Grupo de Neurobiologia Molecular, IBMC-Instituto de Biologia Molecular e Celular, Porto, Portugal.
FEBS Lett. 2011 Aug 4;585(15):2424-30. doi: 10.1016/j.febslet.2011.06.030. Epub 2011 Jul 2.
Several natural polyphenols with potent inhibitory effects on amyloid fibril formation have been reported. Herein, we studied modulation of transthyretin (TTR) fibrillogenesis by selected polyphenols. We demonstrate that both curcumin and nordihydroguaiaretic acid (NDGA) bind to TTR and stabilize the TTR tetramer. However, while NDGA slightly reduced TTR aggregation, curcumin strongly suppressed TTR amyloid fibril formation by generating small "off-pathway" oligomers and EGCG maintained most of the protein in a non-aggregated soluble form. This indicates alternative mechanisms of action supported by the occurrence of different non-toxic intermediates. Moreover, EGCG and curcumin efficiently disaggregated pre-formed TTR amyloid fibrils. Our studies, together with the safe toxicological profile of these phytochemicals may guide a novel pharmacotherapy for TTR-related amyloidosis targeting different steps in fibrillogenesis.
已有报道称，有几种具有强烈抑制淀粉样纤维形成的天然多酚。在此，我们研究了一些多酚对转甲状腺素蛋白（TTR）纤维形成的调节作用。我们证明姜黄素和去甲二氢愈创木酸（NDGA）都与 TTR 结合并稳定 TTR 四聚体。然而，虽然 NDGA 略微减少了 TTR 的聚集，但姜黄素通过生成小的“偏离途径”寡聚物强烈抑制 TTR 淀粉样纤维的形成，并使大多数蛋白质保持在非聚集的可溶性形式。这表明不同的无毒中间体的存在支持不同的作用机制。此外，EGCG 和姜黄素有效地解聚了预先形成的 TTR 淀粉样纤维。我们的研究，以及这些植物化学物质的安全毒理学特征，可能为 TTR 相关淀粉样变性的新型药物治疗提供指导，针对纤维形成的不同步骤。
