Jimenez Lucia, Silva Andreia, Calissi Giampaolo, Grenho Inês, Monteiro Rita, Mayoral-Varo Victor, Blanco-Aparicio Carmen, Pastor Joaquin, Bustos Victor, Bracher Franz, Megías Diego, Ferreira Bibiana I, Link Wolfgang
Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Faro, Portugal.
J Gerontol A Biol Sci Med Sci. 2022 Aug 12;77(8):1485-1493. doi: 10.1093/gerona/glab265.
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).
包括天然产物在内的几种化合物已被认为对与年龄相关的疾病有效或对健康生活有益。另一方面，叉头框O（FOXO）蛋白正成为与人类极端长寿相关的关键细胞成分。FOXO蛋白主要通过翻译后修饰进行调节，由于这些修饰是可逆的，因此可以通过药物治疗实现FOXO的激活和失活。在这里，我们质疑一组具有已知健康益处的化合物是否有能力诱导FOXO因子的活性。我们发现，葡萄和其他食品中含有的植物抗毒素白藜芦醇、长胡椒果实中发现的酰胺生物碱胡椒碱以及植物来源的β-咔啉化合物去氢骆驼蓬碱可诱导FOXO3的核转位。我们还发现，胡椒碱和去氢骆驼蓬碱而非白藜芦醇可激活FOXO依赖的转录。我们确定了白藜芦醇、胡椒碱和去氢骆驼蓬碱诱导FOXO转位的半数最大有效浓度（EC50）值，并分析了它们对染色体维持蛋白1（CRM1）介导的核输出和活性氧（ROS）产生的抑制作用。我们还使用化学生物学方法和蛋白质免疫印迹分析来探索潜在的分子机制。我们发现，去氢骆驼蓬碱、胡椒碱和白藜芦醇可独立于磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）信号通路和CRM1介导的核输出激活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，并且可以通过抑制沉默调节蛋白（SIRT）来逆转。
