Next Article in Journal
Antibacterial Action of Nanoparticle Loaded Nanocomposites Based on Graphene and Its Derivatives: A Mini-Review
Next Article in Special Issue
High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways
Previous Article in Journal
Serum Exosomal miRNAs for Grading Hepatic Fibrosis Due to Schistosomiasis
Previous Article in Special Issue
Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 21
Issue 10
10.3390/ijms21103561
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Polyphenols with Anti-Amyloid β Aggregation Show Potential Risk of Toxicity Via Pro-Oxidant Properties

by
Hatasu Kobayashi
1,
Mariko Murata
1,
Shosuke Kawanishi
2 and
Shinji Oikawa
1,*
1
Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
2
Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(10), 3561; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103561
Submission received: 8 April 2020 / Revised: 13 May 2020 / Accepted: 13 May 2020 / Published: 18 May 2020
(This article belongs to the Special Issue Amyloid-β: Structure, Function, and Pathophysiological Significance in Neurodegenerative Diseases)
Browse Figures
Versions Notes

Abstract

:
Alzheimer’s disease (AD) is the most common form of dementia among older people. Amyloid β (Aβ) aggregation has been the focus for a therapeutic target for the treatment of AD. Naturally occurring polyphenols have an inhibitory effect on Aβ aggregation and have attracted a lot of attention for the development of treatment strategies which could mitigate the symptoms of AD. However, considerable evidence has shown that the pro-oxidant mechanisms of polyphenols could have a deleterious effect. Our group has established an assay system to evaluate the pro-oxidant characteristics of chemical compounds, based on their reactivity with DNA. In this review, we have summarized the anti-Aβ aggregation and pro-oxidant properties of polyphenols. These findings could contribute to understanding the mechanism underlying the potential risk of polyphenols. We would like to emphasize the importance of assessing the pro-oxidant properties of polyphenols from a safety point of view.

1. Amyloid β Aggregation in Alzheimer’s Disease

Alzheimer’s disease (AD) is the leading cause of dementia, and disease prevalence has been increasing dramatically with a worldwide increase in the aging population [1]. Numerous studies have suggested that accumulation of the Amyloid β (Aβ) peptide in the brain is the initial pathological event for AD [2]. The Aβ peptide is a soluble, extracellular fragment generated from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases [3]. Aβ accumulation promotes conformational changes in the peptide, resulting in the formation of oligomers and fibrils; ultimately, resulting in plaque deposition—one of the hallmarks of AD pathology [2,4]. The nucleation-dependent polymerization mechanism, which separates the amyloid fibrillization process into a nucleation phase and an elongation phase [5], is currently proposed as an aggregation mechanism for the Aβ peptide (Figure 1). During the nucleation phase, soluble Aβ monomers undergo conformational changes and self-associate to form oligomeric nuclei that are rich in β-sheets. During the elongation phase, these oligomeric nuclei act as a template and associate with monomers to initiate polymerization [6]. There are currently four approved medications for AD (three cholinesterase inhibitors and one uncompetitive NMDA receptor modulator), but they have a small effect size and show no effect on long-term disease progression [7]. Therefore, new drugs directed against various identified targets of AD, such as Aβ, tau, ApoE, and neuroinflammation are urgently needed [7]. Among these therapeutic targets, researchers have largely focused on Aβ aggregation for the prevention and treatment of AD, based on the “amyloid cascade hypothesis”.

2. Beneficial Anti-Aβ Aggregation and Adverse Pro-Oxidant Effects of Polyphenols

Researchers have investigated the inhibitory effects of various chemical and biological molecules on Aβ aggregation to develop a strategy for mitigating AD. These compounds include small organic molecules, peptide derivatives, chemical and molecular chaperones, and antibodies, to name a few [4]. Polyphenols are naturally occurring secondary metabolites found in large quantities in fruits, vegetables, seeds, and plant-derived oils; thus exhibit easy availability [14,15]. In vitro studies have shown that several polyphenols reduce Aβ aggregation by inhibiting the nucleation phase or elongation phase, or both, and redirecting the Aβ oligomers to the less-toxic “off-pathway” aggregation (Figure 1). Details of the anti-Aβ aggregation activity of each polyphenol are described below (Section 2.1–2.4). The anti-Aβ aggregation activities of some compounds have been confirmed in animal studies, and clinical studies have either been performed or are being performed to test these selected polyphenols [16,17]. However, considerable evidence has raised the concern that polyphenols could exert deleterious effects through their pro-oxidant mechanisms [18,19,20]. Many polyphenols involved in anti-Aβ aggregation have been reported to display pro-oxidant activities, which are potentially linked with toxic effects (Table 1, Figure 2).
A common feature of polyphenols, especially those harboring hydroxyl groups in the phenol ring, is that they can readily participate in redox reactions [21], which is associated with both their antioxidant and pro-oxidant properties. Our group has established an assay to evaluate the pro-oxidant characteristics of chemical compounds on the basis of their ability to induce oxidative DNA damage, and investigated the mechanisms of the reactive oxygen species (ROS) generation [22]. Based on our results and that of others in the literature, in this review we have focused on polyphenols whose mechanisms of inhibiting Aβ aggregation have been well-studied, and have summarized their pro-oxidant properties. In addition, recent studies have suggested that biological activities of polyphenols were attributed to not only the polyphenols themselves but also their metabolites generated in vivo [23,24]. Therefore, we also have described some cases showing that metabolites are involved in pro-oxidant properties.

2.1. Polyphenols Involved in Inhibiting Nucleation

Myricetin

Myricetin is one of the most common naturally occurring compounds found in a large variety of plants and has been reported to show good biological activity as an antioxidant, anti-inflammatory, and anti-tumorigenic agent [64,65]. Studies using fluorescence spectroscopy with thioflavin T and electron microscopy have shown that myricetin inhibits the formation of Aβ fibrils [66]. Ono et al. demonstrated that myricetin blocked Aβ oligomer formation and bound to monomeric Aβ by an assay using a photoinduced cross-linking agent and nuclear magnetic resonance (NMR) [8]. These findings suggested that myricetin could prevent nucleation via direct binding to the Aβ monomer. Myricetin was also shown to reduce the number of high molecular weight oligomers and prevent the development of AD pathology in an AD mouse model [67].
Despite these encouraging results, myricetin has been reported to have mutagenic activity [32,33]. A recent study showed that myricetin tested positive in a bacterial mutagenicity assay and in vitro micronuclei formation assay [32]. Metal-mediated DNA damage induced by myricetin has been demonstrated in studies using plasmid DNA, isolated nuclei, and cultured cells [28,29,30,31]. The inhibitory effects of several ROS scavengers on DNA damage [28,31] and the generation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), an indicator of oxidative DNA damage [31], have indicated pro-oxidant mechanisms of myricetin-induced DNA damage.

2.2. Polyphenols Involved in Inhibiting Nucleation and Elongation

Morin and Datiscetin

Morin a member of the flavonoid family, was originally isolated from the members of the Moraceae family and is found in a wide variety of fruits, vegetables, and herbs [68,69]. Morin, which has antioxidant and anti-inflammatory activities, has been reported to show pharmacological effects in several diseases [68,69,70]. The inhibitory effect of morin towards Aβ aggregation has been reported in several in vitro studies that tested naturally occurring compounds [66,71]. Furthermore, sustained treatment with morin could reduce the production of insoluble Aβ and the formation of amyloid plaques [72] and rescue cognitive impairment [72,73] in AD and dementia animal models. NMR analysis has shown that morin could prevent both the nucleation and the elongation phases during Aβ42 aggregation by interacting with His13, His14, and Gln15, which are close to the intermolecular β-sheet region of Aβ42 [9]. This anti-Aβ aggregation activity has been attributed to the C-1 oxygen of the C-ring and the 2′-hydroxyl group of the B-ring (Figure 3), which stabilize the flatness between the A-, B-, and C-rings of morin and enable it to interact with the intermolecular β-sheet region [74]. Datiscetin, which has the same structure as morin except for the 4′-hydroxyl group of the B-ring, also prevents Aβ aggregation by the same mechanism [9,74].
Previously, morin has been shown to promote ROS generation. Morin could induce metal-mediated lipid peroxidation of the nuclear membrane and DNA strand break in isolated nuclei [35]. The morin-Cu(II) complex could cleave plasmid DNA via an oxidative pathway [30,37]. Cell model studies have suggested that morin can cause DNA strand breaks though ROS production [34]. Morin was shown to have a mutagenic activity with the Salmonella/microsomal activation system [38]. Recently, we have shown that in the presence of Cu(II), morin induces not only DNA strand breaks but also base modification, including 8-oxodG formation, in isolated DNA [36]. By testing the effects of various ROS scavengers and Cu(I) chelators on DNA damage, we proposed that morin undergoes autoxidation via the Cu(I)/Cu(II) redox cycle, resulting in H2O2 generation to produce Cu(I)-hydroperoxide, which causes oxidative DNA damage (Figure 3) [36]. However, datiscetin, which lacks the 4′-hydroxyl group of the B-ring, did not induce DNA damage under our experimental condition (unpublished data). These results indicated that the 4′-hydroxyl group of the B-ring plays an important role in the pro-oxidant activity of morin.

