A Fluorogenic Molecule for Probing Islet Amyloid Using Flavonoid as a Scaffold Design

Chen, Wei Ling; Ting, Shao-Ying; Chen, Yun Wen; Chao, Yen Cheng; Chan, Ai Ci; Tu, Ling Hsien; Liu, Wei Min

doi:10.1021/acs.biochem.0c00076

Cited by 9 publications

(4 citation statements)

References 54 publications

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“…Replacing hydroxyl groups with methoxy groups causes the compound to lose activity, suggesting the hydroxyl groups may be involved in the interaction with hA ( Velander et al, 2016 ). Furthermore, the flavonoid scaffold lacking any hydroxyl groups can bind with hA but does not inhibit fibrillation, suggesting the flavonoid core structure may interact with the hA peptide but that hydroxyl groups are required to prevent aggregation ( Chen, W. L. et al, 2020 ).…”

Section: Potential Mechanisms Of Actionmentioning

confidence: 99%

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review

Nie

Cooper

2021

Front. Pharmacol.

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Polyphenolic compounds are thought to show considerable promise for the treatment of various metabolic disorders, including type 2 diabetes mellitus (T2DM). This review addresses evidence from in vitro, in vivo, and clinical studies for the antidiabetic effects of certain polyphenolic compounds. We focus on the role of cytotoxic human amylin (hA) aggregates in the pathogenesis of T2DM, and how polyphenols can ameliorate this process by suppressing or modifying their formation. Small, soluble amylin oligomers elicit cytotoxicity in pancreatic islet β-cells and may thus cause β-cell disruption in T2DM. Amylin oligomers may also contribute to oxidative stress and inflammation that lead to the triggering of β-cell apoptosis. Polyphenols may exert antidiabetic effects via their ability to inhibit hA aggregation, and to modulate oxidative stress, inflammation, and other pathways that are β-cell-protective or insulin-sensitizing. There is evidence that their ability to inhibit and destabilize self-assembly by hA requires aromatic molecular structures that bind to misfolding monomers or oligomers, coupled with adjacent hydroxyl groups present on single phenyl rings. Thus, these multifunctional compounds have the potential to be effective against the pleiotropic mechanisms of T2DM. However, substantial further research will be required before it can be determined whether a polyphenol-based molecular entity can be used as a therapeutic for type 2 diabetes.

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Section: Potential Mechanisms Of Actionmentioning

confidence: 99%

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review

Nie

Cooper

2021

Front. Pharmacol.

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“…44 Liu et al rationally designed probes using flavonoid as a scaffold and demonstrated that noncytotoxic 3-HF-ene-4′-OMe (Figure 3, 22) could detect islet amyloid polypeptide (IAPP) aggregates in living cells. 45 Nam et al developed a quinoline-based fluorescent probe (Q-tau 4, Figure 3, 23), that could be used as a tau-specific fluorescent imaging agent with lower background interference. 46 Yu et al present a novel, tau-selective, and AIE-active fluorescent probe (JL-3, Figure 3, 24), which demonstrated a remarkable capacity for bioimaging in living cells, brain tissues, and transgenic mice.…”

Section: Fluorescence Microscopy Utilizing Environment-sensitive Prob...mentioning

confidence: 99%

“…Mach et al designed a fluorescent α-syn probe (Tg-52, Figure , 21 ) with high affinity, discovering that α-synucleinopathies are conformationally different and display distinct small molecule binding sites . Liu et al rationally designed probes using flavonoid as a scaffold and demonstrated that noncytotoxic 3-HF-ene-4′-OMe (Figure , 22 ) could detect islet amyloid polypeptide (IAPP) aggregates in living cells . Nam et al developed a quinoline-based fluorescent probe (Q-tau 4, Figure , 23 ), that could be used as a tau-specific fluorescent imaging agent with lower background interference .…”

Section: Strategies Based On Optical Microscopymentioning

confidence: 99%

Advanced Techniques for Detecting Protein Misfolding and Aggregation in Cellular Environments

Bai,

Zhang,

Dong

et al. 2023

Chem. Rev.

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Protein misfolding and aggregation, a key contributor to the progression of numerous neurodegenerative diseases, results in functional deficiencies and the creation of harmful intermediates. Detailed visualization of this misfolding process is of paramount importance for improving our understanding of disease mechanisms and for the development of potential therapeutic strategies. While in vitro studies using purified proteins have been instrumental in delivering significant insights into protein misfolding, the behavior of these proteins in the complex milieu of living cells often diverges significantly from such simplified environments. Biomedical imaging performed in cell provides cellular-level information with high physiological and pathological relevance, often surpassing the depth of information attainable through in vitro methods. This review highlights a variety of methodologies used to scrutinize protein misfolding within biological systems. This includes optical-based methods, strategies leaning on mass spectrometry, in-cell nuclear magnetic resonance, and cryo-electron microscopy. Recent advancements in these techniques have notably deepened our understanding of protein misfolding processes and the features of the resulting misfolded species within living cells. The progression in these fields promises to catalyze further breakthroughs in our comprehension of neurodegenerative disease mechanisms and potential therapeutic interventions.

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“…Monitoring early stage processes in protein aggregation is essential for the effective understanding and tackling of related neurodegenerative diseases, diabetes, and of other biological processes arising from protein misfolding leading to aggregation. , Beside the archetype thioflavin-T (ThT), other fluorescent dyes, , aggregation-induced-emission fluorogenic moieties (AIEgens), − and luminescent conjugated oligomers and polymers (LCOs and LCPs) , have been proposed for monitoring the early stages of protein aggregation . Among these novel probes, LCOs and LCPs stand out due to the versatility of their structure, tailored to optimize the interactions with protein aggregates, with the most performing ones displaying a polyanionic character (multiple negatively charged carboxylates and/or sulfonates) and a hydrophobic backbone, yielding only partial water solubility.…”

Section: Introductionmentioning

confidence: 99%

Fluorogenic Hyaluronan Nanogels Track Individual Early Protein Aggregates Originated under Oxidative Stress

Cingolani,

Lugli,

Zaffagnini

et al. 2024

ACS Appl. Mater. Interfaces

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Proteins are broadly versatile biochemical materials, whose functionality is tightly related to their folding state. Native folding can be lost to yield misfolded conformations, often leading to formation of protein oligomers, aggregates, and biomolecular phase condensates. The fluorogenic hyaluronan HA-RB, a nonsulfonated glycosaminoglycan with a combination of polyanionic character and of hydrophobic spots due to rhodamine B dyes, binds to early aggregates of the model protein cytoplasmic glyceraldehyde-3-phosphate dehydrogenase 1 from Arabidopsis thaliana (AtGAPC1) since the very onset of the oligomeric phase, making them brightly fluorescent. This initial step of aggregation has, until now, remained elusive with other fluorescence-or scattering-based techniques. The information gathered from nanotracking (via light-sheet fluorescence microscopy) and from FCS in a confocal microscope converges to highlight the ability of HA-RB to bind protein aggregates from the very early steps of aggregation and with high affinity. Altogether, this fluorescencebased approach allows one to monitor and track individual early AtGAPC1 aggregates in the size range from 10 to 100 nm with high time (∼10−2 s) and space (∼250 nm) resolution.

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A Fluorogenic Molecule for Probing Islet Amyloid Using Flavonoid as a Scaffold Design

Cited by 9 publications

References 54 publications

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review

Advanced Techniques for Detecting Protein Misfolding and Aggregation in Cellular Environments

Fluorogenic Hyaluronan Nanogels Track Individual Early Protein Aggregates Originated under Oxidative Stress

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