Natural Inhibitors of Amyloid Aggregation
- (1)
- As largely documented above, the biological effects and the related therapeutic potential of the molecules presented and investigated are, as a rule, astoundingly diverse, which gives room for plenty of further research. However, particularly noteworthy in this respect is the capability of some compounds to act effectively towards a repertoire of different diseases. For instance, this is the case of the polyphenol hydroxytyrosol, which was initially proven to be effective in preventing insulin amyloid aggregation [3] and subsequently displayed a protective action against both β-amyloid aggregation [6] and doxorubicin-induced apoptosis in cardiomyocytes [7]. Thus, it is to be expected that for many such drugs, there is room for the discovery of new therapeutic applications.
- (2)
- Interestingly, based on the fact that different molecules generally act via different repertoires of therapeutic mechanisms, it has been suggested that the combined administration of multiple drugs may result in synergistic effects [5], a strategy that generally deserves to be explored when searching for new therapeutic approaches.
- (3)
- In this context, bioinformatics holds a promising potential because of developing new therapeutic molecules, as highlighted by the contribution by Muscat and Coll. [8]. Using a combination of ensemble docking and molecular dynamics, they assessed the destabilizing effect of 57 compounds on the S-shaped Aβ42 (the most stable conformer). In this way, they found that the polyphenols oleuropein, curcumin, gossypin, piceatannol, and the related 6-shogaol appreciably affected protein stability, reducing the percentual content of beta sheets. Even more importantly, the authors suggest that a pharmacophore model might be developed based on the compounds’ shared features to rationally design novel, more effective compounds.
- (4)
- Of course, some caveats should be considered when evaluating the therapeutic effects of the compounds dealt with in the issue, primarily hormesis, as well as possible chemical modifications they might undergo after administration. Hormesis is defined as any process in a cell or an organism characterized by a biphasic response to the exposure to increasing amounts of a stressing condition or substance (stressor) [2]. Briefly speaking, besides their beneficial effects, polyphenols can also act as stressors so that a favorable biological response can only occur within a given range of administered doses (the so-called hormetic zone). In contrast, cell damage can occur when this is exceeded. This obvious precautionary principle cannot be disregarded, particularly when long-term administration is required. As far as the effects of chemical modifications are concerned, the contribution by Sternke-Hoffmann and Coll. is of remarkable interest [4]. When assessing the effect of EGCG on α-synuclein amyloid fibril formation, a complex picture emerged, whereby the process was significantly affected by the chemical-physical conditions and, particularly, the oxidized form of EGCG (whose appearance was prevented at slightly acidic pH and favored by a neutral one) was shown to more effectively prevent aggregation. Based on these observations, one should be aware of the impact on the process of both chemical stability of the compounds under investigation and physiological/working conditions.
- (5)
- Concerning molecules that are supposed to be effective as pharmaceuticals, another factor that should be carefully considered is their bioavailability and efficacy in vivo. This issue is related to several others, including the one mentioned in the previous point 4), wherein the effects of EGCG have been discussed. In a more general perspective, the question arises as to how results achieved using a given experimental model may predict clinical trial outcomes. Regarding γ-secretase modulators, investigations were conducted on several models, including rodents, nematodes, and cell cultures [5]. To date, different molecules of herbal origin are candidates for Alzheimer’s disease treatment, although only one (EVP-0015962) will enter a clinical phase II trial. A major constraint is blood–brain barrier penetrance. Hydroxytyrosol is endowed with this capability [9], which identifies it as a promising neuroprotective agent. Additionally noteworthy is the use of induced pluripotent stem cells (iPSC) [5]. They are excellent cellular models as they can be differentiated into various types of neuronal cells from the stem cell stage, and used as a cellular individualized platform starting from a patient’s iPSC.
- (6)
- In conclusion, what are the most promising developments related to and following this Special Issue? In our opinion, two perspectives are worth mentioning. In the first place, given Alzheimer’s disease treatment, nanoformulations are feasible strategies aimed at improving the low bioavailability of apolar drugs, notably curcumin [10]. In the second place, the modulation of gut microbiota via a suitable dietary intake is coming in the foreground as a major line of action to check Alzheimer’s disease progression, with polyphenols and fibers representing the nutritional compounds with the highest potential of counterbalancing the pathophysiological mechanisms of dementia [11]. Thus, despite the complexities and uncertainties one has to cope with when searching for new therapeutic strategies, there seems to be plenty of room for developing innovative approaches.
Conflicts of Interest
References
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Tortora, P.; Aprile, F.A. Natural Inhibitors of Amyloid Aggregation. Int. J. Mol. Sci. 2023, 24, 13310. https://doi.org/10.3390/ijms241713310
Tortora P, Aprile FA. Natural Inhibitors of Amyloid Aggregation. International Journal of Molecular Sciences. 2023; 24(17):13310. https://doi.org/10.3390/ijms241713310
Chicago/Turabian StyleTortora, Paolo, and Francesco A. Aprile. 2023. "Natural Inhibitors of Amyloid Aggregation" International Journal of Molecular Sciences 24, no. 17: 13310. https://doi.org/10.3390/ijms241713310