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Open AccessArticle

Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β25-35 Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action

1
Department of Food and Life Science, Pukyong National University, Busan 48513, Korea
2
Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Korea
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2019, 17(11), 600; https://doi.org/10.3390/md17110600
Received: 4 October 2019 / Revised: 19 October 2019 / Accepted: 20 October 2019 / Published: 23 October 2019
Both amyloid-β (Aβ) and insulin are amyloidogenic peptides, and they play a critical role in Alzheimer’s disease (AD) and type-2 diabetes (T2D). Misfolded or aggregated Aβ and glycated insulin are commonly found in AD and T2D patients, respectively, and exhibit neurotoxicity and oxidative stress. The present study examined the anti-Aβ25-35 aggregation and anti-insulin glycation activities of five phlorotannins isolated from Ecklonia stolonifera. Thioflavin-T assay results suggest that eckol, dioxinodehydroeckol, dieckol, and phlorofucofuroeckol-A (PFFA) significantly inhibit Aβ25-35 self-assembly. Molecular docking and dynamic simulation analyses confirmed that these phlorotannins have a strong potential to interact with Aβ25-35 peptides and interrupt their self-assembly and conformational transformation, thereby inhibiting Aβ25-35 aggregation. In addition, PFFA dose-dependently inhibited d-ribose and d-glucose induced non-enzymatic insulin glycation. To understand the molecular mechanism for insulin glycation and its inhibition, we predicted the binding site of PFFA in insulin via computational analysis. Interestingly, PFFA strongly interacted with the Phe1 in insulin chain-B, and this interaction could block d-glucose access to the glycation site of insulin. Taken together, our novel findings suggest that phlorofucofuroeckol-A could be a new scaffold for AD treatment by inhibiting the formation of β-sheet rich structures in Aβ25-35 and advanced glycation end-products (AGEs) in insulin. View Full-Text
Keywords: phlorotannin; amyloid-β aggregation; insulin glycation; dynamic simulation phlorotannin; amyloid-β aggregation; insulin glycation; dynamic simulation
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Seong, S.H.; Paudel, P.; Jung, H.A.; Choi, J.S. Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β25-35 Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action. Mar. Drugs 2019, 17, 600.

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