Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, 400076Mumbai, Maharashtra, India.
Department of Biotechnology, Savitribai Phule Pune University (Formerly University of Pune), Ganeshkhind, 411007Pune, Maharashtra, India.
Biol Chem. 2020 Sep 16;402(2):179-194. doi: 10.1515/hsz-2020-0176. Print 2021 Jan 27.
The aberrant misfolding and self-assembly of human islet amyloid polypeptide (hIAPP)-a hormone that is co-secreted with insulin from pancreatic β-cells-into toxic oligomers, protofibrils and fibrils has been observed in type 2 diabetes mellitus (T2DM). The formation of these insoluble aggregates has been linked with the death and dysfunction of β-cells. Therefore, hIAPP aggregation has been identified as a therapeutic target for T2DM management. Several natural products are now being investigated for their potential to inhibit hIAPP aggregation and/or disaggregate preformed aggregates. In this study, we attempt to identify the anti-amyloidogenic potential of Myricetin (MYR)- a polyphenolic flavanoid, commonly found in fruits (like ). Our results from biophysical studies indicated that MYR supplementation inhibits hIAPP aggregation and disaggregates preformed fibrils into non-toxic species. This protection was accompanied by inhibition of oxidative stress, reduction in lipid peroxidation and the associated membrane damage and restoration of mitochondrial membrane potential in INS-1E cells. MYR supplementation also reversed the loss of functionality in hIAPP exposed pancreatic islets via restoration of glucose-stimulated insulin secretion. Molecular dynamics simulation studies suggested that MYR molecules interact with the hIAPP pentameric fibril model at the amyloidogenic core region and thus prevents aggregation and distort the fibrils.
在 2 型糖尿病（T2DM）中，已经观察到人类胰岛淀粉样多肽（hIAPP）——一种与胰岛素从胰腺β细胞共同分泌的激素——的异常错误折叠和自组装成有毒寡聚体、原纤维和纤维。这些不溶性聚集体的形成与β细胞的死亡和功能障碍有关。因此，hIAPP 聚集已被确定为 T2DM 管理的治疗靶点。现在正在研究几种天然产物，以评估它们抑制 hIAPP 聚集和/或解聚预制聚集体的潜力。在这项研究中，我们试图确定杨梅素（MYR）——一种常见于水果中的多酚类黄酮——的抗淀粉样变性潜力。我们的生物物理研究结果表明，MYR 补充剂抑制 hIAPP 聚集并将预制纤维解聚成无毒物质。这种保护伴随着抑制氧化应激、减少脂质过氧化以及相关的膜损伤和恢复 INS-1E 细胞中的线粒体膜电位。MYR 补充还通过恢复葡萄糖刺激的胰岛素分泌来逆转暴露于 hIAPP 的胰腺胰岛的功能丧失。分子动力学模拟研究表明，MYR 分子与 hIAPP 五聚体纤维模型在淀粉样形成核心区域相互作用，从而防止聚集并扭曲纤维。
