National Engineering Research Center for Nanomedicine, College of Life Science and Technology , Huazhong University of Science and Technology , Wuhan 430074 , China.
Wuhan Institute of Biotechnology , Wuhan 430075 , China.
ACS Appl Mater Interfaces. 2018 Sep 19;10(37):31069-31079. doi: 10.1021/acsami.8b11078. Epub 2018 Sep 7.
Misfolding and aggregation of human islet amyloid polypeptide (hIAPP) into fibrils are important contributions to the pathology of type 2 diabetes. Developing effective inhibitors of protein aggregation and fibrillation has been considered a promising therapeutic approach to preventing and treating type 2 diabetes. Herein, we report that Shiitake-derived polysaccharide lentinan manipulates in vitro hIAPP fibrillation and modulates IAPP-induced cytotoxicity in a conformation-dependent manner. In its triple-helical conformation, lentinan effectively inhibits hIAPP fibrillation, either in bulk solution or in the presence of lipid membrane, suppresses reactive oxygen species (ROS) generation, and attenuates hIAPP-induced cell toxicity. In contrast, lentinan accelerates hIAPP aggregation when it exists in a random-coil conformation and shows no suppression on hIAPP-mediated ROS production. Further investigation shows that the interaction between triple-helical lentinan and monomeric hIAPP is more favorable than the intermolecular binding of hIAPP, which redirects hIAPP aggregates to discrete nontoxic nanocomposites. To the best of our knowledge, this is the first time to report a conformation-dependent inhibition of hIAPP aggregation, which will provide new insights for our understanding of the manipulation mechanisms on hIAPP by natural polysaccharides and open a new avenue for designing and screening potential amyloid inhibitors against type 2 diabetes.
人胰岛淀粉样多肽（hIAPP）错误折叠和聚集到纤维中是 2 型糖尿病发病机制的重要贡献。开发有效的蛋白质聚集和纤维化抑制剂已被认为是预防和治疗 2 型糖尿病的一种很有前途的治疗方法。在此，我们报告说，香菇衍生多糖香菇多糖以构象依赖的方式操纵体外 hIAPP 纤维形成并调节 IAPP 诱导的细胞毒性。在其三螺旋构象中，香菇多糖有效地抑制 hIAPP 纤维形成，无论是在本体溶液中还是在脂质膜存在下，抑制活性氧（ROS）的产生，并减轻 hIAPP 诱导的细胞毒性。相比之下，当香菇多糖处于无规卷曲构象时，它会加速 hIAPP 聚集，并且对 hIAPP 介导的 ROS 产生没有抑制作用。进一步的研究表明，三螺旋香菇多糖与单体 hIAPP 之间的相互作用比 hIAPP 之间的分子间结合更有利，这将 hIAPP 聚集体重定向到离散的无毒纳米复合材料。据我们所知，这是首次报道 hIAPP 聚集的构象依赖性抑制，这将为我们理解天然多糖对 hIAPP 的操纵机制提供新的见解，并为设计和筛选针对 2 型糖尿病的潜在淀粉样抑制剂开辟新途径。
