The food additive fast green FCF inhibits α-synuclein aggregation, disassembles mature fibrils and protects against amyloid-induced neurotoxicity

Wang, Fenghua; Wang, Ying; Jiang, Luying; Wang, Wenqian; Sang, Jingcheng; Wang, Xinyu; Lu, Fuping; Liu, Fufeng

doi:10.1039/d0fo03301d

Cited by 18 publications

(12 citation statements)

References 59 publications

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“…The results of the thioflavin T fluorescence assays also demonstrated that kaempferol reduced the β-sheet content of amyloid fibril formation of α-Syn. Moreover, the TEM results confirmed that the amyloid fibril formation of α-Syn was altered by kaempferol to form a structure resembling an amorphous aggregation that had low cytotoxicity [ 14 , 21 ] or made it more easily degradable by autophagy. Thus, the present results indicate that kaempferol is a candidate prototype for the development of drugs that could prevent the aggregation of amyloid fibril formation of α-Syn in synucleinopathies.…”

Section: Discussionmentioning

confidence: 84%

Kaempferol Has Potent Protective and Antifibrillogenic Effects for α-Synuclein Neurotoxicity In Vitro

Inden

Takagi

Kitai

et al. 2021

IJMS

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Aggregation of α-synuclein (α-Syn) is implicated in the pathogenesis of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Therefore, the removal of α-Syn aggregation could lead to the development of many new therapeutic agents for neurodegenerative diseases. In the present study, we succeeded in generating a new α-Syn stably expressing cell line using a piggyBac transposon system to investigate the neuroprotective effect of the flavonoid kaempferol on α-Syn toxicity. We found that kaempferol provided significant protection against α-Syn-related neurotoxicity. Furthermore, kaempferol induced autophagy through an increase in the biogenesis of lysosomes by inducing the expression of transcription factor EB and reducing the accumulation of α-Syn; thus, kaempferol prevented neuronal cell death. Moreover, kaempferol directly blocked the amyloid fibril formation of α-Syn. These results support the therapeutic potential of kaempferol in diseases such as synucleinopathies that are characterized by α-Syn aggregates.

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Section: Discussionmentioning

confidence: 84%

Kaempferol Has Potent Protective and Antifibrillogenic Effects for α-Synuclein Neurotoxicity In Vitro

Inden

Takagi

Kitai

et al. 2021

IJMS

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“…The IC 50 value was negatively correlated to the inhibitory effect on αSN aggregation. The significantly lower IC 50 values for Hst compared to that for previously reported αSN aggregation inhibitors, such as fast green FCF (IC 50 = 37.9 μM), 3-methoxy-4-acetamidoxycinnamic acid (IC 50 = 50.0 μM), and rifampicin (IC 50 = 502.3 μM), indicate that Hst had a better inhibitory effect on αSN fibrillation. Nevertheless, the inhibitory effect of Hst was not as good as that of recognized high-efficiency inhibitors such as epigallocatechin gallate (EGCG) (IC 50 = 4.5 μM) and brazilin (IC 50 = 8.2 μM) (Table ).…”

Section: Results and Discussionmentioning

confidence: 71%

Citrus Flavonoid Hesperetin Inhibits α-Synuclein Fibrillogenesis, Disrupts Mature Fibrils, and Reduces Their Cytotoxicity: In Vitro and In Vivo Studies

Wang,

Qu,

Cui

et al. 2023

J. Agric. Food Chem.

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Misfolding and subsequent fibrillogenesis of α-synuclein (αSN) significantly influence the development of Parkinson’s disease (PD). This study reports the inhibitory effect of citrus flavonoid hesperetin (Hst) on αSN fibrillation. Based on thioflavin T fluorometry and atomic force microscopy studies, Hst inhibited αSN fibrillation by interfering with initial nucleation and slowing the elongation rate. Furthermore, the inhibitory effect was concentration-dependent with a half-maximal inhibitory concentration of 24.4 μM. Cytotoxicity experiments showed that 100 μM Hst significantly reduced the cytotoxicity of αSN aggregates and maintained 98.4% cell activity. In addition, Hst disassembled the preprepared αSN fibrils into smaller and less-toxic aggregates. Excitingly, supplementation with 100 μM Hst inhibited the accumulation of 36.3% αSN in NL5901 and restored the amyloid-induced reduction in NL5901 lipid abundance, extending the mean lifespan of NL5901 to 23 d. These findings could support the use of Hst as a dietary supplement to regulate αSN fibrillation and prevent the development of PD.

