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

Abstract

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.

Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell

“…Phlorotannins, polymers of phloroglucinol units, are found in brown algae such as Sargassum species, kelps and rockweeds. As a major phlorotannin, dieckol decreased the self-aggregation of Aβ 25–35 with an IC 50 value of 7.9 ± 0.2 [ 24 ]. Our group identified phlorotannins, including eckol, dieckol, and 8,8′-bieckol, as novel BACE1 inhibitors [ 25 ].…”

Bioactive Properties of Marine Phenolics

“…Furthermore, brown algal extracts containing phlorotannins exhibited protective effects against AGEs formation in Caenorhabditis elegans (a species of nematode) with induced hyperglycemia [ 178 ]. From five phlorotannins isolated from E. stolonifera , only phlorofucofuroeckol-A inhibited, in a dose-dependent form, the induced non-enzymatic insulin glycation of D-ribose and D-glucose (IC 50 29.50 μM and 43.55 μM, respectively) [ 179 ]. These authors used computational analysis to find that phlorofucofuroeckol-A interacts with the Phe1 in insulin chain-B, blocking D-glucose access to the glycation site of insulin.…”

Polyphenols from Brown Seaweeds (Ochrophyta, Phaeophyceae): Phlorotannins in the Pursuit of Natural Alternatives to Tackle Neurodegeneration

“…Phlorotannins have been found to exert their neuroprotective effects through multimodal action ( Figure 2 , Table 1 and Table 2 ), as evidenced in in vitro studies by their capacity to inhibit CNS-related enzymes [ 24 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ], modulate neuronal receptors [ 52 , 62 ], and regulate signaling pathways linked to oxidative stress-mediated neuronal cell death [ 24 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] and neuroinflammation [ 73 , 74 , 75 , 76 , 77 ].…”

“…Different agents, including hydrogen peroxide (H 2 O 2 ), rotenone, glutamate, and Aβ oligomers, have been employed as neurotoxic challenge paradigm to evaluate and characterize the effects of phlorotannins in different aspects of neuroprotection [ 24 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ].…”

“…Among the phlorotannin compounds studied so far, phlorofucofuroeckol-A demonstrated a strong potential to interact with Aβ peptides, preventing their self-assembly and therefore inhibiting Aβ aggregation [ 69 ]. In fact, in a previous report by Ahn et al [ 70 ], the anti-amyloidogenic activity of this phloroglucinol pentamer was disclosed and it was hypothesized that the neuroprotective effects may be mediated through reduced intracellular ROS and Ca 2+ generation [ 70 ].…”