Nuclear factor E2-related factor 2 (Nrf2) is fundamental to the maintenance of redox homeostasis within cells via the regulation of a series of phase II antioxidant enzymes. The unique olive-derived phenolic compound hydroxytyrosol (HT) is recognized as an Nrf2 activator, but knowledge of the HT derivative hydroxytyrosol acetate (HTac) on Nrf2 activation remains limited. In this study, we observed that an HT pretreatment could protect the cell viability, mitochondrial membrane potential, and redox homeostasis of ARPE-19 cells against a t-butyl hydroperoxide challenge at 50 μM. HTac exhibited similar benefits at 10 μM, indicating a more effective antioxidative capacity compared with HT. HTac consistently and more efficiently activated the expression of Nrf2-regulated phase II enzymes than HT. PI3K/Akt was the key pathway accounting for the beneficial effects of HTac in ARPE-19 cells. A further RNA-Seq analysis revealed that in addition to the consistent upregulation of phase II enzymes, the cells presented distinct expression profiles after HTac and HT treatments. This indicated that HTac could trigger a diverse cellular response despite its similar molecular structure to HT. The evidence in this study suggests that Nrf2 activation is the major cellular activity shared by HTac and HT, and HTac is more efficient at activating the Nrf2 system. This supports its potential future employment in various disease management strategies.

中文翻译：

---

羟基酪醇乙酸酯与羟基酪醇激活II相酶的比较研究

核因子 E2 相关因子 2 (Nrf2) 通过调节一系列 II 相抗氧化酶，对于维持细胞内氧化还原稳态至关重要。独特的橄榄衍生酚类化合物羟基酪醇 (HT) 被认为是 Nrf2 激活剂，但对 HT 衍生物羟基酪醇乙酸酯 (HTac) 对 Nrf2 激活的了解仍然有限。在这项研究中，我们观察到 HT 预处理可以保护 ARPE-19 细胞的细胞活力、线粒体膜电位和氧化还原稳态，以应对 50 μM 叔丁基过氧化氢的挑战。HTac 在 10 μM 时表现出类似的益处，表明与 HT 相比具有更有效的抗氧化能力。HTac 比 HT 更一致且更有效地激活 Nrf2 调节的 II 期酶的表达。PI3K/Akt 是 HTac 对 ARPE-19 细胞产生有益作用的关键途径。进一步的 RNA-Seq 分析表明，除了 II 相酶的一致上调之外，在 HTac 和 HT 处理后，细胞还呈现出不同的表达谱。这表明，尽管 HTac 的分子结构与 HT 相似，但它可以引发多种细胞反应。这项研究的证据表明，Nrf2 激活是 HTac 和 HT 共有的主要细胞活动，并且 HTac 在激活 Nrf2 系统方面更有效。这支持了其未来在各种疾病管理策略中的潜在应用。