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“…For kinetics, the pretreated Aβ 40 (25 μM) monomer was coincubated with ThT iependently or in the presence of different concentrations of TTR or TP. ThT fluorescence was monitored at a regular interval of 10 min at 37 °C to study the fibrillization kinetics with a fluorescence plate reader (Infinite M200 Pro, TECAN, Salzburg, Austria) . The excitation and emission wavelengths of ThT are 440 and 480 nm, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…ThT fluorescence was monitored at a regular interval of 10 min at 37 °C to study the fibrillization kinetics with a fluorescence plate reader (Infinite M200 Pro, TECAN, Salzburg, Austria). 59 The excitation and emission wavelengths of ThT are 440 and 480 nm, respectively. The samples without Aβ 40 were subtracted as the background.…”

Section: ■ Conclusionmentioning

confidence: 99%

Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer’s Amyloid-β Fibrillogenesis with High Blood Brain Barrier Crossing Capability

Wang,

Liu,

Sun

et al. 2024

Bioconjugate Chem.

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The design of a potent amyloid-β protein (Aβ) inhibitor plays a pivotal role in the prevention and treatment of Alzheimer’s disease (AD). Despite endogenous transthyretin (TTR) being recognized as an Aβ inhibitor, the weak inhibitory and blood brain barrier (BBB) crossing capabilities hinder it for Aβ aggregation inhibition and transport. Therefore, we have herein designed a recombinant TTR by conjugating a cationic cell penetrating peptide (penetratin, Pen), which not only enabled the fusion protein, TTR-Pen (TP), to present high BBB penetration but also greatly enhanced the potency of Aβ inhibition. Namely, the protein fusion made TP positively charged, leading to a potent suppression of Aβ40 fibrillization at a low concentration (1.5 μM), while a TTR concentration as high as 12.5 μM was required to gain a similar function. Moreover, TP could mitigate Aβ-induced neuronal death, increase cultured cell viability from 72% to 92% at 2.5 μM, and extend the lifespan of AD nematodes from 14 to 18 d. Thermodynamic studies revealed that TP, enriched in positive charges, presented extensive electrostatic interactions with Aβ40. Importantly, TP showed excellent BBB penetration performance, with a 10 times higher BBB permeability than TTR, which would allow TP to enter the brain of AD patients and participate in the transport of Aβ species out of the brain. Thus, it is expected that the fusion protein has great potential for drug development in AD treatment.

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The food additive fast green FCF inhibits α-synuclein aggregation, disassembles mature fibrils and protects against amyloid-induced neurotoxicity

Abstract: α-Synuclein (α-syn) aggregates into cytotoxic amyloid fibrils, which are recognized as the defining neuropathological feature of Parkinson’s disease (PD). Therefore, inhibiting α-syn fibrillogenesis and disrupting the preformed fibrils are both...

Cited by 18 publications

References 59 publications

Kaempferol Has Potent Protective and Antifibrillogenic Effects for α-Synuclein Neurotoxicity In Vitro

Kaempferol Has Potent Protective and Antifibrillogenic Effects for α-Synuclein Neurotoxicity In Vitro

Citrus Flavonoid Hesperetin Inhibits α-Synuclein Fibrillogenesis, Disrupts Mature Fibrils, and Reduces Their Cytotoxicity: In Vitro and In Vivo Studies

Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer’s Amyloid-β Fibrillogenesis with High Blood Brain Barrier Crossing Capability

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