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Anti-neovascularization effects of DMBT in age-related macular degeneration by inhibition of VEGF secretion through ROS-dependent signaling pathway

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Abstract

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China

    Shang Chen, Yue Zhou, Lichun Zhou, Yanhui Guan, Yu Zhang & Xiuzhen Han

  2. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China

    Yue Zhou

  3. Key Laboratory of Chemical Biology of Natural Products, Ministry of Education, Jinan, China

    Xiuzhen Han

  4. Department of Ophthalmology, Graduate School of Medicine, Yamaguchi University, Minamikoguchi 1-1-1, Ube, Yamaguchi, 755-8505, Japan

    Shang Chen

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  1. Shang Chen
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Correspondence to Xiuzhen Han.

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Chen, S., Zhou, Y., Zhou, L. et al. Anti-neovascularization effects of DMBT in age-related macular degeneration by inhibition of VEGF secretion through ROS-dependent signaling pathway. Mol Cell Biochem 448, 225–235 (2018). https://doi.org/10.1007/s11010-018-3328-6

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