Zhou Hongyu, Pang Jianhui, Wu Baiyang, Zhuang Yanan, Li Shenjun, Jiang Jing
College of Pharmacy, Binzhou Medical University, Binzhou, Shandong, China.
Non-Clinical Research Department, RemeGen Co., Ltd, Yantai, Shandong, China.
Front Pharmacol. 2025 Aug 21;16:1588970. doi: 10.3389/fphar.2025.1588970. eCollection 2025.
Age-related macular degeneration (AMD) is a leading cause of vision loss in older adults, with limited effective treatments available. This study aimed to investigate the pharmacological effects of dihydromyricetin (DHM) on AMD and to identify its putative pharmacological targets through network analysis and molecular docking approaches.
experiments established an AMD model using sodium iodate (SI)-induced ARPE-19 cells, with CCK-8 assays determining 15 mM SI as the optimal modeling concentration and 100 μM DHM as the optimal treatment concentration. For validation, an AMD model was generated in C57 mice via tail vein injection of SI (30 mg/kg). Subsequent oral gavage with DHM (50 or 100 mg/kg) was administered. Integrated network analysis, molecular docking, and RT- qPCR validation were employed.
RT-qPCR analysis revealed that DHM reversed SI-induced aberrant expression of AMD-associated biomarkers (). Light microscopy and flow cytometry demonstrated DHM's significant mitigation of SI-triggered cellular morphological alterations and apoptosis (35% reduction). Western blot analysis further confirmed DHM-mediated suppression of apoptosis through regulation of p53, Bax, cleaved caspase-3, and Bcl-2 expression. High-dose DHM significantly attenuated retinal thinning (10.7% reduction), decreased pigment loss, and ameliorated structural disorganization in the outer nuclear layer (ONL). These analyses predicted seven putative targets implicated in functional categories including neurodegeneration, apoptosis, and DNA modification. Subsequent PPI network construction and GO/KEGG enrichment analyses revealed these targets' involvement in biological processes such as angiogenesis and extracellular matrix organization.
In conclusion, the present study demonstrates that DHM can mitigate AMD-related damage in both and models, while predicting putative targets and signaling pathways through which DHM may exert its effects against AMD. These findings offer promising directions for the development of AMD therapies and lay the groundwork for further investigation into DHM as a candidate drug for treating and preventing AMD.
年龄相关性黄斑变性（AMD）是老年人视力丧失的主要原因，可用的有效治疗方法有限。本研究旨在探讨二氢杨梅素（DHM）对AMD的药理作用，并通过网络分析和分子对接方法确定其潜在的药理靶点。
实验使用碘酸钠（SI）诱导ARPE - 19细胞建立AMD模型，CCK - 8测定确定15 mM SI为最佳建模浓度，100 μM DHM为最佳治疗浓度。为进行验证，通过尾静脉注射SI（30 mg/kg）在C57小鼠中建立AMD模型。随后进行DHM（50或100 mg/kg）灌胃。采用综合网络分析、分子对接和RT - qPCR验证。
RT - qPCR分析表明，DHM逆转了SI诱导的AMD相关生物标志物的异常表达。光学显微镜和流式细胞术表明，DHM显著减轻了SI引发的细胞形态改变和细胞凋亡（减少35%）。蛋白质印迹分析进一步证实，DHM通过调节p53、Bax、裂解的caspase - 3和Bcl - 2的表达介导对细胞凋亡的抑制。高剂量DHM显著减轻视网膜变薄（减少10.7%），减少色素丢失，并改善外核层（ONL）的结构紊乱。这些分析预测了七个潜在靶点，涉及神经退行性变、细胞凋亡和DNA修饰等功能类别。随后的蛋白质 - 蛋白质相互作用（PPI）网络构建和基因本体论（GO）/京都基因与基因组百科全书（KEGG）富集分析表明，这些靶点参与血管生成和细胞外基质组织等生物过程。
总之，本研究表明，DHM可以减轻细胞和小鼠模型中与AMD相关的损伤，同时预测DHM可能对AMD发挥作用的潜在靶点和信号通路。这些发现为AMD治疗的发展提供了有希望的方向，并为进一步研究DHM作为治疗和预防AMD的候选药物奠定了基础。
