Glucose-impaired Corneal Re-epithelialization Is Promoted by a Novel Derivate of Dimethyl Fumarate.

Giovanni Giurdanella,Sebastiano Intagliata,Giuseppe Romeo,Gabriella Lupo,Alfio Distefano,Giovanni Li Volti,Valeria Pittalà,Loredana Salerno,Carmelina Daniela Anfuso,Claudio Bucolo,Anna Longo,Chiara Bianca Maria Platania

doi:10.3390/antiox10060831

Giovanni Giurdanella, Sebastiano Intagliata + Show 10 more

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https://doi.org/10.3390/antiox10060831

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Journal: Antioxidants	Publication Date: May 22, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: University of Catania

Abstract

Glucose induces corneal epithelial dysfunctions characterized by delayed wound repair. Nuclear erythroid 2-related factor 2 (Nrf2) mediates cell protection mechanisms even through the Heme oxygenase-1 (HO-1) up-regulation. Here, we synthesized new HO-1 inducers by modifying dimethyl fumarate (DMF) and used docking studies to select VP13/126 as a promising compound with the best binding energy to Kelch-like ECH-associated protein 1 (keap1), which is the the regulator of Nrf2 nuclear translocation. We verified if VP13/126 protects SIRC cells from hyperglycemia compared to DMF. SIRC were cultured in normal (5 mM) or high glucose (25 mM, HG) in presence of DMF (1–25 μM) or VP13/126 (0.1–5 μM) with or without ERK1/2 inhibitor PD98059 (15 μM). VP13/126 was more effective than DMF in the prevention of HG-induced reduction of cell viability and proliferation. Reduction of wound closure induced by HG was similarly counteracted by 1 μM VP13/126 and 10 μM DMF. VP13/126 strongly increased phospho/total ERK1/2 and restored HO-1 protein in HG-treated SIRC; these effects are completely counteracted by PD98059. Moreover, high-content screening analysis showed a higher rate of Nrf2 nuclear translocation induced by VP13/126 than DMF in HG-stimulated SIRC. These data indicate that VP13/126 exerts remarkable pro-survival properties in HG-stimulated SIRC, promoting the Nrf2/HO-1 axis.

Highlights

Dimethyl fumarate (DMF) derivatives are good Heme oxygenase-1 (HO-1) expression/activation inducers [37], we analyzed the putative role of this new compound VP13/126 to protect Seruminstitut rabbit corneal (SIRC) from cell damage induced by high glucose (HG) damage
We show that the detrimental role of high glucose produced effects in SIRC according to literature such as the reduction of cell viability, proliferation rate and wound healing capability (Figures 2–4) [14,52,53]
In SIRC treated with HG and 25 μM DMF we observed a significant increase of HO-1 protein levels in comparison to HG-treated cell, close to those observed in the controls

Summary

Introduction

Corneal epithelium represents a multilayered cellular barrier that lines the ocular surface [1]. It constitutes a proper cellular barrier of the innate immune system against mechanical stimuli, microbial invasion and environmental insults [2]. Age-related eye diseases are often associated to impairment of the corneal epithelium, increasing the risk of bacterial infections and compromising the refractive eye’s capabilities [5]. Diabetes causes profound ocular changes by altering the eye barriers. It has been shown that the exposure of retinal microcapillary endothelial cells and pericytes to high glucose concentrations leads to the Antioxidants 2021, 10, 831.

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