2.3. Polyphenols Involved in Inhibiting Elongation

2.3.1. Curcumin

Curcumin is the main naturally occurring polyphenol found in turmeric, which is isolated from the rhizome of Curcuma longa and is extensively used as a spice in curries and mustards [75]. Turmeric has also been traditionally used as a medicinal herb for the treatment of various diseases in Ayurvedic and traditional Chinese medicine [76]. Research on curcumin has shown that it possesses several protective and therapeutic properties, including anti-inflammatory, antioxidant, anti-microbial, and anti-cancer activity [77,78]. Recently, in the context of therapies for AD and other neurodegenerative diseases, Schubert et al. proposed a novel drug screening platform which finds candidates with multiple neuroprotective activities, and identified curcumin as a lead compound from the screening of natural product libraries [79]. As one of the neuroprotective properties, several in vitro [80,81] and in vivo [81,82] studies have demonstrated that curcumin can inhibit Aβ aggregation. Curcumin has been shown to prevent the formation and extension of Aβ fibrils and destabilize preformed Aβ fibrils in vitro [80]. Curcumin inhibits Aβ aggregation by directly binding Aβ to block its self-assembly in an in vitro aggregation assay [81]. NMR analysis has indicated that curcumin interacts with residue number 12 and 17–21, included in the β-sheet structure of the Aβ42 fibrils [10], suggesting that it has an inhibitory effect on fibril elongation. On the other hand, some researchers caution that these wide-range bioactivities of curcumin are characteristics of a pan-assay interference compound (PAINS) [83,84]. PAINS are compounds displaying activities which do not depend on a specific and drug-like interaction between molecule and protein, leading to artifact in multiple types of assays [83,84]. Thus, further research is needed to explore the therapeutic value of curcumin.
Curcumin has also been reported to have pro-oxidant properties under some conditions [85]. Several studies have reported ROS generation and DNA damage in cultured cells exposed to curcumin [39,40,41]. A National Toxicology Program study has revealed that the dietary intake of turmeric oleoresin, which contains a high curcumin content (79–85%), induced hyperplasia of the colon mucosa in rats and increased hepatocellular adenoma in mice [43]. These findings raise the possibility that curcumin-induced oxidative DNA damage may promote tumorigenesis [78]. However, we have previously shown that curcumin does not cause damage to isolated DNA by itself, even in the presence of Cu(II) [42]. Curcumin/Cu(II)-mediated oxidative DNA damage has occurred only when curcumin was pre-treated with cytochrome P450 (CYP) enzymes, suggesting that metabolites of curcumin act as DNA-damaging agents [42]. Mass spectral analysis indicated CYP2D6-mediated o-demethyl curcumin formation, which was considered to generate Cu(I)-hydroperoxide during the autoxidation of o-demethyl curcumin, resulting in DNA damage [42]. CYP enzymes are known to be related to bioactivation of several chemical carcinogens [86], suggesting that curcumin-mediated hepatocellular adenoma in mice [43] might be explained by particular metabolisms of hepatocytes. o-demethyl curcumin has a catechol moiety (phenol with two hydroxy groups in the ortho-position), resulting from CYP-mediated demethylation of curcumin, that is likely to play a critical role in oxidative damage (Figure 4A). Thus, some antioxidants could be converted to pro-oxidants in particular metabolic conditions. These findings suggest that it is important to evaluate not only target polyphenols but also their metabolites.

2.3.2. Quercetin and Kaempferol

Quercetin, a readily available naturally occurring polyphenol, is found abundantly in vegetables and fruits, such as onions and apples [87]. Quercetin is well known to have antioxidant and anti-inflammatory properties, and is expected to play protective roles in a wide range of diseases [88,89,90]. In vitro aggregation studies show that quercetin inhibits Aβ fibril formation by strengthening the hydrophobic interactions between the Aβ β-sheet structure and the aromatic ring by hydrogen bonding [91]. Quercetin exerts an anti-amyloidogenic effect in vitro by preferentially binding to Aβ fibrils at the growth edge, rather than to Aβ monomers, resulting in inhibition of fibril elongation [11]. Quercetin also reduces Aβ-induced neurotoxicity in a cell system overexpressing mutant APP, which is associated with early-onset familial AD [91]. Treatment with quercetin reduced the number and size of Aβ plaques and improves cognitive function in an AD mouse model [92]. Kaempferol, an analog of quercetin, also showed anti-Aβ aggregation activity [66]
Although the beneficial effects of quercetin are widely accepted, there is a concern about its potential pro-oxidant and cytotoxic activities when used therapeutically [93]. Results from several in vitro and in vivo studies suggest that quercetin has a pro-oxidant effect in addition to its antioxidant effect [34,94]. Quercetin has been reported to be mutagenic [47,48,49], and induce renal tubule adenocarcinomas [48] and intestinal and bladder cancer [50] in rats. We have previously shown that quercetin induced oxidative DNA damage both in isolated and cellular DNA [45,46]. Quercetin caused 8-oxodG formation in HL-60 cells, but not in their H2O2-resistant clones, HP100 cells, indicating that H2O2 is the main mediator of DNA damage and cytotoxicity in this context [45]. The pro-oxidant activity of quercetin is likely due to the presence of the catechol moiety and the resultant susceptibility to autoxidation, leading to conversion into ortho-semiquinone and ortho-quinone [95,96]. This finding is supported by the observation that kaempferol, a quercetin analog without catechol moieties, induces markedly weaker oxidative DNA damage than quercetin (Figure 4B) [46]. Furthermore, quercetin exhibits both mutagenicity and carcinogenicity [48,49,50], whereas kaempferol exhibits only mutagenicity (Table 1) [47], which might reflect the different extent of oxidative DNA damage caused by quercetin and kaempferol.

2.4. Polyphenols Involved in Inhibiting Elongation and Redirecting Aβ Monomers to “Off-Pathway” Aggregation

2.4.1. Epigallocatechin Gallate (EGCG) and Other Green Tea Catechins

Numerous epidemiological studies have demonstrated that consumption of green tea has many health benefits [97]. Among green tea catechins, EGCG is most abundant (65% of the total catechin content in green tea) and most biologically active [98]. EGCG is a powerful antioxidant, anti-inflammatory, and anti-infective agent, and is suggested to have protective effects in fighting many diseases [99,100,101]. EGCG inhibits Aβ fibrillogenesis by directly binding to natively unfolded polypeptides and promoting the formation of unstructured and nontoxic oligomers (so-called “off-pathway” aggregation) instead of toxic β-sheet–rich fibril [12,102]. EGCG oxidation products, such as quinones, may be involved in redirecting “off-pathway” aggregation by covalently binding to lysine of Aβ through a Schiff base formation [103]. In vitro studies have also demonstrated the ability of EGCG to convert mature Aβ fibrils into “off-pathway” aggregation by directly binding to the β-sheet-rich fibril and mediating conformational change [104]. In addition, Rezai-Zadeh et al. have reported that EGCG treatment decreases the Aβ plaque burden in the brain and improves working memory, using an AD mouse model [105,106].
However, many reports have suggested links between intake of high dose of EGCG and damage in several organs, especially the liver, in humans [56,107,108]. In 2018, the European Food Safety Authority concluded that intake of doses equal or above 800 mg EGCG/day, taken as a food supplement, can induce a significant increase of serum transaminases, which is indicative of liver injury [107]. A National Toxicology Program study reported that oral administration of green tea extracts containing EGCG (48.4% by weight) induced lesions in the gastrointestinal tract and liver in rats and mice [55]. A few cell model studies have shown that EGCG induces cellular DNA damage [53,109]. These potential harmful effects of EGCG have been attributed to its pro-oxidant activity [110,111,112]. Our previous report has indicated that EGCG significantly increases the content of 8-oxodG of DNA in cultured cells, but not in its H2O2-resistant clone cell [54], which is consistent with studies demonstrating intracellular ROS generation in cultured cells treated with EGCG [113,114]. Furthermore, EGCG caused oxidative damage to isolated DNA in the presence of Fe(III) and Cu(II) [54]. This was likely due to the generation of different ROS: hydroxy radical from the reaction of Fe(II) with H2O2 and Cu(I)-hydroperoxide from the reaction of Cu(I) with H2O2 [54]. To investigate the association between the chemical structure of green tea polyphenols and metal-mediated ROS generation, we compared EGCG-induced oxidative DNA damage in the presence of Fe(III) and Cu(II) with epicatechin gallate [115], epigallocatechin [116] and catechin [116], which are the other main green tea polyphenols that exert anti-Aβ aggregation activities. The results showed that EGCG, epicatechin gallate and epigallocatechin induced oxidative DNA damage in the presence of Fe(III) and Cu(II), whereas catechin did so in the presence of Cu(II) alone [54], suggesting that the pyrogallol moiety (phenolic three hydroxyl group) may be critical for Fe(III)-mediated ROS generation in green tea catechins (Figure 5).

