Nedumpully-Govindan Praveen, Gurzov Esteban N, Chen Pengyu, Pilkington Emily H, Stanley William J, Litwak Sara A, Davis Thomas P, Ke Pu Chun, Ding Feng
Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA.
Phys Chem Chem Phys. 2016 Jan 7;18(1):94-100. doi: 10.1039/c5cp05924k. Epub 2015 Dec 2.
Human islet amyloid polypeptide (hIAPP or amylin) aggregation is directly associated with pancreatic β-cell death and subsequent insulin deficiency in type 2 diabetes (T2D). Since no cure is currently available for T2D, it is of great benefit to devise new anti-aggregation molecules, which protect β-cells against hIAPP aggregation-induced toxicity. Engineered nanoparticles have been recently exploited as anti-aggregation nanomedicines. In this work, we studied graphene oxide (GO) nanosheets for their potential for hIAPP aggregation inhibition by combining computational modeling, biophysical characterization and cell toxicity measurements. Using discrete molecular dynamics (DMD) simulations and in vitro studies, we showed that GO exhibited an inhibitory effect on hIAPP aggregation. DMD simulations indicated that the strong binding of hIAPP to GO nanosheets was driven by hydrogen bonding and aromatic stacking and that the strong peptide-GO binding efficiently inhibited hIAPP self-association and aggregation on the nanosheet surface. Secondary structural changes of hIAPP upon GO binding derived from DMD simulations were consistent with circular dichroism (CD) spectroscopy measurements. Transmission electron microscopy (TEM) images confirmed the reduction of hIAPP aggregation in the presence of GO. Furthermore, we carried out a cell toxicity assay and found that these nanosheets protected insulin-secreting NIT-1 pancreatic β-cells against hIAPP-induced toxicity. Our multidisciplinary study suggests that GO nanosheets have the potential to be utilized as an anti-aggregation nanomedicine itself in addition to a biosensor or delivery vehicle for the mitigation of T2D progression.
人胰岛淀粉样多肽（hIAPP或胰淀素）聚集与2型糖尿病（T2D）中胰腺β细胞死亡及随后的胰岛素缺乏直接相关。由于目前尚无治愈T2D的方法，设计新的抗聚集分子具有极大益处，这些分子可保护β细胞免受hIAPP聚集诱导的毒性。工程化纳米颗粒最近已被用作抗聚集纳米药物。在这项工作中，我们通过结合计算建模、生物物理表征和细胞毒性测量，研究了氧化石墨烯（GO）纳米片抑制hIAPP聚集的潜力。使用离散分子动力学（DMD）模拟和体外研究，我们表明GO对hIAPP聚集具有抑制作用。DMD模拟表明，hIAPP与GO纳米片的强结合是由氢键和芳香堆积驱动的，并且强肽 - GO结合有效地抑制了hIAPP在纳米片表面的自缔合和聚集。DMD模拟得出的hIAPP与GO结合后的二级结构变化与圆二色性（CD）光谱测量结果一致。透射电子显微镜（TEM）图像证实了在GO存在下hIAPP聚集的减少。此外，我们进行了细胞毒性测定，发现这些纳米片可保护分泌胰岛素的NIT - 1胰腺β细胞免受hIAPP诱导的毒性。我们的多学科研究表明，除了作为生物传感器或递送载体用于减轻T2D进展外，GO纳米片本身有潜力被用作抗聚集纳米药物。
