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Myricetin protects pancreatic β-cells from human islet amyloid polypeptide (hIAPP) induced cytotoxicity and restores islet function
Biological Chemistry ( IF 3.7 ) Pub Date : 2021-01-27 , DOI: 10.1515/hsz-2020-0176
Richa Dubey 1 , Shruti H Kulkarni 2 , Sarath Chandra Dantu 1, 3 , Rajlaxmi Panigrahi 1 , Devika M Sardesai 2 , Nikita Malik 1 , Jhankar D Acharya 4 , Jeetender Chugh 5, 6 , Shilpy Sharma 2 , Ashutosh Kumar 1
Affiliation  

Abstract 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 Syzygium cumini). 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.

中文翻译:

杨梅素保护胰岛 β 细胞免受人胰岛淀粉样多肽 (hIAPP) 诱导的细胞毒性并恢复胰岛功能

摘要 在 2 型糖尿病 (T2DM) 中观察到人类胰岛淀粉样多肽 (hIAPP)(一种与胰岛 β 细胞中的胰岛素共同分泌的激素)异常错误折叠和自组装成有毒低聚物、原纤维和原纤维。 . 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。目前正在研究几种天然产物抑制 hIAPP 聚集和/或分解预制聚集体的潜力。在这项研究中,我们试图确定杨梅素 (MYR) 的抗淀粉样蛋白生成潜力 - 一种多酚类黄酮,常见于水果(如 Syzygium cumini)。我们的生物物理研究结果表明,MYR 补充剂可抑制 hIAPP 聚集并将预先形成的原纤维分解为无毒物种。这种保护伴随着氧化应激的抑制、脂质过氧化的减少以及相关的膜损伤和 INS-1E 细胞线粒体膜电位的恢复。MYR 补充剂还通过恢复葡萄糖刺激的胰岛素分泌,逆转了 hIAPP 暴露的胰岛功能的丧失。分子动力学模拟研究表明,MYR 分子与淀粉样蛋白核心区域的 hIAPP 五聚原纤维模型相互作用,从而防止原纤维聚集和扭曲。INS-1E 细胞中脂质过氧化的减少和相关的膜损伤和线粒体膜电位的恢复。MYR 补充剂还通过恢复葡萄糖刺激的胰岛素分泌,逆转了 hIAPP 暴露的胰岛功能的丧失。分子动力学模拟研究表明,MYR 分子与淀粉样蛋白核心区域的 hIAPP 五聚原纤维模型相互作用,从而防止原纤维聚集和扭曲。INS-1E 细胞中脂质过氧化的减少和相关的膜损伤和线粒体膜电位的恢复。MYR 补充剂还通过恢复葡萄糖刺激的胰岛素分泌,逆转了 hIAPP 暴露的胰岛功能的丧失。分子动力学模拟研究表明,MYR 分子与淀粉样蛋白核心区域的 hIAPP 五聚原纤维模型相互作用,从而防止原纤维聚集和扭曲。
更新日期:2021-01-27
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