2.4.2. Propyl Gallate and Gallic Acid

Propyl gallate and gallic acid have been reported to inhibit Aβ aggregation [117]. The anti-Aβ aggregation activities of gallic acid have been well-studied; the mechanism by which propyl gallate inhibits Aβ aggregation remains unknown. Gallic acid is an abundantly found polyphenol in the plant kingdom and is present in tea, wine, and fruits, such as grape and berries [118]. Gallic acid has been reported to have a beneficial effect on health and is pharmacologically effective in many diseases [119]. In relation to AD, several in vitro studies have demonstrated that gallic acid can reduce Aβ aggregation [13,117,120,121]. Molecular docking studies have shown that gallic acid interacts with Aβ aggregates and inhibits Aβ fibril formation by disrupting the Lys28-Ala42 salt bridge of Aβ [13]. Alternatively, gallic acid may convert toxic Aβ aggregates into “off-pathway” aggregation [122], similar to previously reported properties of EGCG [12,102]. Recently, Yu et al. have reported that gallic acid treatment alleviates cognitive decline in an AD mouse model at both early and late stages [13].
In contrast, potential harmful effects of propyl gallate and gallic acid, associated with their pro-oxidant properties, have also been reported [59,60,61,62,63]. Propyl gallate, but not gallic acid, is carcinogenic in mice and rats [123]. While propyl gallate led to 8-oxodG formation in cultured cells, it did not induce damage in isolated DNA [60]. Propyl gallate has been known to convert to gallic acid by an esterase (Figure 6) [124]. Therefore, to clarify its mechanism of carcinogenicity, we studied isolated DNA damage caused by gallic acid. Gallic acid and esterase-treated propyl gallate could induce Fe(III)- and Cu(II)-dependent oxidative DNA damage in isolated DNA through metal-mediated autoxidation [60]. These results suggest that gallic acid converted from propyl gallate plays an important role in propyl gallate-mediated carcinogenicity. To understand why gallic acid, but not propyl gallate, induces oxidative DNA damage, highest occupied molecular orbital (HOMO) energy estimation [125] was performed. The HOMO energy of the anionic form of gallic acid is smaller than that of propyl gallate, suggesting that gallic acid can readily undergo autoxidation compared to propyl gallate (Figure 6) [60]. Furthermore, gallic acid has been reported to display toxic effects other than carcinogenesis [59,62,63]. Administration of gallic acid induces liver injury [62,63] in mice and rats, and renal damage [63] in rats. ROS-associated cytotoxicity of gallic acid against noncancerous cell has been demonstrated using rat primary cultured hepatocytes [62] and vascular smooth muscle cells [59].

3. The Role of Phenolic Hydroxyl Groups in Anti-Aβ Aggregation and Pro-Oxidant Activities of Polyphenols

The phenolic hydroxyl groups of polyphenols are considered to be essential for its anti-Aβ aggregation activity. Quinones generated from phenolic hydroxyl groups can react with the lysine side chains of proteins [126]. Lys28 of Aβ has been reported to be critical for Aβ42 aggregation [127]. Therefore, quinones, especially catechol-type quinones, may contribute to the inhibition of Aβ aggregation. This is supported by the finding that the interactions between quinones from several polyphenols and lysine of Aβ play an important role in the inhibition of Aβ aggregation [103,128]. In contrast, our studies have shown ROS generation by several polyphenols through their autoxidation and quinone formation in the presence of metal ions such as Cu(II) [36,42,45,46,54,60,129]. In addition, some metabolites of target polyphenols also display pro-oxidant activities via quinone formation, even though target polyphenols themselves are not pro-oxidant [42,60].
Some studies have reported binding of the phenolic hydroxyl groups with histidine in anti-amyloid aggregation activity [9,130]. Histidine residues of Aβ impact Aβ aggregation by affecting the oligomeric equilibria [131] and interacting with metal ions [132]. Morin interacts with His13, His14, and Gln15 of Aβ42, corresponding to the intermolecular regions of β-sheets, and prevents Aβ assembly likely via its aromatic rings [9]. In the case of islet amyloid polypeptide, curcumin was shown to prevent inter-peptide interaction between Phe15 and His18, which is important for the aggregation of amyloids [130]. However, we have suggested that phenolic hydroxyl groups of morin and a metabolite of curcumin react with Cu(II), which leads to ROS generation and oxidative DNA damage [36,42].
Interestingly, copper is also thought to be associated with the enhancement of Aβ aggregation. The level of copper is elevated in the blood of AD patients [133] and Aβ plaques in an AD mouse model [134]. Cu(II) interacts with Aβ and enables the formation of β-sheets via its binding to His13 and His14, thereby forming a brace between Aβ strands [135]. Several polyphenols enable the chelating of various metal ions [136,137]. A recent report has shown that EGCG inhibits Cu(II)-associated amyloid aggregation of α-synuclein [138]. These findings suggest that polyphenols may inhibit Aβ aggregation via a Cu(II) chelating mechanism. However, as mentioned above, the interaction of polyphenols with Cu(II) leads to concomitant oxidative DNA damage [36,42,45,46,54,60,129].
These findings suggest that polyphenols can block Aβ aggregation and cause oxidative damage under certain circumstances, such as when they are in proximity to DNA.

4. Conclusions

Naturally occurring polyphenols are generally regarded as safe, based on their long history of use in the diet. However, when used at pharmacological concentrations, they have potential risks [18,19,20]. In this review, the pro-oxidant properties and the associated toxic effects of several naturally occurring polyphenols with anti-Aβ aggregation activity have been summarized. The pro-oxidant and anti-Aβ aggregation effects can be attributed to the structural features of polyphenols, suggesting a potential risk of oxidative damage. Therefore, we would like to emphasize the importance of assessing pro-oxidant properties of polyphenols from the point of view of safety.

Author Contributions

H.K. and S.O. wrote the first draft of the manuscript; M.M. and S.K. read the draft and made substantial and critical revisions. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ADAlzheimer’s disease
Aβamyloid β
APPamyloid precursor protein
ROSreactive oxygen species
EGCGepigallocatechin gallate
NMRnuclear magnetic resonance
8-oxodG8-oxo-7,8-dihydro-2′-deoxyguanosine
PAINSpan-assay interference compound
CYPcytochrome P450
HOMO energyhighest occupied molecular orbital energy

