Potential Role of Natural Polyphenols against Protein Aggregation Toxicity: In Vitro, In Vivo, and Clinical Studies

Henríquez, Gabriela; Gómez, Ana-María; Guerrero, Erick Damian; Narayan, Mahesh

doi:10.1021/acschemneuro.0c00381

Cited by 58 publications

(48 citation statements)

References 246 publications

(527 reference statements)

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“…Furthermore, some natural compounds, such as EGCG have been shown to interact with many amyloidogenic proteins, such as Aβ, αSyn, islet amyloid polypeptide (IAPP), huntingtin, tau, and immunoglobulin light chains, revealing that they act on aggregation through a similar mechanism (Andrich and Bieschke, 2015;Martinez et al, 2020). In addition to EGCG, also OleA and quercetin have been classified as potent polyphenols sharing common amyloid targets, namely Aβ, tau and α-Syn (Henriquez et al, 2020a). These observations strongly suggest that the structural knowledge of the mechanism of action of these natural compounds should be exploited as a starting point to design and develop therapeutic solutions for the prevention and treatment of different neurodegenerative diseases.…”

Section: Resultsmentioning

confidence: 99%

Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

Pagano¹,

Tomaselli²,

Molinari³

et al. 2020

Front. Neurosci.

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Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, with no cure and preventive therapy. Misfolding and extracellular aggregation of Amyloid-β (Aβ) peptides are recognized as the main cause of AD progression, leading to the formation of toxic Aβ oligomers and to the deposition of β-amyloid plaques in the brain, representing the hallmarks of AD. Given the urgent need to provide alternative therapies, natural products serve as vital resources for novel drugs. In recent years, several natural compounds with different chemical structures, such as polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received attention for their role against the neurodegenerative pathological processes. However, only for a small subset of them experimental evidences are provided on their mechanism of action. This review focuses on those natural compounds shown to interfere with Aβ aggregation by direct interaction with Aβ peptide and whose inhibitory mechanism has been investigated by means of biophysical and structural biology experimental approaches. In few cases, the combination of approaches offering a macroscopic characterization of the oligomers, such as TEM, AFM, fluorescence, together with high-resolution methods could shed light on the complex mechanism of inhibition. In particular, solution NMR spectroscopy, through peptide-based and ligand-based observation, was successfully employed to investigate the interactions of the natural compounds with both soluble NMR-visible (monomer and low molecular weight oligomers) and NMR-invisible (high molecular weight oligomers and protofibrils) species. The molecular determinants of the interaction of promising natural compounds are here compared to infer the chemical requirements of the inhibitors and the common mechanisms of inhibition. Most of the data converge to indicate that the Aβ regions relevant to perturb the aggregation cascade and regulate the toxicity of the stabilized oligomers, are the N-term and β1 region. The ability of the natural aggregation inhibitors to cross the brain blood barrier, together with the tactics to improve their low bioavailability are discussed. The analysis of the data ensemble can provide a rationale for the selection of natural compounds as molecular scaffolds for the design of new therapeutic strategies against the progression of early and late stages of AD.

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Section: Resultsmentioning

confidence: 99%

Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

Pagano¹,

Tomaselli²,

Molinari³

et al. 2020

Front. Neurosci.

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“…The major mechanisms through which NPs exert their neuroprotective effects include antioxidant, anti-inflammatory, antithrombotic, antiapoptotic, and neurotrophic activities, as well as acetylcholinesterase and monoamine oxidase inhibition [123]. Among neuroprotective NPs, phenolic molecules are of particular interest since most can target both amyloid aggregation and oxidative stress, as confirmed by numerous studies with phenolic compounds such as EGCG, curcumin, resveratrol, quercetin, and oleuropein [123][124][125][126]. Evidence also exists that some of these NPs suppress the neurotoxicity of the most toxic oligomer species [127][128][129][130][131].…”

Section: Natural Products Against Neurodegenerationmentioning

confidence: 99%

“…Finally, targeting protein misfolding with different NPs has been recognized as one of the most promising therapeutic strategies against NDs since many NDs involve the misfolding and aggregation of specific proteins into abnormal, toxic species [125,132]. Therefore, the use of small molecules to stop, slow, or reverse the protein misfolding and aggregation process may be a valuable approach to reduce neurodegeneration [17,20].…”

Section: Natural Products Against Neurodegenerationmentioning

confidence: 99%

Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

2021

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The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer’s disease (AD), and α-synuclein, linked to Parkinson’s disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders.

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“…For example, dietary saffron regulates apoptosis, inflammation and mitochondrial dysfunction by upregulating several genes (Cyr61, Gpx8, Ndufs4, and Nos1ap) with known neuroprotective actions [ 61 ]. Others, for example, natural polyphenols, are more specific and prevent the aggregation of α-synuclein and other prone-to-aggregate proteins [ 64 , 65 ], or regulate the expression of genes involved in PD, DLB and MSA pathogenesis [ 60 , 62 ].…”

Section: Phytochemicalsmentioning

confidence: 99%

“…Polyphenols are widely present in cloves, berries, beans, nuts, etc. They regulate free radical production by several mechanisms, including the effect on the expression of the genes inhibiting oxidative stress and neutralizing free radicals [ 64 , 65 ].…”

Section: Phytochemicalsmentioning

confidence: 99%

Phytochemicals as Regulators of Genes Involved in Synucleinopathies

Surguchov

Bernal²,

Surguchev

2021

Biomolecules

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Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein aggregates in neurons, nerve fibers or glial cells. Three main types of diseases belong to the synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. All of them develop as a result of an interplay of genetic and environmental factors. Emerging evidence suggests that epigenetic mechanisms play an essential role in the development of synucleinopathies. Since there is no disease-modifying treatment for these disorders at this time, interest is growing in plant-derived chemicals as a potential treatment option. Phytochemicals are substances of plant origin that possess biological activity, which might have effects on human health. Phytochemicals with neuroprotective activity target different elements in pathogenic pathways due to their antioxidants, anti-inflammatory, and antiapoptotic properties, and ability to reduce cellular stress. Multiple recent studies demonstrate that the beneficial effects of phytochemicals may be explained by their ability to modulate the expression of genes implicated in synucleinopathies and other diseases. These substances may regulate transcription directly via transcription factors (TFs) or play the role of epigenetic regulators through their effect on histone modification, DNA methylation, and RNA-based mechanisms. Here, we summarize new data about the impact of phytochemicals on the pathogenesis of synucleinopathies through regulation of gene expression.

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Potential Role of Natural Polyphenols against Protein Aggregation Toxicity: In Vitro, In Vivo, and Clinical Studies

Cited by 58 publications

References 246 publications

Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

Phytochemicals as Regulators of Genes Involved in Synucleinopathies

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