Anti-neovascularization effects of DMBT in age-related macular degeneration by inhibition of VEGF secretion through ROS-dependent signaling pathway
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Choroidal neovascularization (CNV) is the hallmark of late-staged wet age-related macular degeneration (AMD). Vascular endothelial growth factor (VEGF) is a key component in the development and progression of wet AMD. DMBT, 6,6′-bis(2,3-dimethoxybenzoyl)-α,α-d-trehalose, had been proved that it could suppress tumor angiogenesis and metastasis by inhibiting production of VEGF. But the effects of DMBT on CNV were not known. This study was to investigate effects and mechanisms of DMBT on CNV in vitro and in vivo. Results showed that DMBT could inhibit migration and tube formation of RF/6A cells under ARPE-19 hypoxia conditioned medium. DMBT could reduce lesion area in laser-induced CNV model mice. ELISA and Western blotting assay showed that DMBT markedly inhibited secretion of VEGF in vitro and in vivo. Furthermore, DMBT restrained ROS level under hypoxia via suppressing Nrf2/HO-1 pathway. DMBT effectively suppressed hypoxia-induced the up-regulation of p-Akt, p-NF-κB, and HIF-1α. These results suggest that DMBT can inhibit CNV by down-regulation of VEGF in retina through Akt/NF-κB/HIF-1α and ERK/Nrf2/HO-1/HIF-1α pathway. DMBT might be a promising lead molecule for anti-CNV and serve as a therapeutic agent to inhibit CNV.
KeywordsChoroidal neovascularization DMBT Hypoxia VEGF HIF-1α
This work was supported by Natural Science Foundation of Shandong Province (No. ZR2013HM084) and Key Research and Development Program of Shandong Province (2016GSF201152) of P. R. China. Compounds DMBT used in this study were synthesized by Prof. Zhaopeng Liu, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University. Thanks are due to Dr. Yanai at the Department of Ophthalmology, Graduate School of Medicine, Yamaguchi University, for his help and guide in this study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
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