References

  1. Winblad, B.; Amouyel, P.; Andrieu, S.; Ballard, C.; Brayne, C.; Brodaty, H.; Cedazo-Minguez, A.; Dubois, B.; Edvardsson, D.; Feldman, H.; et al. Defeating Alzheimer’s disease and other dementias: A priority for European science and society. Lancet. Neurol. 2016, 15, 455–532. [Google Scholar] [CrossRef] [Green Version]
  2. Panza, F.; Lozupone, M.; Logroscino, G.; Imbimbo, B.P. A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 2019, 15, 73–88. [Google Scholar] [CrossRef] [PubMed]
  3. LaFerla, F.M.; Green, K.N.; Oddo, S. Intracellular amyloid-β in Alzheimer’s disease. Nat. Rev. Neurosci. 2007, 8, 499–509. [Google Scholar] [CrossRef] [PubMed]
  4. Ayala, S.; Genevaux, P.; Hureau, C.; Faller, P. (Bio)chemical Strategies To Modulate Amyloid-beta Self-Assembly. Acs Chem. Neurosci. 2019, 10, 3366–3374. [Google Scholar] [CrossRef]
  5. Arosio, P.; Knowles, T.P.; Linse, S. On the lag phase in amyloid fibril formation. Phys. Chem. Chem. Phys. Pccp 2015, 17, 7606–7618. [Google Scholar] [CrossRef] [Green Version]
  6. Kumar, S.; Walter, J. Phosphorylation of amyloid beta (Aβ) peptides–A trigger for formation of toxic aggregates in Alzheimer’s disease. Aging (Albany Ny) 2011, 3, 803. [Google Scholar] [CrossRef]
  7. Long, J.M.; Holtzman, D.M. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell 2019, 179, 312–339. [Google Scholar] [CrossRef]
  8. Ono, K.; Li, L.; Takamura, Y.; Yoshiike, Y.; Zhu, L.; Han, F.; Mao, X.; Ikeda, T.; Takasaki, J.; Nishijo, H.; et al. Phenolic compounds prevent amyloid beta-protein oligomerization and synaptic dysfunction by site-specific binding. J. Biol. Chem. 2012, 287, 14631–14643. [Google Scholar] [CrossRef] [Green Version]
  9. Hanaki, M.; Murakami, K.; Akagi, K.; Irie, K. Structural insights into mechanisms for inhibiting amyloid beta42 aggregation by non-catechol-type flavonoids. Bioorganic Med. Chem. 2016, 24, 304–313. [Google Scholar] [CrossRef]
  10. Masuda, Y.; Fukuchi, M.; Yatagawa, T.; Tada, M.; Takeda, K.; Irie, K.; Akagi, K.-i.; Monobe, Y.; Imazawa, T.; Takegoshi, K. Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid β-protein fibrils. Bioorganic Med. Chem. 2011, 19, 5967–5974. [Google Scholar] [CrossRef]
  11. Hirohata, M.; Hasegawa, K.; Tsutsumi-Yasuhara, S.; Ohhashi, Y.; Ookoshi, T.; Ono, K.; Yamada, M.; Naiki, H. The anti-amyloidogenic effect is exerted against Alzheimer’s beta-amyloid fibrils in vitro by preferential and reversible binding of flavonoids to the amyloid fibril structure. Biochemistry 2007, 46, 1888–1899. [Google Scholar] [CrossRef] [PubMed]
  12. Ehrnhoefer, D.E.; Bieschke, J.; Boeddrich, A.; Herbst, M.; Masino, L.; Lurz, R.; Engemann, S.; Pastore, A.; Wanker, E.E. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat. Struct. Mol. Biol. 2008, 15, 558–566. [Google Scholar] [CrossRef] [PubMed]
  13. Yu, M.; Chen, X.; Liu, J.; Ma, Q.; Zhuo, Z.; Chen, H.; Zhou, L.; Yang, S.; Zheng, L.; Ning, C.; et al. Gallic acid disruption of Abeta1-42 aggregation rescues cognitive decline of APP/PS1 double transgenic mouse. Neurobiol. Dis. 2019, 124, 67–80. [Google Scholar] [CrossRef] [PubMed]
  14. Dhouafli, Z.; Cuanalo-Contreras, K.; Hayouni, E.A.; Mays, C.E.; Soto, C.; Moreno-Gonzalez, I. Inhibition of protein misfolding and aggregation by natural phenolic compounds. Cell. Mol. Life Sci. Cmls 2018, 75, 3521–3538. [Google Scholar] [CrossRef] [PubMed]
  15. Perez-Jimenez, J.; Neveu, V.; Vos, F.; Scalbert, A. Systematic analysis of the content of 502 polyphenols in 452 foods and beverages: An application of the phenol-explorer database. J. Agric. Food Chem. 2010, 58, 4959–4969. [Google Scholar] [CrossRef] [PubMed]
  16. Velander, P.; Wu, L.; Henderson, F.; Zhang, S.; Bevan, D.R.; Xu, B. Natural product-based amyloid inhibitors. Biochem. Pharmacol. 2017, 139, 40–55. [Google Scholar] [CrossRef] [Green Version]
  17. Yamada, M.; Ono, K.; Hamaguchi, T.; Noguchi-Shinohara, M. Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis. Adv. Exp. Med. Biol. 2015, 863, 79–94. [Google Scholar]
  18. Sen, S.; Chakraborty, R. Antioxidant Supplements: Friend or Foe? In Free Radicals in Human Health and Disease 2015, 293–322. [Google Scholar] [CrossRef]
  19. Martin, K.R.; Appel, C.L. Polyphenols as dietary supplements: A double-edged sword. Nutr. Diet. Suppl. 2009, 2, 1–12. [Google Scholar] [CrossRef] [Green Version]
  20. Lambert, J.D.; Sang, S.; Yang, C.S. Possible controversy over dietary polyphenols: Benefits vs risks. Chem. Res. Toxicol. 2007, 20, 583–585. [Google Scholar] [CrossRef]
  21. Cieślik, E.; Gręda, A.; Adamus, W. Contents of polyphenols in fruit and vegetables. Food Chem. 2006, 94, 135–142. [Google Scholar] [CrossRef]
  22. Murata, M.; Kawanishi, S. Mechanisms of oxidative DNA damage induced by carcinogenic arylamines. Front. Biosci. (Landmark Ed.) 2011, 16, 1132–1143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Almeida, A.F.; Dos Santos, C.N.; Ventura, M.R. Polyphenols, their Metabolites and Derivatives as Drug Leads. Curr. Pharm. Des. 2018, 24, 2188–2207. [Google Scholar] [CrossRef] [PubMed]
  24. Carregosa, D.; Carecho, R.; Figueira, I.; Santos, C.N. Low-Molecular Weight Metabolites from Polyphenols as Effectors for Attenuating Neuroinflammation. J. Agric. Food Chem. 2020, 68, 1790–1807. [Google Scholar] [CrossRef] [Green Version]
  25. Sahu, S.C.; Flynn, T.J.; Bradlaw, J.A.; Roth, W.L.; Barton, C.N.; Yates, J.G. Pro-oxidant effects of the flavonoid myricetin on rat hepatocytes in culture. Toxicol. Methods 2001, 11, 277–283. [Google Scholar] [CrossRef]
  26. Park, H.; Park, S.; Bazer, F.W.; Lim, W.; Song, G. Myricetin treatment induces apoptosis in canine osteosarcoma cells by inducing DNA fragmentation, disrupting redox homeostasis, and mediating loss of mitochondrial membrane potential. J. Cell. Physiol. 2018, 233, 7457–7466. [Google Scholar] [CrossRef]
  27. Knickle, A.; Fernando, W.; Greenshields, A.L.; Rupasinghe, H.P.V.; Hoskin, D.W. Myricetin-induced apoptosis of triple-negative breast cancer cells is mediated by the iron-dependent generation of reactive oxygen species from hydrogen peroxide. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2018, 118, 154–167. [Google Scholar] [CrossRef]
  28. Sahu, S.C.; Gray, G.C. Interactions of flavonoids, trace metals, and oxygen: Nuclear DNA damage and lipid peroxidation induced by myricetin. Cancer Lett. 1993, 70, 73–79. [Google Scholar] [CrossRef]
  29. Arif, H.; Sohail, A.; Farhan, M.; Rehman, A.A.; Ahmad, A.; Hadi, S.M. Flavonoids-induced redox cycling of copper ions leads to generation of reactive oxygen species: A potential role in cancer chemoprevention. Int. J. Biol. Macromol. 2018, 106, 569–578. [Google Scholar] [CrossRef]
  30. Jomova, K.; Hudecova, L.; Lauro, P.; Simunkova, M.; Alwasel, S.H.; Alhazza, I.M.; Valko, M. A Switch between Antioxidant and Prooxidant Properties of the Phenolic Compounds Myricetin, Morin, 3’,4’-Dihydroxyflavone, Taxifolin and 4-Hydroxy-Coumarin in the Presence of Copper(II) Ions: A Spectroscopic, Absorption Titration and DNA Damage Study. Molecules (Basel, Switz.) 2019, 24, 4335. [Google Scholar] [CrossRef] [Green Version]
  31. Yoshino, M.; Haneda, M.; Naruse, M.; Murakami, K. Prooxidant activity of flavonoids: Copper-dependent strand breaks and the formation of 8-hydroxy-2’-deoxyguanosine in DNA. Mol. Genet. Metab. 1999, 68, 468–472. [Google Scholar] [CrossRef] [PubMed]
  32. Hobbs, C.A.; Swartz, C.; Maronpot, R.; Davis, J.; Recio, L.; Koyanagi, M.; Hayashi, S.M. Genotoxicity evaluation of the flavonoid, myricitrin, and its aglycone, myricetin. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2015, 83, 283–292. [Google Scholar] [CrossRef] [PubMed]
  33. Silva, I.D.; Gaspar, J.; Rodrigues, A.; da Costa, G.G.; Laires, A.; Rueff, J. Mechanisms of myricetin mutagenicity in V79 cells: Involvement of radicalar species. Teratog. Carcinog. Mutagenesis 1996, 16, 253–268. [Google Scholar] [CrossRef]
  34. Yen, G.C.; Duh, P.D.; Tsai, H.L.; Huang, S.L. Pro-oxidative properties of flavonoids in human lymphocytes. Biosci. Biotechnol. Biochem. 2003, 67, 1215–1222. [Google Scholar] [CrossRef] [Green Version]
  35. Sahu, S.C.; Gray, G.C. Lipid peroxidation and DNA damage induced by morin and naringenin in isolated rat liver nuclei. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 1997, 35, 443–447. [Google Scholar] [CrossRef]
