Abstract
Exogenous insulin, used as a therapeutic agent for diabetes, forms insoluble deposits containing amyloid fibrillar structures near the administration site. We have analyzed the in vitro anti-amyloid activity of four green tea constituents: (-)-epigallocatechin gallate (EGCG), (-)-epicatechin (EC), gallic acid (GA), caffeine (CF), and their equimolar mixtures. Regarding individually tested compounds, only EGCG inhibited the fibrillization process. The individual EC, GA, and CF molecules were ineffective. The presence of EGCG in equimolar combinations with GA, EC, or CF was required for the inhibitory activity of most mixtures. Molecular docking revealed that EGCG interacts with an essential amyloidogenic region of insulin chain B. Individually inactive GA had a potentiating effect on the activity of EGCG. In contrast, EC and CF had a negative impact on the activity of the mixtures. We have observed diverse morphology and the amount of insulin amyloid aggregates formed in the presence of studied compounds. The distinct types of amyloid aggregates created in vitro in the presence of EGCG and other green tea constituents were characterized. Results indicate that the biological activity of individual molecules is not directly applicable to the pooled samples effects prediction.
Highlights
Exogenous insulin, used as a therapeutic agent for diabetes, forms insoluble deposits containing amyloid fibrillar structures near the administration site
The goal of this study was to investigate the effects of the green tea constituents (Fig. 1) and their equimolar mixtures (Table 1) on the formation of amyloid fibrils derived from human insulin
The formation of amyloid aggregates is accompanied by an increase of Thioflavin T (ThT) fluorescence intensity as a result of ThT binding to the cross-β sheet structure of amyloids
Summary
Exogenous insulin, used as a therapeutic agent for diabetes, forms insoluble deposits containing amyloid fibrillar structures near the administration site. We have analyzed the in vitro anti-amyloid activity of four green tea constituents: (-)-epigallocatechin gallate (EGCG), (-)-epicatechin (EC), gallic acid (GA), caffeine (CF), and their equimolar mixtures. The initialization of amyloidogenesis is followed by an opening of the interior regions of the protein when hydrophobic amino acid residues are shifted to the surface of insulin From this new position, they incline to the association and formation of oligomers, subsequently extending to the protofibrils and insoluble mature fibrils[3]. Drinking of green tea in large doses is associated with a reduced prevalence of cognitive impairment in elderly Japanese people[17] It has an impact on the extracellular deposition of the amyloid-β peptide, hyperphosphorylation of tau protein, and can affect basal mechanisms of Alzheimer’s disease[18]. EGCG and gallic acid reduce amyloid-β aggregation and formation of Aβ-derived neurotoxin ligands[19]
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