Inhibitory activities of flavonoids from Scutellaria baicalensis Georgi on amyloid aggregation related to type 2 diabetes and the possible structural requirements for polyphenol in inhibiting the nucleation phase of hIAPP aggregation

Wang, Ying; Hu, Ting; Wei, Jingjing; Yin, Xiaoying; Gao, Zhonghong; Li, Yong

doi:10.1016/j.ijbiomac.2022.06.107

Cited by 19 publications

(5 citation statements)

References 58 publications

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“…Under these conditions, autophagy activation has protective effects and inhibits pancreatic b cell death, being a natural defense (42,43). Flavonoids have also been involved in the protection of the deleterious effects of hIAPP aggregates in these cells (105)(106)(107)(108)(109). Apart from the actions of flavonoids already explained, flavonoids have been also involved in an increase in antioxidant enzymes, as a protective mechanism (110,111).…”

Section: Prevention Of Beta Cell Dysfunction By Polyphenolsmentioning

confidence: 99%

Targeting pancreatic beta cell death in type 2 diabetes by polyphenols

Garcimartín

Guillén

2022

Front. Endocrinol.

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Diabetes is a very complex disease which is characterized by the appearance of insulin resistance that is primarily compensated by an increase in pancreatic beta cell mass, generating hyperinsulinemia. After time, pancreatic beta cells die by apoptosis appearing in the second phase of the disease, and characterized by hypoinsulinemia. There are multiple conditions that can alter pancreatic beta cell homeostasis and viability, being the most relevant ones; ER stress, cytotoxicity by amylin, mTORC1 hyperactivity, oxidative stress, mitochondrial dysfunction, inflammation and alterations in autophagy/mitophagy flux. In addition, the possible effects that different polyphenols could exert in the modulation of these mechanisms and regulating pancreatic beta cell viability are analyzed. It is necessary a profound analysis and understanding of all the possible mechanisms involved in the control and maintenance of pancreatic beta cell viability to develop more accurate and target treatments for controlling beta cell homeostasis and preventing or even reversing type 2 diabetes mellitus.

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Section: Prevention Of Beta Cell Dysfunction By Polyphenolsmentioning

confidence: 99%

Targeting pancreatic beta cell death in type 2 diabetes by polyphenols

Garcimartín

Guillén

2022

Front. Endocrinol.

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“…The aggregation kinetics of medin, 1,11 similar to other amyloid peptides such as Aβ 12,13 and human amylin, 14,15 exhibits a typical sigmoid curve with three phases: a lag phase of nucleation of monomers into oligomers and proto-fibrils, a growth phase of rapid elongation of fibrils, and an equilibrium plateau of mature fibrils. Prior studies using circular dichroism (CD) spectroscopy and nuclear magnetic resonance (NMR) have suggested that the monomeric form of medin primarily adopts random coil and β-sheet structures, 16−18 although some partial helix structures have also been observed.…”

Section: ■ Introductionmentioning

confidence: 99%

Unveiling Medin Folding and Dimerization Dynamics and Conformations via Atomistic Discrete Molecular Dynamics Simulations

Huang,

Fan,

Wang

et al. 2023

J. Chem. Inf. Model.

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Medin is a principal component of localized amyloid found in the vasculature of individuals over 50 years old. Its amyloid aggregation has been linked to endothelial dysfunction and vascular inflammation, contributing to the pathogenesis of various vascular diseases. Despite its significance, the structures of the medin monomer, oligomer, and fibril remain elusive, and the dynamic processes of medin aggregation are not fully understood. In this study, we comprehensively investigated the medin folding and dimerization dynamics and conformations using atomistic discrete molecular dynamics simulations. Our simulation results suggested that the folding initiation of the medin involved the formation of β-sheets around medin 30−41 and medin 42−50 , with subsequent capping of other segments to their β-sheet edges. Medin monomers typically consisted of three or four β-strands, along with a dynamic N-terminal helix. Two isolated medin peptides readily aggregated into a β-sheet-rich dimer, displaying a strong aggregation propensity. Dimerization of medin not only enhanced the β-sheet conformations but also led to the formation of β-barrel oligomers. The aggregation tendencies of medin 1−18 and medin 19−29 were relatively weak. However, the segments of medin 30−41 and medin 42−50 played a crucial role as they primarily formed a β-sheet core and facilitated medin 1−18 and medin 19−29 to form intra-and interpeptide β-sheets. The findings highlight the critical role of the medin 30−41 and medin 42−50 regions in stabilizing the monomer structure and driving the medin amyloid aggregation. These regions could potentially serve as promising targets for designing antiamyloid inhibitors against amyloid aggregation of medin. Additionally, our study provides a full picture of the monomer conformations and dimerization dynamics for medin, which will help better understand the pathology of medin aggregation.

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“…The mechanism of hIAPP aggregation is reported by many studies, and the potential inhibitors, such as short peptides, natural products and metal complexes, are extensively investigated against amyloid fibril formation of hIAPP. [9][10][11][12][13][14][15] Natural products are a promising source of inhibitors, as they have made great contributions to the treatment of some serious diseases, especially cancer and infectious diseases. [16] Besides, natural compounds are more accessible, efficient and less toxic than conventional synthetic small molecules.…”

Section: Introductionmentioning

confidence: 99%

β‐Carboline Alkaloids Resist the Aggregation and Cytotoxicity of Human Islet Amyloid Polypeptide

et al. 2023

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β‐carboline alkaloids have a variety of pharmacological activities, such as anti‐tumor, antibiosis and anti‐diabetes. Harmine and harmol are two structurally similar β‐carbolines that occur in many medicinal plants. In this work, we chose harmine and harmol to impede the amyloid fibril formation of human islet amyloid polypeptide (hIAPP) associated with type 2 diabetes mellitus (T2DM), by a series of physicochemical and biochemical methods. The results indicate that harmine and harmol effectively prevent peptide fibrillation and alleviate toxic oligomer species. In addition, both small molecules exhibit strong binding affinities with hIAPP mainly through hydrophobic and hydrogen bonding interactions, reducing the cytotoxicity induced by hIAPP. Their distinct binding pattern with hIAPP is closely linked to the molecular configuration of two small molecules, affecting their ability to impede peptide aggregation. The study is of great significance for the application and development of β‐carboline alkaloids against T2DM.

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Inhibitory activities of flavonoids from Scutellaria baicalensis Georgi on amyloid aggregation related to type 2 diabetes and the possible structural requirements for polyphenol in inhibiting the nucleation phase of hIAPP aggregation

Cited by 19 publications

References 58 publications

Targeting pancreatic beta cell death in type 2 diabetes by polyphenols

Targeting pancreatic beta cell death in type 2 diabetes by polyphenols

Unveiling Medin Folding and Dimerization Dynamics and Conformations via Atomistic Discrete Molecular Dynamics Simulations

β‐Carboline Alkaloids Resist the Aggregation and Cytotoxicity of Human Islet Amyloid Polypeptide

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