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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. [ABSTRACT FROM AUTHOR]

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.

NF-E2-related factor 2 (Nrf2), the key transcription regulator of phase II enzymes, has been considered beneficial for neuronal protection. We previously designed a novel chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), that could specifically activate Nrf2 in vitro. Here, we report that Tak confers significant hippocampal neuronal protection both in vitro and in vivo. Treatment with Tak has no significant toxicity on cultured neuronal cells. Instead, Tak increases cellular ATP production by increasing mitochondrial function and decreases the levels of reactive oxygen species by activating Nrf2-mediated phase II enzyme expression. Tak pretreatment prevents glutamate-induced excitotoxic neuronal death accompanied by suppressed mitochondrial respiration, increased superoxide production, and activation of apoptosis. Further investigation indicates that the protective effect of Tak is mediated by the Akt signaling pathway. Meanwhile, Tak administration in mice can sufficiently abrogate scopolamine-induced cognitive impairment via decreasing hippocampal oxidative stress. In addition, consistent benefits are also observed in an energy stress mouse model under a high-fat diet, as the administration of Tak remarkably increases Akt signaling-mediated antioxidative enzyme expression and prevents hippocampal neuronal apoptosis without significant effect on the mouse metabolic status. Overall, our study demonstrates that Tak protects cognitive function by Akt-mediated Nrf2 activation to maintain redox status both vivo and in vitro, suggesting that Tak is a promising pharmacological candidate for the treatment of oxidative neuronal diseases.

Asbestos exposure triggers inflammatory processes associated with oxidative stress and tissue damage linked to malignancy. LGM2605 is the synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant, and anti-inflammatory properties in diverse inflammatory cell and mouse models, including exposure to asbestos fibers. Nuclear factor-E2 related factor 2 (Nrf2) activation and boosting of endogenous tissue defenses were associated with the protective action of LGM2605 from asbestos-induced cellular damage. To elucidate the role of Nrf2 induction by LGM2605 in protection from asbestos-induced cellular damage, we evaluated LGM2605 in asbestos-exposed macrophages from wild-type (WT) and Nrf2 disrupted (Nrf2-/-) mice. Cells were pretreated with LGM2605 (50 μM and 100 μM) and exposed to asbestos fibers (20 μg/cm²) and evaluated 8 h and 24 h later for inflammasome activation, secreted cytokine levels (interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα)), cytotoxicity and cell death, nitrosative stress, and Nrf2-regulated enzyme levels. Asbestos exposure induced robust oxidative and nitrosative stress, cell death and cytotoxicity, which were equally mitigated by LGM2605. Inflammasome activation was significantly attenuated in Nrf2-/- macrophages compared to WT, and the protective action of LGM2605 was seen only in WT cells. In conclusion, in a cell model of asbestos-induced toxicity, LGM2605 acts via protective mechanisms that may not involve Nrf2 activation. [ABSTRACT FROM AUTHOR]

Asbestos exposure triggers inflammatory processes associated with oxidative stress and tissue damage linked to malignancy. LGM2605 is the synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant, and anti-inflammatory properties in diverse inflammatory cell and mouse models, including exposure to asbestos fibers. Nuclear factor-E2 related factor 2 (Nrf2) activation and boosting of endogenous tissue defenses were associated with the protective action of LGM2605 from asbestos-induced cellular damage. To elucidate the role of Nrf2 induction by LGM2605 in protection from asbestos-induced cellular damage, we evaluated LGM2605 in asbestos-exposed macrophages from wild-type (WT) and Nrf2 disrupted (Nrf2−/−) mice. Cells were pretreated with LGM2605 (50 µM and 100 µM) and exposed to asbestos fibers (20 µg/cm2) and evaluated 8 h and 24 h later for inflammasome activation, secreted cytokine levels (interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα)), cytotoxicity and cell death, nitrosative stress, and Nrf2-regulated enzyme levels. Asbestos exposure induced robust oxidative and nitrosative stress, cell death and cytotoxicity, which were equally mitigated by LGM2605. Inflammasome activation was significantly attenuated in Nrf2−/− macrophages compared to WT, and the protective action of LGM2605 was seen only in WT cells. In conclusion, in a cell model of asbestos-induced toxicity, LGM2605 acts via protective mechanisms that may not involve Nrf2 activation.

NF-E2-related factor 2 (Nrf2), the key transcription regulator of phase II enzymes, has been considered beneficial for neuronal protection. We previously designed a novel chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), that could specifically activate Nrf2 in vitro. Here, we report that Tak confers significant hippocampal neuronal protection both in vitro and in vivo. Treatment with Tak has no significant toxicity on cultured neuronal cells. Instead, Tak increases cellular ATP production by increasing mitochondrial function and decreases the levels of reactive oxygen species by activating Nrf2-mediated phase II enzyme expression. Tak pretreatment prevents glutamate-induced excitotoxic neuronal death accompanied by suppressed mitochondrial respiration, increased superoxide production, and activation of apoptosis. Further investigation indicates that the protective effect of Tak is mediated by the Akt signaling pathway. Meanwhile, Tak administration in mice can sufficiently abrogate scopolamine-induced cognitive impairment via decreasing hippocampal oxidative stress. In addition, consistent benefits are also observed in an energy stress mouse model under a high-fat diet, as the administration of Tak remarkably increases Akt signaling-mediated antioxidative enzyme expression and prevents hippocampal neuronal apoptosis without significant effect on the mouse metabolic status. Overall, our study demonstrates that Tak protects cognitive function by Akt-mediated Nrf2 activation to maintain redox status both vivo and in vitro, suggesting that Tak is a promising pharmacological candidate for the treatment of oxidative neuronal diseases. [ABSTRACT FROM AUTHOR]