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首页> 外文期刊>RSC Advances >Brazilin inhibits fibrillogenesis of human islet amyloid polypeptide, disassembles mature fibrils, and alleviates cytotoxicity
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Brazilin inhibits fibrillogenesis of human islet amyloid polypeptide, disassembles mature fibrils, and alleviates cytotoxicity

机译：Brazilin抑制人胰岛淀粉样多肽的原纤维形成，分解成熟原纤维，并减轻细胞毒性

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Fibrillogenesis of human islet amyloid polypeptide (hIAPP) is a pathological hallmark of type II diabetes mellitus (T2DM), and the inhibition of hIAPP fibrillogenesis is an important strategy for the prevention and treatment of T2DM. In this study, the inhibitory effects of brazilin on the fibrillization and cytotoxicity of hIAPP were examined using the thioflavin T fluorescence (ThT) assay, transmission electron microscopy (TEM), circular dichroism (CD) spectroscopy, cytotoxicity assays, and molecular dynamics simulations. Both the ThT and TEM results have shown that brazilin inhibits hIAPP fibrillogenesis in a dose-dependent manner. CD studies revealed that brazilin delays the conformational transition of hIAPP from its initial α-helical to the β-sheet form. As a result, brazilin greatly alleviates hIAPP-induced cytotoxicity. Moreover, we also found that brazilin disassembles preexisting hIAPP fibrils, and alleviates the cytotoxicity of hIAPP aggregates. The results of free energy decomposition studies calculated using molecular mechanics-Poisson–Boltzmann surface area analysis revealed that hydrophobic interactions contribute more than 75% of the free energy of binding in the brazilin–hIAPP complex, while electrostatic interactions (i.e., hydrogen bonds) play a secondary role (<25%). Two binding sites of brazilin on the hIAPP pentamer were identified, encompassing the N-terminal region and the turn region. There are 11 important residues of hIAPP that strongly interact with brazilin – Asn3, Thr4, Thr9, Arg11, Asn14, Phe15, His18, Ser19, Ser20, Asn21 and Phe23. The findings presented here will contribute to a comprehensive understanding of the inhibitory effect of brazilin on the fibrillogenesis of hIAPP, which is critical for the search for more effective agents that can inhibit hIAPP fibrillogenesis.
机译：人胰岛淀粉样多肽（hIAPP）的原纤维形成是II型糖尿病（T2DM）的病理标志，抑制hIAPP的原纤维形成是预防和治疗T2DM的重要策略。在这项研究中，使用硫代黄素T荧光（ThT）测定，透射电子显微镜（TEM），圆二色性（CD）光谱，细胞毒性测定和分子动力学模拟研究了巴西林对hIAPP的原纤维化和细胞毒性的抑制作用。 ThT和TEM结果均表明，巴西林以剂量依赖性方式抑制hIAPP原纤维形成。 CD研究表明，巴西林延缓了hIAPP从其最初的α-螺旋到β-折叠形式的构象转变。结果，巴西林极大地减轻了hIAPP诱导的细胞毒性。此外，我们还发现，巴西林可拆解先前存在的hIAPP原纤维，并减轻hIAPP聚集体的细胞毒性。使用分子力学-泊松-玻尔兹曼表面积分析法计算的自由能分解研究结果表明，疏水相互作用在巴西-hIAPP复合物中的结合自由能占结合自由能的75％以上，而静电相互作用（ ie ，氢键）起次要作用（<25％）。鉴定了hIAPP五聚体上的巴西灵芝的两个结合位点，包括N端区域和转向区域。 hIAPP的11个重要残基与巴西林强烈相互作用-Asn3，Thr4，Thr9，Arg11，Asn14，Phe15，His18，Ser19，Ser20，Asn21和Phe23。此处提出的发现将有助于人们全面了解巴西林对hIAPP纤维化的抑制作用，这对于寻找可抑制hIAPP纤维化的更有效药物至关重要。

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