  36. Mori, Y.; Kato, S.; Fujisawa, Y.; Ohnishi, S.; Hiraku, Y.; Kawanishi, S.; Murata, M.; Oikawa, S. Mechanisms of DNA damage induced by morin, an inhibitor of amyloid beta-peptide aggregation. Free Radic. Res. 2019, 53, 115–123. [Google Scholar] [CrossRef]
  37. Roy, A.S.; Samanta, S.K.; Ghosh, P.; Tripathy, D.R.; Ghosh, S.K.; Dasgupta, S. Cell cytotoxicity and serum albumin binding capacity of the morin-Cu(ii) complex and its effect on deoxyribonucleic acid. Mol. Biosyst. 2016, 12, 2818–2833. [Google Scholar] [CrossRef]
  38. Jurado, J.; Alejandre-Duran, E.; Alonso-Moraga, A.; Pueyo, C. Study on the mutagenic activity of 13 bioflavonoids with the Salmonella Ara test. Mutagenesis 1991, 6, 289–295. [Google Scholar] [CrossRef]
  39. Yoshino, M.; Haneda, M.; Naruse, M.; Htay, H.H.; Tsubouchi, R.; Qiao, S.L.; Li, W.H.; Murakami, K.; Yokochi, T. Prooxidant activity of curcumin: Copper-dependent formation of 8-hydroxy-2’-deoxyguanosine in DNA and induction of apoptotic cell death. Toxicol. Vitr. Int. J. Publ. Assoc. Bibra 2004, 18, 783–789. [Google Scholar] [CrossRef]
  40. Woo, J.H.; Kim, Y.H.; Choi, Y.J.; Kim, D.G.; Lee, K.S.; Bae, J.H.; Min, D.S.; Chang, J.S.; Jeong, Y.J.; Lee, Y.H.; et al. Molecular mechanisms of curcumin-induced cytotoxicity: Induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis 2003, 24, 1199–1208. [Google Scholar] [CrossRef] [Green Version]
  41. Urbina-Cano, P.; Bobadilla-Morales, L.; Ramírez-Herrera, M.A.; Corona-Rivera, J.R.; Mendoza-Magaña, M.L.; Troyo-Sanromán, R.; Corona-Rivera, A. DNA damage in mouse lymphocytes exposed to curcumin and copper. J. Appl. Genet. 2006, 47, 377–382. [Google Scholar] [CrossRef] [PubMed]
  42. Sakano, K.; Kawanishi, S. Metal-mediated DNA damage induced by curcumin in the presence of human cytochrome P450 isozymes. Arch. Biochem. Biophys. 2002, 405, 223–230. [Google Scholar] [CrossRef]
  43. National Toxicology Program. NTP Toxicology and Carcinogenesis Studies of Turmeric Oleoresin (CAS No. 8024-37-1) (Major Component 79%–85% Curcumin, CAS No. 458-37-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). Natl. Toxicol. Program Tech. Rep. Ser. 1993, 427, 1–275. [Google Scholar]
  44. Lapidot, T.; Walker, M.D.; Kanner, J. Antioxidant and prooxidant effects of phenolics on pancreatic β-cells in vitro. J. Agric. Food Chem. 2002, 50, 7220–7225. [Google Scholar] [CrossRef] [PubMed]
  45. Yamashita, N.; Kawanishi, S. Distinct mechanisms of DNA damage in apoptosis induced by quercetin and luteolin. Free Radic. Res. 2000, 33, 623–633. [Google Scholar] [CrossRef]
  46. Yamashita, N.; Tanemura, H.; Kawanishi, S. Mechanism of oxidative DNA damage induced by quercetin in the presence of Cu(II). Mutat. Res. 1999, 425, 107–115. [Google Scholar] [CrossRef]
  47. Resende, F.A.; Vilegas, W.; Dos Santos, L.C.; Varanda, E.A. Mutagenicity of flavonoids assayed by bacterial reverse mutation (Ames) test. Molecules (Basel, Switz.) 2012, 17, 5255–5268. [Google Scholar] [CrossRef]
  48. National Toxicology Program. Toxicology and Carcinogenesis Studies of Quercetin (CAS No. 117-39-5) in F344 Rats (Feed Studies). Natl. Toxicol. Program Tech. Rep. Ser. 1992, 409, 1–171. [Google Scholar]
  49. Gaspar, J.; Rodrigues, A.; Laires, A.; Silva, F.; Costa, S.; Monteiro, M.J.; Monteiro, C.; Rueff, J. On the mechanisms of genotoxicity and metabolism of quercetin. Mutagenesis 1994, 9, 445–449. [Google Scholar] [CrossRef]
  50. Pamukcu, A.M.; Yalciner, S.; Hatcher, J.F.; Bryan, G.T. Quercetin, a rat intestinal and bladder carcinogen present in bracken fern (Pteridium aquilinum). Cancer Res. 1980, 40, 3468–3472. [Google Scholar]
  51. Chan, M.M.; Soprano, K.J.; Weinstein, K.; Fong, D. Epigallocatechin-3-gallate delivers hydrogen peroxide to induce death of ovarian cancer cells and enhances their cisplatin susceptibility. J. Cell. Physiol. 2006, 207, 389–396. [Google Scholar] [CrossRef] [PubMed]
  52. Nakagawa, H.; Hasumi, K.; Woo, J.-T.; Nagai, K.; Wachi, M. Generation of hydrogen peroxide primarily contributes to the induction of Fe (II)-dependent apoptosis in Jurkat cells by (−)-epigallocatechin gallate. Carcinogenesis 2004, 25, 1567–1574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Johnson, M.K.; Loo, G. Effects of epigallocatechin gallate and quercetin on oxidative damage to cellular DNA. Mutat. Res. 2000, 459, 211–218. [Google Scholar] [CrossRef] [Green Version]
  54. Furukawa, A.; Oikawa, S.; Murata, M.; Hiraku, Y.; Kawanishi, S. (-)-Epigallocatechin gallate causes oxidative damage to isolated and cellular DNA. Biochem. Pharmacol. 2003, 66, 1769–1778. [Google Scholar] [CrossRef]
  55. National Toxicology Program. Toxicology Studies of green tea extract in F344/NTac Rats and B6C3F1/N mice and toxicology and carcinogenesis studies of green tea extract in Wistar Han [Crl:WI(Han)] rats and B6C3F1/N Mice (gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 2016, 585, 1–192. [Google Scholar]
  56. Hu, J.; Webster, D.; Cao, J.; Shao, A. The safety of green tea and green tea extract consumption in adults—Results of a systematic review. Regul. Toxicol. Pharmacol. Rtp 2018, 95, 412–433. [Google Scholar] [CrossRef]
  57. Lee, K.W.; Hur, H.J.; Lee, H.J.; Lee, C.Y. Antiproliferative effects of dietary phenolic substances and hydrogen peroxide. J. Agric. Food Chem. 2005, 53, 1990–1995. [Google Scholar] [CrossRef]
  58. Isuzugawa, K.; Inoue, M.; Ogihara, Y. Catalase contents in cells determine sensitivity to the apoptosis inducer gallic acid. Biol. Pharm. Bull. 2001, 24, 1022–1026. [Google Scholar] [CrossRef] [Green Version]
  59. Qiu, X.; Takemura, G.; Koshiji, M.; Hayakawa, Y.; Kanoh, M.; Maruyama, R.; Ohno, Y.; Minatoguchi, S.; Akao, S.; Fukuda, K.; et al. Gallic acid induces vascular smooth muscle cell death via hydroxyl radical production. Heart Vessel. 2000, 15, 90–99. [Google Scholar] [CrossRef]
  60. Kobayashi, H.; Oikawa, S.; Hirakawa, K.; Kawanishi, S. Metal-mediated oxidative damage to cellular and isolated DNA by gallic acid, a metabolite of antioxidant propyl gallate. Mutat. Res. 2004, 558, 111–120. [Google Scholar] [CrossRef]
  61. Yoshino, M.; Haneda, M.; Naruse, M.; Htay, H.; Iwata, S.; Tsubouchi, R.; Murakami, K. Prooxidant action of gallic acid compounds: Copper-dependent strand breaks and the formation of 8-hydroxy-2′-deoxyguanosine in DNA. Toxicol. Vitr. 2002, 16, 705–709. [Google Scholar] [CrossRef]
  62. Galati, G.; Lin, A.; Sultan, A.M.; O’Brien, P.J. Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins. Free Radic. Biol. Med. 2006, 40, 570–580. [Google Scholar] [CrossRef]
  63. Abarikwu, S.O.; Durojaiye, M.; Alabi, A.; Asonye, B.; Akiri, O. Curcumin protects against gallic acid-induced oxidative stress, suppression of glutathione antioxidant defenses, hepatic and renal damage in rats. Ren. Fail. 2016, 38, 321–329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Jiang, M.; Zhu, M.; Wang, L.; Yu, S. Anti-tumor effects and associated molecular mechanisms of myricetin. Biomed. Pharmacother. Biomed. Pharmacother. 2019, 120, 109506. [Google Scholar] [CrossRef] [PubMed]
  65. Semwal, D.K.; Semwal, R.B.; Combrinck, S.; Viljoen, A. Myricetin: A Dietary Molecule with Diverse Biological Activities. Nutrients 2016, 8, 90. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Ono, K.; Yoshiike, Y.; Takashima, A.; Hasegawa, K.; Naiki, H.; Yamada, M. Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: Implications for the prevention and therapeutics of Alzheimer’s disease. J. Neurochem. 2003, 87, 172–181. [Google Scholar] [CrossRef] [PubMed]
  67. Hamaguchi, T.; Ono, K.; Murase, A.; Yamada, M. Phenolic compounds prevent Alzheimer’s pathology through different effects on the amyloid-beta aggregation pathway. Am. J. Pathol. 2009, 175, 2557–2565. [Google Scholar] [CrossRef] [Green Version]
  68. Kataria, R.; Sobarzo-Sanchez, E.; Khatkar, A. Role of Morin in Neurodegenerative Diseases: A Review. Curr. Top. Med. Chem. 2018, 18, 901–907. [Google Scholar] [CrossRef]
  69. Caselli, A.; Cirri, P.; Santi, A.; Paoli, P. Morin: A Promising Natural Drug. Curr. Med. Chem. 2016, 23, 774–791. [Google Scholar] [CrossRef]
  70. Sinha, K.; Ghosh, J.; Sil, P.C. Morin and Its Role in Chronic Diseases. Adv. Exp. Med. Biol. 2016, 928, 453–471. [Google Scholar]
