Structure-activity relationships for flavone interactions with amyloid β reveal a novel anti-aggregatory and neuroprotective effect of 2′,3′,4′-trihydroxyflavone (2-D08)

Marsh, Dylan T.; Das, Sukanya; Ridell, Jessica; Smid, Scott D.

doi:10.1016/j.bmc.2017.05.041

Cited by 34 publications

(18 citation statements)

References 27 publications

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“…We previously reported that 2-D08 exerted a novel anti-aggregatory and neuroprotective effect against Aβ compared to transilitin and quercetin, which have A and C-ring hydroxylation (Marsh et al, 2017 ). In the present study, 2-D08 induced inhibition of αS aggregation and neuroprotection was as pronounced as myricetin, a generic amyloid aggregation inhibitor, and supports the idea that restricted B-ring tri-hydroxylation is adequate for targeting both αS and Aβ (Ono and Yamada, 2006 ; Hirohata et al, 2007 ; Zelus et al, 2012 ; Liu et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we have investigated the anti-amyloid effect of semi-synthetic, 2′, 3′, 4′ trihydroxy flavone (2-D08) that has only vicinal trihydroxylation in the B-ring. This flavone has shown improved inhibition of amyloid β (Aβ) aggregation and toxicity through its localized B-ring trihydroxylation (Marsh et al, 2017 ). We compared it with myricetin, a known inhibitor of αS aggregation (Meng et al, 2010 ; Liu et al, 2015 ) which also has vicinal trihydroxylation in the B-ring along with -OH groups at flavone 3, 5, and 7 positions.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the Structural Diversity in Inhibitors of α-Synuclein Amyloidogenic Folding, Aggregation, and Neurotoxicity

2018

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Aggregation of α-Synuclein (αS) protein to amyloid fibrils is a neuropathological hallmark of Parkinson's disease (PD). Growing evidence suggests that extracellular αS aggregation plays a pivotal role in neurodegeneration found in PD in addition to the intracellular αS aggregates in Lewy bodies (LB). Here, we identified and compared a diverse set of molecules capable of mitigating protein aggregation and exogenous toxicity of αSA53T, a more aggregation-prone αS mutant found in familial PD. For the first time, we investigated the αS anti-amyloid activity of semi-synthetic flavonoid 2′, 3′, 4′ trihydroxyflavone or 2-D08, which was compared with natural flavones myricetin and transilitin, as well as such structurally diverse polyphenols as honokiol and punicalagin. Additionally, two novel synthetic compounds with a dibenzyl imidazolidine scaffold, Compound 1 and Compound 2, were also investigated as they exhibited favorable binding with αSA53T. All seven compounds inhibited αSA53T aggregation as demonstrated by Thioflavin T fluorescence assays, with modified fibril morphology observed by transmission electron microscopy. Ion mobility-mass spectrometry (IM-MS) was used to monitor the structural conversion of native αSA53T into amyloidogenic conformations and all seven compounds preserved the native unfolded conformations of αSA53T following 48 h incubation. The presence of each test compound in a 1:2 molar ratio was also shown to inhibit the neurotoxicity of preincubated αSA53T using phaeochromocytoma (PC12) cell viability assays. Among the seven tested compounds 2-D08, honokiol, and the synthetic Compound 2 demonstrated the highest inhibition of aggregation, coupled with neuroprotection from preincubated αSA53T in vitro. Molecular docking predicted that all compounds bound near the lysine-rich region of the N-terminus of αSA53T, where the flavonoids and honokiol predominantly interacted with Lys 23. Overall, these findings highlight that (i) restricted vicinal trihydroxylation in the flavone B-ring is more effective in stabilizing the native αS conformations, thus blocking amyloidogenic aggregation, than dihydroxylation aggregation in both A and B-ring, and (ii) honokiol, punicalagin, and the synthetic imidazolidine Compound 2 also inhibit αS amyloidogenic aggregation by stabilizing its native conformations. This diverse set of molecules acting on a singular pathological target with predicted binding to αSA53T in the folding-prone N-terminal region may contribute toward novel drug-design for PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the Structural Diversity in Inhibitors of α-Synuclein Amyloidogenic Folding, Aggregation, and Neurotoxicity

2018

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“…Flavonoids (baicalein, kaempferol, catechin, EGCG, myricetin), theaflavins, oleocathal (a phenolic compound of extra-virgin olive oil), rosmarinic acid (an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid), tannic acid, and curcumin inhibited formation and accumulation of the oligomers and fibrils [131,132]. Polyphenols (curcumin, EGCG, apigenin, baicalein, genistein morin, myricetin, rosmarinic acid, 2′,3′,4′-trihydroxyflavone), and black tea extract promoted clearance of amyloid aggregates of Aβ, wild and mutant αSyn (A30P, A53T) and tau-441 protein, and prevented the MPT [133,134,135,136,137].…”

