Among therapeutic approaches for amyloid-related diseases, attention has recently turned to the use of natural products as effective anti-aggregation compounds. Although a wealth of in vitro and in vivo evidence indicates some common inhibitory activity of these compounds, they don’t generally suggest the same mechanism of action. Here, we show that taxifolin, a ubiquitous bioactive constituent of foods and herbs, inhibits formation of HEWL amyloid fibrils and their related toxicity by causing formation of very large globular, chain-like aggregates. A range of amyloid-specific techniques were employed to characterize this process. We found that taxifolin exerts its effect by binding to HEWL prefibrillar species, rather than by stabilizing the molecule in its native-like state. Furthermore, it’s binding results in diverting the amyloid pathway toward formation of very large globular, chain-like aggregates with low β-sheet content and reduced solvent-exposed hydrophobic patches. ThT fluorescence measurements show that the binding capacity of taxifolin is significantly reduced, upon generation of large protofibrillar aggregates at the end of growth phase. We believe these results may help design promising inhibitors of protein aggregation for amyloid-related diseases.
The 25-35 fragment of the amyloid β (Aβ) peptide is a naturally occurring proteolytic by-product that retains the pathophysiology of its larger parent molecule, whose deposition has been shown to involve mitochondrial dysfunction. Hence, disruption of Aβ(25-35) aggregates could afford an effective remedial strategy for Alzheimer's disease (AD). In the present study, the effect of a number of selected small-molecule natural products (polyphenols: resveratrol, quercetin, biochanin A, and indoles: indole-3-acetic acid, indole-3-carbinol (I3C)) on Aβ(25-35) fibrillogenesis was explored under physiological conditions, and interaction of the resulting structures with rat brain mitochondria was investigated. Several techniques, including fluorescence, circular dichroism, and transmission electron microscopy were utilized to characterize the aggregation products, and possible mitochondrial membrane permeabilization was determined following release of marker enzymes. Results demonstrate the capacity of Aβ(25-35) fibrils to damage mitochondria and suggest how small molecules may afford protection. While I3C appeared more effective in inhibiting the fibrillation process, all natural products behaved similarly in destabilizing preformed aggregates. It is concluded that elucidation of such protection may provide important insights into the development of preventive and therapeutic agents for AD.
Investigation of non-covalent interaction of hydrophobic surfaces with the protein G (PrG) is necessary due to their frequent utilization in immunosensors and ELISA. It has been confirmed that surfaces, including carbonous-nanostructures (CNS) could orient proteins for a better activation. Herein, PrG interaction with single-walled carbon nanotube (SWCNT) and graphene (Gra) nanostructures was studied by employing experimental and MD simulation techniques. It is confirmed that the PrG could adequately interact with both SWCNT and Gra and therefore fine dispersion for them was achieved in the media. Results indicated that even though SWCNT was loaded with more content of PrG in comparison with the Gra, the adsorption of the PrG on Gra did not induce significant changes in the IgG tendency. Several orientations of the PrG were adopted in the presence of SWCNT or Gra; however, SWCNT could block the PrG-FcR. Moreover, it was confirmed that SWCNT reduced the α-helical structure content in the PrG. Reduction of α-helical structure of the PrG and improper orientation of the PrG-SWCNT could remarkably decrease the PrG tendency to the Fc of the IgG. Importantly, the Gra could appropriately orient the PrG by both exposing the PrG-FcR and also by blocking the fragment of the PrG that had tendency to interact with Fab in IgG.
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