  71. Kim, H.; Park, B.S.; Lee, K.G.; Choi, C.Y.; Jang, S.S.; Kim, Y.H.; Lee, S.E. Effects of naturally occurring compounds on fibril formation and oxidative stress of beta-amyloid. J. Agric. Food Chem. 2005, 53, 8537–8541. [Google Scholar] [CrossRef] [PubMed]
  72. Du, Y.; Qu, J.; Zhang, W.; Bai, M.; Zhou, Q.; Zhang, Z.; Li, Z.; Miao, J. Morin reverses neuropathological and cognitive impairments in APPswe/PS1dE9 mice by targeting multiple pathogenic mechanisms. Neuropharmacology 2016, 108, 1–13. [Google Scholar] [CrossRef] [PubMed]
  73. Sharma, D.; Singh, M.; Kumar, P.; Vikram, V.; Mishra, N. Development and characterization of morin hydrate loaded microemulsion for the management of Alzheimer’s disease. Artif. Cells Nanomed. Biotechnol. 2017, 45, 1620–1630. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Murakami, K.; Irie, K. Three Structural Features of Functional Food Components and Herbal Medicine with Amyloid beta42 Anti-Aggregation Properties. Molecules (Basel,Switz.) 2019, 24. [Google Scholar]
  75. Gupta, S.C.; Sung, B.; Kim, J.H.; Prasad, S.; Li, S.; Aggarwal, B.B. Multitargeting by turmeric, the golden spice: From kitchen to clinic. Mol. Nutr. Food Res. 2013, 57, 1510–1528. [Google Scholar] [CrossRef] [PubMed]
  76. Kocaadam, B.; Sanlier, N. Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit. Rev. Food Sci. Nutr. 2017, 57, 2889–2895. [Google Scholar] [CrossRef]
  77. Jin, T.R. Curcumin and dietary polyphenol research: Beyond drug discovery. Acta Pharmacol. Sin. 2018, 39, 779–786. [Google Scholar] [CrossRef] [Green Version]
  78. Pulido-Moran, M.; Moreno-Fernandez, J.; Ramirez-Tortosa, C.; Ramirez-Tortosa, M. Curcumin and Health. Molecules (Basel, Switz.) 2016, 21, 264. [Google Scholar] [CrossRef]
  79. Schubert, D.; Currais, A.; Goldberg, J.; Finley, K.; Petrascheck, M.; Maher, P. Geroneuroprotectors: Effective Geroprotectors for the Brain. Trends Pharm. Sci 2018, 39, 1004–1007. [Google Scholar] [CrossRef]
  80. Ono, K.; Hasegawa, K.; Naiki, H.; Yamada, M. Curcumin has potent anti-amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro. J. Neurosci. Res. 2004, 75, 742–750. [Google Scholar] [CrossRef]
  81. Yang, F.; Lim, G.P.; Begum, A.N.; Ubeda, O.J.; Simmons, M.R.; Ambegaokar, S.S.; Chen, P.P.; Kayed, R.; Glabe, C.G.; Frautschy, S.A.; et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 2005, 280, 5892–5901. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Garcia-Alloza, M.; Borrelli, L.A.; Rozkalne, A.; Hyman, B.T.; Bacskai, B.J. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J. Neurochem. 2007, 102, 1095–1104. [Google Scholar] [CrossRef] [PubMed]
  83. Baell, J.; Walters, M.A. Chemistry: Chemical con artists foil drug discovery. Nature 2014, 513, 481–483. [Google Scholar] [CrossRef] [PubMed]
  84. Nelson, K.M.; Dahlin, J.L.; Bisson, J.; Graham, J.; Pauli, G.F.; Walters, M.A. The Essential Medicinal Chemistry of Curcumin. J. Med. Chem. 2017, 60, 1620–1637. [Google Scholar] [CrossRef]
  85. Malik, P.; Mukherjee, T.K. Structure-Function Elucidation of Antioxidative and Prooxidative Activities of the Polyphenolic Compound Curcumin. Chin. J. Biol. 2014, 2014, 1–8. [Google Scholar] [CrossRef] [Green Version]
  86. Alzahrani, A.M.; Rajendran, P. The Multifarious Link between Cytochrome P450s and Cancer. Oxidative Med. Cell. Longev. 2020, 2020, 3028387. [Google Scholar] [CrossRef]
  87. Wang, W.; Sun, C.; Mao, L.; Ma, P.; Liu, F.; Yang, J.; Gao, Y. The biological activities, chemical stability, metabolism and delivery systems of quercetin: A review. Trends Food Sci. Technol. 2016, 56, 21–38. [Google Scholar] [CrossRef]
  88. Xu, D.; Hu, M.J.; Wang, Y.Q.; Cui, Y.L. Antioxidant Activities of Quercetin and Its Complexes for Medicinal Application. Molecules (Basel, Switz.) 2019, 24, 1123. [Google Scholar] [CrossRef] [Green Version]
  89. Li, Y.; Yao, J.; Han, C.; Yang, J.; Chaudhry, M.T.; Wang, S.; Liu, H.; Yin, Y. Quercetin, Inflammation and Immunity. Nutrients 2016, 8, 167. [Google Scholar] [CrossRef]
  90. Khan, H.; Ullah, H.; Aschner, M.; Cheang, W.S.; Akkol, E.K. Neuroprotective Effects of Quercetin in Alzheimer’s Disease. Biomolecules 2019, 10, 59. [Google Scholar] [CrossRef] [Green Version]
  91. Jimenez-Aliaga, K.; Bermejo-Bescos, P.; Benedi, J.; Martin-Aragon, S. Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells. Life Sci. 2011, 89, 939–945. [Google Scholar] [CrossRef] [PubMed]
  92. Wang, D.-M.; Li, S.-Q.; Wu, W.-L.; Zhu, X.-Y.; Wang, Y.; Yuan, H.-Y. Effects of long-term treatment with quercetin on cognition and mitochondrial function in a mouse model of Alzheimer’s disease. Neurochem. Res. 2014, 39, 1533–1543. [Google Scholar] [CrossRef] [PubMed]
  93. Dajas, F.; Abin-Carriquiry, J.A.; Arredondo, F.; Blasina, F.; Echeverry, C.; Martinez, M.; Rivera, F.; Vaamonde, L. Quercetin in brain diseases: Potential and limits. Neurochem. Int. 2015, 89, 140–148. [Google Scholar] [CrossRef] [PubMed]
  94. Parveen, N.; Shadab, G.G. The dual clastogenic and anti-clastogenic properties of quercetin is dose dependent. Front. Biosci. (Sch. Ed.) 2017, 9, 139–153. [Google Scholar]
  95. Walle, T. Methylation of dietary flavones increases their metabolic stability and chemopreventive effects. Int. J. Mol. Sci. 2009, 10, 5002–5019. [Google Scholar] [CrossRef] [PubMed]
  96. Chang, H.; Mi, M.; Ling, W.; Zhu, J.; Zhang, Q.; Wei, N.; Zhou, Y.; Tang, Y.; Yuan, J. Structurally related cytotoxic effects of flavonoids on human cancer cells in vitro. Arch. Pharmacal Res. 2008, 31, 1137–1144. [Google Scholar] [CrossRef]
  97. Hara, Y.; Yang, C.S.; Isemura, M.; Tomita, I. Health benefits of green tea: An evidence-based approach; CABI: Wallingford, UK, 2017; ISBN 9781786392398. [Google Scholar]
  98. Islam, M.A. Cardiovascular effects of green tea catechins: Progress and promise. Recent Pat. Cardiovasc. Drug Discov. 2012, 7, 88–99. [Google Scholar] [CrossRef]
  99. Eng, Q.Y.; Thanikachalam, P.V.; Ramamurthy, S. Molecular understanding of Epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases. J. Ethnopharmacol. 2018, 210, 296–310. [Google Scholar] [CrossRef]
  100. Singh, N.A.; Mandal, A.K.; Khan, Z.A. Potential neuroprotective properties of epigallocatechin-3-gallate (EGCG). Nutr. J. 2016, 15, 60. [Google Scholar] [CrossRef] [Green Version]
  101. Chakrawarti, L.; Agrawal, R.; Dang, S.; Gupta, S.; Gabrani, R. Therapeutic effects of EGCG: A patent review. Expert Opin. Ther. Pat. 2016, 26, 907–916. [Google Scholar] [CrossRef]
  102. Ngo, S.T.; Truong, D.T.; Tam, N.M.; Nguyen, M.T. EGCG inhibits the oligomerization of amyloid beta (16-22) hexamer: Theoretical studies. J. Mol. Graph. Model. 2017, 76, 1–10. [Google Scholar] [CrossRef] [PubMed]
  103. Palhano, F.L.; Lee, J.; Grimster, N.P.; Kelly, J.W. Toward the molecular mechanism(s) by which EGCG treatment remodels mature amyloid fibrils. J. Am. Chem. Soc. 2013, 135, 7503–7510. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Bieschke, J.; Russ, J.; Friedrich, R.P.; Ehrnhoefer, D.E.; Wobst, H.; Neugebauer, K.; Wanker, E.E. EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc. Natl. Acad. Sci. USA 2010, 107, 7710–7715. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Rezai-Zadeh, K.; Arendash, G.W.; Hou, H.; Fernandez, F.; Jensen, M.; Runfeldt, M.; Shytle, R.D.; Tan, J. Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res. 2008, 1214, 177–187. [Google Scholar] [CrossRef]
  106. Rezai-Zadeh, K.; Shytle, D.; Sun, N.; Mori, T.; Hou, H.; Jeanniton, D.; Ehrhart, J.; Townsend, K.; Zeng, J.; Morgan, D.; et al. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J. Neurosci. Off. J. Soc. Neurosci. 2005, 25, 8807–8814. [Google Scholar] [CrossRef] [Green Version]
  107. Younes, M.; Aggett, P.; Aguilar, F.; Crebelli, R.; Dusemund, B.; Filipič, M.; Frutos, M.J.; Galtier, P.; Gott, D.; Gundert-Remy, U.; et al. Scientific opinion on the safety of green tea catechins. Efsa J. 2018, 16. [Google Scholar]
  108. Dekant, W.; Fujii, K.; Shibata, E.; Morita, O.; Shimotoyodome, A. Safety assessment of green tea based beverages and dried green tea extracts as nutritional supplements. Toxicol. Lett. 2017, 277, 104–108. [Google Scholar] [CrossRef]
  109. Bertram, B.; Bollow, U.; Rajaee-Behbahani, N.; Burkle, A.; Schmezer, P. Induction of poly(ADP-ribosyl)ation and DNA damage in human peripheral lymphocytes after treatment with (-)-epigallocatechin-gallate. Mutat. Res. 2003, 534, 77–84. [Google Scholar] [CrossRef]