Section: Polyphenols Modulate Mitochondrial Function and Exhibit Nmentioning

confidence: 99%

Mitochondria in Neuroprotection by Phytochemicals: Bioactive Polyphenols Modulate Mitochondrial Apoptosis System, Function and Structure

Naoi

Shamoto-Nagai

et al. 2019

IJMS

121

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In aging and neurodegenerative diseases, loss of distinct type of neurons characterizes disease-specific pathological and clinical features, and mitochondria play a pivotal role in neuronal survival and death. Mitochondria are now considered as the organelle to modulate cellular signal pathways and functions, not only to produce energy and reactive oxygen species. Oxidative stress, deficit of neurotrophic factors, and multiple other factors impair mitochondrial function and induce cell death. Multi-functional plant polyphenols, major groups of phytochemicals, are proposed as one of most promising mitochondria-targeting medicine to preserve the activity and structure of mitochondria and neurons. Polyphenols can scavenge reactive oxygen and nitrogen species and activate redox-responsible transcription factors to regulate expression of genes, coding antioxidants, anti-apoptotic Bcl-2 protein family, and pro-survival neurotrophic factors. In mitochondria, polyphenols can directly regulate the mitochondrial apoptosis system either in preventing or promoting way. Polyphenols also modulate mitochondrial biogenesis, dynamics (fission and fusion), and autophagic degradation to keep the quality and number. This review presents the role of polyphenols in regulation of mitochondrial redox state, death signal system, and homeostasis. The dualistic redox properties of polyphenols are associated with controversial regulation of mitochondrial apoptosis system involved in the neuroprotective and anti-carcinogenic functions. Mitochondria-targeted phytochemical derivatives were synthesized based on the phenolic structure to develop a novel series of neuroprotective and anticancer compounds, which promote the bioavailability and effectiveness. Phytochemicals have shown the multiple beneficial effects in mitochondria, but further investigation is required for the clinical application.

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“…The relationship between exposure to tea extracts and neuronal protective effects has been widely investigated in both in vivo and in vitro models [4,5]. Many compounds in tea have been found to have neuroprotective effects in vitro associated with detoxifying Aβ fibrils and aggregates, such as catechins, flavonol glycosides and gallic acid, amongst others [6,7,8,9]. Clinical studies have also revealed that people who consume tea may have a slower decline in cognitive function [10,11,12].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective and Anti-Amyloid β Effect and Main Chemical Profiles of White Tea: Comparison Against Green, Oolong and Black Tea

Smid

Lin

et al. 2019

Molecules

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White tea (WT) is one of six tea types originally derived from Fujian Province, China. White tea is known for its health-promoting properties. However, the neuroprotective and anti-aggregatory properties of WT against the hallmark toxic Alzheimer’s protein, Aβ have not been investigated. In this study, WT, green tea (GT), oolong tea (OT) and black tea (BT) were manufactured using tea leaves from the cultivar Camellia sinensis (Jin Guanyin). The protective effects of these tea extracts were then studied under oxidative stress conditions via t-bhp and H2O2 exposure, in addition to Aβ treatment using a PC-12 cell model. Each tea type failed to rescue PC-12 cells from either t-bhp or H2O2-mediated toxicity, however each extract exerted significant protection against Aβ-evoked neurotoxicity. Results of the Thioflavin T Kinetic (ThT) and TEM assay showed that Aβ aggregate formation was inhibited by each tea type. Additionally, TEM also supported the different anti-aggregatory effect of WT by modifying Aβ into an amorphous and punctate aggregate morphology. Higher accumulated precedent or potential neuroprotective compounds in WT, including ECG’’3Me, 8-C-ascorbyl-EGCG, GABA and Gln, in addition to flavonol or flavone glycosides detected by using UPLC-QTOF-MS and UPLC-QqQ-MS, may contribute to a favourable anti-aggregative and neuroprotective effect of WT against Aβ.

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Structure-activity relationships for flavone interactions with amyloid β reveal a novel anti-aggregatory and neuroprotective effect of 2′,3′,4′-trihydroxyflavone (2-D08)

Cited by 34 publications

References 27 publications

Exploring the Structural Diversity in Inhibitors of α-Synuclein Amyloidogenic Folding, Aggregation, and Neurotoxicity

Exploring the Structural Diversity in Inhibitors of α-Synuclein Amyloidogenic Folding, Aggregation, and Neurotoxicity

Mitochondria in Neuroprotection by Phytochemicals: Bioactive Polyphenols Modulate Mitochondrial Apoptosis System, Function and Structure

Neuroprotective and Anti-Amyloid β Effect and Main Chemical Profiles of White Tea: Comparison Against Green, Oolong and Black Tea

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