Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China.
Department of Ophthalmology, Graduate School of Medicine, Yamaguchi University, Minamikoguchi 1-1-1, Ube, Yamaguchi, 755-8505, Japan.
Mol Cell Biochem. 2018 Nov;448(1-2):225-235. doi: 10.1007/s11010-018-3328-6. Epub 2018 Feb 14.
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.
脉络膜新生血管（CNV）是晚期湿性年龄相关性黄斑变性（AMD）的标志。血管内皮生长因子（VEGF）是湿性 AMD 发展和进展的关键组成部分。6,6'-双（2,3-二甲氧基苯甲酰基）-α,α-D-海藻糖（DMBT）已被证明可以通过抑制 VEGF 的产生来抑制肿瘤血管生成和转移。但是，DMBT 对 CNV 的影响尚不清楚。本研究旨在研究 DMBT 在体外和体内对 CNV 的作用及其机制。结果表明，DMBT 可抑制 ARPE-19 低氧条件培养基下 RF/6A 细胞的迁移和管形成。DMBT 可减少激光诱导的 CNV 模型小鼠的病变面积。ELISA 和 Western blot 检测结果表明，DMBT 可显著抑制体外和体内 VEGF 的分泌。此外，DMBT 通过抑制 Nrf2/HO-1 通路抑制缺氧下的 ROS 水平。DMBT 有效抑制了缺氧诱导的 p-Akt、p-NF-κB 和 HIF-1α的上调。这些结果表明，DMBT 可以通过下调视网膜中的 VEGF 来抑制 CNV，通过 Akt/NF-κB/HIF-1α 和 ERK/Nrf2/HO-1/HIF-1α 通路。DMBT 可能是一种有前途的抗 CNV 先导分子，并可作为抑制 CNV 的治疗剂。