  110. Wang, D.; Wei, Y.; Wang, T.; Wan, X.; Yang, C.S.; Reiter, R.J.; Zhang, J. Melatonin attenuates (-)-epigallocatehin-3-gallate-triggered hepatotoxicity without compromising its downregulation of hepatic gluconeogenic and lipogenic genes in mice. J. Pineal Res. 2015, 59, 497–507. [Google Scholar] [CrossRef]
  111. Wang, D.; Wang, Y.; Wan, X.; Yang, C.S.; Zhang, J. Green tea polyphenol (-)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: Responses of major antioxidant enzymes and the Nrf2 rescue pathway. Toxicol. Appl. Pharmacol. 2015, 283, 65–74. [Google Scholar] [CrossRef]
  112. Takumi-Kobayashi, A.; Ogura, R.; Morita, O.; Nishiyama, N.; Kasamatsu, T. Involvement of hydrogen peroxide in chromosomal aberrations induced by green tea catechins in vitro and implications for risk assessment. Mutat. Res. 2008, 657, 13–18. [Google Scholar] [CrossRef] [PubMed]
  113. Kucera, O.; Mezera, V.; Moravcova, A.; Endlicher, R.; Lotkova, H.; Drahota, Z.; Cervinkova, Z. In vitro toxicity of epigallocatechin gallate in rat liver mitochondria and hepatocytes. Oxidative Med. Cell. Longev. 2015, 2015, 476180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Isbrucker, R.A.; Bausch, J.; Edwards, J.A.; Wolz, E. Safety studies on epigallocatechin gallate (EGCG) preparations. Part 1: Genotoxicity. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2006, 44, 626–635. [Google Scholar] [CrossRef] [PubMed]
  115. Rho, T.; Choi, M.S.; Jung, M.; Kil, H.W.; Hong, Y.D.; Yoon, K.D. Identification of fermented tea (Camellia sinensis) polyphenols and their inhibitory activities against amyloid-beta aggregation. Phytochemistry 2019, 160, 11–18. [Google Scholar] [CrossRef]
  116. Xie, H.; Wang, J.R.; Yau, L.F.; Liu, Y.; Liu, L.; Han, Q.B.; Zhao, Z.; Jiang, Z.H. Catechins and procyanidins of Ginkgo biloba show potent activities towards the inhibition of beta-amyloid peptide aggregation and destabilization of preformed fibrils. Molecules (Basel, Switz.) 2014, 19, 5119–5134. [Google Scholar] [CrossRef] [Green Version]
  117. Chan, S.; Kantham, S.; Rao, V.M.; Palanivelu, M.K.; Pham, H.L.; Shaw, P.N.; McGeary, R.P.; Ross, B.P. Metal chelation, radical scavenging and inhibition of Abeta(4)(2) fibrillation by food constituents in relation to Alzheimer’s disease. Food Chem. 2016, 199, 185–194. [Google Scholar] [CrossRef] [Green Version]
  118. Verma, S.; Singh, A.; Mishra, A. Gallic acid: Molecular rival of cancer. Environ. Toxicol. Pharmacol. 2013, 35, 473–485. [Google Scholar] [CrossRef]
  119. Badhani, B.; Sharma, N.; Kakkar, R. Gallic acid: A versatile antioxidant with promising therapeutic and industrial applications. Rsc Adv. 2015, 5, 27540–27557. [Google Scholar] [CrossRef]
  120. Bastianetto, S.; Yao, Z.X.; Papadopoulos, V.; Quirion, R. Neuroprotective effects of green and black teas and their catechin gallate esters against beta-amyloid-induced toxicity. Eur. J. Neurosci. 2006, 23, 55–64. [Google Scholar] [CrossRef]
  121. Liu, Y.; Pukala, T.L.; Musgrave, I.F.; Williams, D.M.; Dehle, F.C.; Carver, J.A. Gallic acid is the major component of grape seed extract that inhibits amyloid fibril formation. Bioorganic Med. Chem. Lett. 2013, 23, 6336–6340. [Google Scholar] [CrossRef]
  122. LeVine, H.; Lampe, L.; Abdelmoti, L.; Augelli-Szafran, C.E. Dihydroxybenzoic Acid Isomers Differentially Dissociate Soluble Biotinyl-Aβ(1–42) Oligomers. Biochemistry 2012, 51, 307–315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. National Toxicology Program. NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study). Natl. Toxicol. Program Tech. Rep. Ser. 1982, 240, 1–152. [Google Scholar]
  124. Locatelli, C.; Filippin-Monteiro, F.B.; Creczynski-Pasa, T.B. Alkyl esters of gallic acid as anticancer agents: A review. Eur. J. Med. Chem. 2013, 60, 233–239. [Google Scholar] [CrossRef] [PubMed]
  125. Hirakawa, K.; Yoshida, M.; Oikawa, S.; Kawanishi, S. Base oxidation at 5’ site of GG sequence in double-stranded DNA induced by UVA in the presence of xanthone analogues: Relationship between the DNA-damaging abilities of photosensitizers and their HOMO energies. Photochem. Photobiol. 2003, 77, 349–355. [Google Scholar] [CrossRef]
  126. Ishii, T.; Mori, T.; Tanaka, T.; Mizuno, D.; Yamaji, R.; Kumazawa, S.; Nakayama, T.; Akagawa, M. Covalent modification of proteins by green tea polyphenol (–)-epigallocatechin-3-gallate through autoxidation. Free Radic. Biol. Med. 2008, 45, 1384–1394. [Google Scholar] [CrossRef]
  127. Xiao, Y.; Ma, B.; McElheny, D.; Parthasarathy, S.; Long, F.; Hoshi, M.; Nussinov, R.; Ishii, Y. Aβ (1–42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer’s disease. Nat. Struct. Mol. Biol. 2015, 22, 499–505. [Google Scholar] [CrossRef] [Green Version]
  128. Sato, M.; Murakami, K.; Uno, M.; Nakagawa, Y.; Katayama, S.; Akagi, K.-i.; Masuda, Y.; Takegoshi, K.; Irie, K. Site-specific inhibitory mechanism for amyloid β42 aggregation by catechol-type flavonoids targeting the Lys residues. J. Biol. Chem. 2013, 288, 23212–23224. [Google Scholar] [CrossRef] [Green Version]
  129. Oikawa, S.; Furukawa, A.; Asada, H.; Hirakawa, K.; Kawanishi, S. Catechins induce oxidative damage to cellular and isolated DNA through the generation of reactive oxygen species. Free Radic. Res. 2003, 37, 881–890. [Google Scholar] [CrossRef]
  130. Nedumpully-Govindan, P.; Kakinen, A.; Pilkington, E.H.; Davis, T.P.; Chun Ke, P.; Ding, F. Stabilizing Off-pathway Oligomers by Polyphenol Nanoassemblies for IAPP Aggregation Inhibition. Sci. Rep. 2016, 6, 19463. [Google Scholar] [CrossRef] [Green Version]
  131. Przygonska, K.; Pacewicz, M.; Sadowska, W.; Poznanski, J.; Bal, W.; Dadlez, M. His6, His13, and His14 residues in Abeta 1-40 peptide significantly and specifically affect oligomeric equilibria. Sci. Rep. 2019, 9, 9449. [Google Scholar] [CrossRef]
  132. Kong, X.; Zhao, Z.; Lei, X.; Zhang, B.; Dai, D.; Jiang, L. Interaction of metal ions with the His13-His14 sequence relevant to Alzheimer’s disease. J. Phys. Chem. A 2015, 119, 3528–3534. [Google Scholar] [CrossRef] [PubMed]
  133. Vaz, F.N.C.; Fermino, B.L.; Haskel, M.V.L.; Wouk, J.; de Freitas, G.B.L.; Fabbri, R.; Montagna, E.; Rocha, J.B.T.; Bonini, J.S. The Relationship Between Copper, Iron, and Selenium Levels and Alzheimer Disease. Biol. Trace Elem. Res. 2018, 181, 185–191. [Google Scholar] [CrossRef] [PubMed]
  134. James, S.A.; Churches, Q.I.; de Jonge, M.D.; Birchall, I.E.; Streltsov, V.; McColl, G.; Adlard, P.A.; Hare, D.J. Iron, Copper, and Zinc Concentration in Abeta Plaques in the APP/PS1 Mouse Model of Alzheimer’s Disease Correlates with Metal Levels in the Surrounding Neuropil. Acs Chem. Neurosci. 2017, 8, 629–637. [Google Scholar] [CrossRef] [PubMed]
  135. Yugay, D.; Goronzy, D.P.; Kawakami, L.M.; Claridge, S.A.; Song, T.B.; Yan, Z.; Xie, Y.H.; Gilles, J.; Yang, Y.; Weiss, P.S. Copper Ion Binding Site in beta-Amyloid Peptide. Nano Lett. 2016, 16, 6282–6289. [Google Scholar] [CrossRef] [PubMed]
  136. Mira, L.; Fernandez, M.T.; Santos, M.; Rocha, R.; Florencio, M.H.; Jennings, K.R. Interactions of flavonoids with iron and copper ions: A mechanism for their antioxidant activity. Free Radic. Res. 2002, 36, 1199–1208. [Google Scholar] [CrossRef]
  137. Vestergaard, M.; Kerman, K.; Tamiya, E. An electrochemical approach for detecting copper-chelating properties of flavonoids using disposable pencil graphite electrodes: Possible implications in copper-mediated illnesses. Anal. Chim. Acta 2005, 538, 273–281. [Google Scholar] [CrossRef]
  138. Teng, Y.; Zhao, J.; Ding, L.; Ding, Y.; Zhou, P. Complex of EGCG with Cu(II) Suppresses Amyloid Aggregation and Cu(II)-Induced Cytotoxicity of alpha-Synuclein. Molecules (Basel, Switz.) 2019, 24. [Google Scholar]
Ijms 21 03561 g001 550
Figure 1. A schematic model showing the inhibitory effects of polyphenols on Aβ aggregation, based on the “amyloid cascade hypothesis.” Myricetin inhibits nucleation [8]. Morin and datiscetin inhibit nucleation and elongation [9]. Curcumin [10], quercetin [11], and kaempferol [9] inhibit elongation. EGCG [12] and gallic acid [13] inhibit elongation and redirect Aβ oligomers to “off-pathway” aggregation. Aβ: amyloid β, EGCG: epigallocatechin gallate.
