Several chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived β-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).

中文翻译：

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筛选促进健康的化合物诱导 FOXO3 活性的能力


包括天然产物在内的几种化合物已被认为可以有效对抗与年龄相关的疾病或有益于健康生活。另一方面，叉头盒 O (FOXO) 蛋白正在成为与人类极端长寿相关的关键细胞成分。 FOXO蛋白主要受到翻译后修饰的调节，并且由于这些修饰是可逆的，因此可以通过药物治疗来激活和灭活FOXO。在这里，我们质疑一组具有已知有益健康特性的化合物是否有能力诱导 FOXO 因子的活性。我们发现白藜芦醇（存在于葡萄和其他食品中的一种植物抗毒素）、荜茇果实中发现的酰胺生物碱胡椒长明以及植物来源的β-咔啉化合物骆驼蓬碱可诱导 FOXO3 的核转位。我们还表明胡椒长明和去氢骆驼蓬碱但不包括白藜芦醇激活 FOXO 依赖性转录。我们确定了白藜芦醇、胡椒长明和去氢骆驼蓬碱对 FOXO 易位的半最大有效浓度 (EC50) 值，并分析了它们对染色体维持 1 (CRM1) 介导的核输出和活性氧 (ROS) 产生的抑制影响。我们还使用化学生物学方法和蛋白质印迹分析来探索潜在的分子机制。我们发现去氢骆驼蓬碱、胡椒长明和白藜芦醇独立于磷酸肌醇 3-激酶 (PI3K)/AKT 信号传导和 CRM1 介导的核输出来激活 FOXO3。去氢骆驼蓬碱对 FOXO3 活性的影响至少部分是通过抑制双特异性酪氨酸 (Y) 磷酸化调节激酶 1A (DYRK1A) 介导的，并且可以通过抑制去乙酰化酶 (SIRT) 来逆转。