4.85
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Current Eye Research (publishedVersion)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • Figshare (cc-by)
Funders
  • Error! Hyperlink reference not valid. (81670829, 81970782)
  • China Postdoctoral Science Foundation (2019M652328)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ocular Surface and Contact Lens
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Keywords
melatonin, dry eye, hyperosmolarity, ocular surface damage, PINK1, mitophagy, corneal epithelial cells, MT2 receptor, autophagy, reactive oxygen species, oxidative stress, polymeric micelles, drug delivery, goblet cells, tear secretion
MeSH terms
Animals, Melatonin, Micelles, Polymers, Protein Kinases, Reactive Oxygen Species, Mice, Mitophagy

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