A Systemic Pharmacology Analysis of the Age-Related Eye Disease Study 2 (AREDS2) formula and its role in preventing Age-Related Macular Degeneration (AMD)




Wu, Hongli
Brown, Erica
Yu, Yu
Lou, Alexander
Garcia, Luis
Tran, Myhoa
Duong, Anh
Wang, Miki


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Purpose: According to the major clinical trial sponsored by the National Eye Institute (NEI), oral supplementation with the Age-Related Eye Disease Study 2 (AREDS2) formulation (vitamins C and E, zinc, copper, lutein, and zeaxanthin) has been shown to delay the progression of advanced age-related macular degeneration (AMD). However, the detailed pharmacological mechanisms of AREDS2 have not been fully understood at the molecular level, other than its well-known antioxidative effects. In this study, we intend to develop a systemic approach to predict the AREDS2-associated targets and to build the drug-disease-target network. Methods: Genes of interest were identified via the NCBI database for all compounds in the AREDS2 formula. Cytoscape software was used to visually create a network of source and target nodes to analyze similarities between nodes. Cytoscape was again used to identify major pathways the AREDS2 formula targeted. Results: A total of 158 genes were identified to be targets of the AREDS2 formula. 27 out of 158 genes were a result of multiple components of the AREDS2 formula. The main pathways these genes affect were identified and mapped out to include adipogenesis, angiogenesis, apoptosis cascade, DNA damage response, fluid shear stress and atherosclerosis, glutathione metabolism, HIF1 signaling pathway, innate immune pathway, lipoprotein metabolism, Nrf2 pathway and oxidative stress pathway. The top 5 target genes were GSTP1, Nrf2, VEGFA, HIF1A, and CXCL8. Conclusion: The systemic pharmacology-based approach provides beneficial information for elucidating the potential mechanisms of action of the AREDS2 formula in treating AMD.