Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β<sub>25-35</sub> Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action
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 n...
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| Format: | Article |
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MDPI AG
2019-10-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/17/11/600 |
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| author | Su Hui Seong Pradeep Paudel Hyun Ah Jung Jae Sue Choi |
| author_facet | Su Hui Seong Pradeep Paudel Hyun Ah Jung Jae Sue Choi |
| author_sort | Su Hui Seong |
| collection | DOAJ |
| description | 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-Aβ<sub>25-35</sub> aggregation and anti-insulin glycation activities of five phlorotannins isolated from <i>Ecklonia stolonifera</i>. Thioflavin-T assay results suggest that eckol, dioxinodehydroeckol, dieckol, and phlorofucofuroeckol-A (PFFA) significantly inhibit Aβ<sub>25-35</sub> self-assembly. Molecular docking and dynamic simulation analyses confirmed that these phlorotannins have a strong potential to interact with Aβ<sub>25-35</sub> peptides and interrupt their self-assembly and conformational transformation, thereby inhibiting Aβ<sub>25-35</sub> aggregation. In addition, PFFA dose-dependently inhibited <span style="font-variant: small-caps;">d</span>-ribose and <span style="font-variant: small-caps;">d</span>-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 <span style="font-variant: small-caps;">d</span>-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 Aβ<sub>25-35</sub> and advanced glycation end-products (AGEs) in insulin. |
| first_indexed | 2024-04-11T20:45:59Z |
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| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-11T20:45:59Z |
| publishDate | 2019-10-01 |
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| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-21703ea26d7a42d38ccb9af4c6f5f8ca2022-12-22T04:04:02ZengMDPI AGMarine Drugs1660-33972019-10-01171160010.3390/md17110600md17110600Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β<sub>25-35</sub> Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of ActionSu Hui Seong0Pradeep Paudel1Hyun Ah Jung2Jae Sue Choi3Department of Food and Life Science, Pukyong National University, Busan 48513, KoreaDepartment of Food and Life Science, Pukyong National University, Busan 48513, KoreaDepartment of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, KoreaDepartment of Food and Life Science, Pukyong National University, Busan 48513, KoreaBoth 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-Aβ<sub>25-35</sub> aggregation and anti-insulin glycation activities of five phlorotannins isolated from <i>Ecklonia stolonifera</i>. Thioflavin-T assay results suggest that eckol, dioxinodehydroeckol, dieckol, and phlorofucofuroeckol-A (PFFA) significantly inhibit Aβ<sub>25-35</sub> self-assembly. Molecular docking and dynamic simulation analyses confirmed that these phlorotannins have a strong potential to interact with Aβ<sub>25-35</sub> peptides and interrupt their self-assembly and conformational transformation, thereby inhibiting Aβ<sub>25-35</sub> aggregation. In addition, PFFA dose-dependently inhibited <span style="font-variant: small-caps;">d</span>-ribose and <span style="font-variant: small-caps;">d</span>-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 <span style="font-variant: small-caps;">d</span>-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 Aβ<sub>25-35</sub> and advanced glycation end-products (AGEs) in insulin.https://www.mdpi.com/1660-3397/17/11/600phlorotanninamyloid-β aggregationinsulin glycationdynamic simulation |
| spellingShingle | Su Hui Seong Pradeep Paudel Hyun Ah Jung Jae Sue Choi Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β<sub>25-35</sub> Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action Marine Drugs phlorotannin amyloid-β aggregation insulin glycation dynamic simulation |
| title | Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β<sub>25-35</sub> Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action |
| title_full | Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β<sub>25-35</sub> Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action |
| title_fullStr | Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β<sub>25-35</sub> Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action |
| title_full_unstemmed | Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β<sub>25-35</sub> Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action |
| title_short | Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β<sub>25-35</sub> Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action |
| title_sort | identifying phlorofucofuroeckol a as a dual inhibitor of amyloid β sub 25 35 sub self aggregation and insulin glycation elucidation of the molecular mechanism of action |
| topic | phlorotannin amyloid-β aggregation insulin glycation dynamic simulation |
| url | https://www.mdpi.com/1660-3397/17/11/600 |
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