Figure 1. A schematic model showing the inhibitory effects of polyphenols on Aβ aggregation, based on the “amyloid cascade hypothesis.” Myricetin inhibits nucleation [8]. Morin and datiscetin inhibit nucleation and elongation [9]. Curcumin [10], quercetin [11], and kaempferol [9] inhibit elongation. EGCG [12] and gallic acid [13] inhibit elongation and redirect Aβ oligomers to “off-pathway” aggregation. Aβ: amyloid β, EGCG: epigallocatechin gallate.
Ijms 21 03561 g001
Ijms 21 03561 g002 550
Figure 2. Chemical structures of polyphenols shown in Table 1. EGCG: epigallocatechin gallate
Figure 2. Chemical structures of polyphenols shown in Table 1. EGCG: epigallocatechin gallate
Ijms 21 03561 g002
Ijms 21 03561 g003 550
Figure 3. Possible mechanism of oxidative DNA damage induced by morin in the presence of Cu(II). The 4′-hydroxyl group of the B-ring of morin is responsible for the generation of Cu(I)-hydroperoxide (Cu(I)OOH) and the resultant oxidative DNA damage. Datiscetin, an analog of morin, without the 4′-hydroxyl group, does not damage DNA.
Figure 3. Possible mechanism of oxidative DNA damage induced by morin in the presence of Cu(II). The 4′-hydroxyl group of the B-ring of morin is responsible for the generation of Cu(I)-hydroperoxide (Cu(I)OOH) and the resultant oxidative DNA damage. Datiscetin, an analog of morin, without the 4′-hydroxyl group, does not damage DNA.
Ijms 21 03561 g003
Ijms 21 03561 g004 550
Figure 4. The role of catechol moieties in o-demethyl curcumin- and quercetin-mediated oxidative DNA damage in the presence of Cu(II). (A) o-Demethyl curcumin (with a catechol moiety) induced Cu(II)-mediated oxidative damage, while curcumin, its parent compound (without catechol moieties), did not. (B) Quercetin (with a catechol moiety) induced stronger oxidative damage than kaempferol, its analog (without catechol moieties) in the presence of Cu(II). CYP: cytochrome P450
Figure 4. The role of catechol moieties in o-demethyl curcumin- and quercetin-mediated oxidative DNA damage in the presence of Cu(II). (A) o-Demethyl curcumin (with a catechol moiety) induced Cu(II)-mediated oxidative damage, while curcumin, its parent compound (without catechol moieties), did not. (B) Quercetin (with a catechol moiety) induced stronger oxidative damage than kaempferol, its analog (without catechol moieties) in the presence of Cu(II). CYP: cytochrome P450
Ijms 21 03561 g004
Ijms 21 03561 g005 550
Figure 5. Fe(III)- and Cu(II)-mediated DNA damage caused by green tea polyphenols. Three tea polyphenols with pyrogallol moieties (EGCG, epicatechin gallate, and epigallocatechin) can induce Fe(III)- and Cu(II)-mediated oxidative DNA damage although, catechins, which harbor no pyrogallol moieties, only cause Cu(II)-mediated oxidative DNA damage. (+++), (++), (+), and (-) represent the extent of DNA damage. EGCG: epigallocatechin gallate
Figure 5. Fe(III)- and Cu(II)-mediated DNA damage caused by green tea polyphenols. Three tea polyphenols with pyrogallol moieties (EGCG, epicatechin gallate, and epigallocatechin) can induce Fe(III)- and Cu(II)-mediated oxidative DNA damage although, catechins, which harbor no pyrogallol moieties, only cause Cu(II)-mediated oxidative DNA damage. (+++), (++), (+), and (-) represent the extent of DNA damage. EGCG: epigallocatechin gallate
Ijms 21 03561 g005
Ijms 21 03561 g006 550
Figure 6. Estimation of HOMO energy to assess the pro-oxidant reactivity of gallic acid and propyl gallate. HOMO energies of gallic acid and propyl gallate were estimated from ab initio molecular orbital calculations at Hartree–Fock 6-31G* level. Calculations were performed using Spartan 02 for Windows (Wavefunction Inc., CA) [125]. HOMO energy: highest occupied molecular orbital energy
Figure 6. Estimation of HOMO energy to assess the pro-oxidant reactivity of gallic acid and propyl gallate. HOMO energies of gallic acid and propyl gallate were estimated from ab initio molecular orbital calculations at Hartree–Fock 6-31G* level. Calculations were performed using Spartan 02 for Windows (Wavefunction Inc., CA) [125]. HOMO energy: highest occupied molecular orbital energy
Ijms 21 03561 g006
Table
Table 1. Toxic effects associated with pro-oxidant properties of naturally occurring polyphenols harboring anti-Aβ aggregation activity.
Table 1. Toxic effects associated with pro-oxidant properties of naturally occurring polyphenols harboring anti-Aβ aggregation activity.
Anti-Aβ Aggregation EffectPolyphenolToxic Effects Associated with Pro-Oxidant PropertiesConcentration or Dose Showing Toxic Effects of Polyphenols
Inhibiting nucleationMyricetinCytotoxicity
Cytotoxicity linked with ROS generationCell: 20 μM [25], 50 μM [26,27]
Genotoxicity
Oxidative DNA damageCell: 20 μM [28], 50 μM [29]
DNA: 5 μM [30], 200 μM [31]
Mutagenic activityBacteria: 0.628 μmol/plate [32]
Cell: 42 μM [33]
Inhibiting nucleation and elongationMorinGenotoxicity
Oxidative DNA damageCell: 100 μM [34]
DNA: 5 μM [30],10 μM [35], 20 μM [36], 100 μM [37]
Mutagenic activityBacteria: 0.149 μmol/plate [38]
DatiscetinNo report
Inhibiting elongationCurcuminCytotoxicity
Cytotoxicity linked with ROS generationCell: 5 μM [39], 50 μM [40]
Genotoxicity
DNA damage in cultured cellCell: 50 μM [41]
Curcumin metabolite-mediated oxidative damage in isolated DNADNA: 2 μM [42]
Tumorigenicity
Colon mucosal hyperplasia and hepatocellular adenoma in rats and mice treated with turmeric oleoresin containing curcumin (79%-85%), respectivelyColon hyperplasia: 2000 mg/kg/day (male rats) [43]
Hepatocellular adenoma: 520 mg/kg/day (male mice) [43], 1620 mg/kg/day (female mice) [43]
Inhibiting elongation (continued)QuercetinCytotoxicity
Cytotoxicity linked with ROS generationCell: 50 μM [44]
Genotoxicity
Oxidative DNA damageCell: 30 μM [45], 50 μM [29], 100 μM [34]
DNA: 10 μM [46]
Mutagenic activityBacteria: 0.121 μmol/plate [47]
Cell: 2.2 μM [48], 32.5 μM [49]
Carcinogenesis
Renal tubule adenocarcinomas and intestinal and bladder cancer in ratsRenal tubule adenocarcinomas: 1900 mg/kg/day (male rats) [48]
Intestinal and bladder cancer: 27.8 mM/rat (male, cumulative dose) [50], 25.3 mM/rat (female, cumulative dose) [50]
KaempferolGenotoxicity
Oxidative DNA damageCell: 50 μM [29]
Mutagenic activityBacteria: 0.143 μmol/plate [47]
Inhibiting elongation and redirecting to “off-pathway” aggregationEGCGCytotoxicity
Cytotoxicity linked with ROS generationCell: 2 μM [51], 12.5 μM [52]
Genotoxicity
Oxidative DNA damageCell: 100 μM [53], 200 μM [54]
DNA: 5 μM [54]
Hepatotoxicity and gastrointestinal toxicity
Gastrointestinal tract and liver lesion in rats and mice treated with green tea extract containing EGCG (48.4%)Gastrointestinal tract lesion: 1000 mg/kg/day (male and female rats) [55]
Liver lesion: 1000 mg/kg/day (male and female rats) [55], 300 mg/kg/day (male mice) [55]
High dose intake-associated liver damage in humansHuman: 704 mg/day [56]
Gallic acidCytotoxicity
Cytotoxicity linked with ROS generationCell: 74 μM [57], 294 μM [58,59]
Genotoxicity
Oxidative DNA damageDNA: 5 μM [60], 200 μM [61]
Hepatotoxicity and nephrotoxicity
Liver damage in mice and rats, and renal injury in ratsLiver damage: 200 mg/kg/day (male mice) [62], 100 mg/kg/day (male rats) [63]
Renal injury: 100 mg/kg/day (male rats) [63]
Aβ: amyloid β, ROS: reactive oxygen species, EGCG: epigallocatechin gallate.

Share and Cite

MDPI and ACS Style

Kobayashi, H.; Murata, M.; Kawanishi, S.; Oikawa, S. Polyphenols with Anti-Amyloid β Aggregation Show Potential Risk of Toxicity Via Pro-Oxidant Properties. Int. J. Mol. Sci. 2020, 21, 3561. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103561

AMA Style

Kobayashi H, Murata M, Kawanishi S, Oikawa S. Polyphenols with Anti-Amyloid β Aggregation Show Potential Risk of Toxicity Via Pro-Oxidant Properties. International Journal of Molecular Sciences. 2020; 21(10):3561. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103561

Chicago/Turabian Style

Kobayashi, Hatasu, Mariko Murata, Shosuke Kawanishi, and Shinji Oikawa. 2020. "Polyphenols with Anti-Amyloid β Aggregation Show Potential Risk of Toxicity Via Pro-Oxidant Properties" International Journal of Molecular Sciences 21, no. 10: 3561. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103561

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop