Zeaxanthin induces Nrf2-mediated phase II enzymes in protection of cell death

Abstract

Zeaxanthin (Zea) is a major carotenoid pigment contained in human retina, and its daily supplementation associated with lower risk of age-related macular degeneration. Despite known property of Zea as an antioxidant, its underlying molecular mechanisms of action remain poorly understood. In this study, we aim to study the regulation mechanism of Zea on phase II detoxification enzymes. In normal human retinal pigment epithelium cells, Zea promoted the nuclear translocation of NF-E2-related factor 2 (Nrf2) and induced mRNA and protein expression of phase II enzymes, the induction was suppressed by specific knockdown of Nrf2. Zea also effectively protected against tert-butyl hydroperoxide-induced mitochondrial dysfunction and apoptosis. Glutathione (GSH) as the most important antioxidant was also induced by Zea through Nrf2 activation in a time- and dose-dependent manner, whereas the protective effects of Zea were decimated by inhibition of GSH synthesis. Finally, Zea activated the PI3K/Akt and MAPK/ERK pathway, whereas only PI3K/Akt activation correlated with phase II enzymes induction and Zea protection. In further in vivo analyses, Zea showed effects of inducing phase II enzymes and increased GSH content, which contributed to the reduced lipid and protein peroxidation in the retina as well as the liver, heart, and serum of the Sprague–Dawley rats. For the first time, Zea is presented as a phase II enzymes inducer instead of being an antioxidant. By activating Nrf2-mediated phase II enzymes, Zea could enhance anti-oxidative capacity and prevent cell death both in vivo and in vitro.

Antioxidant efficacy and the upregulation of Nrf2-mediated HO-1 expression by (+)-lariciresinol, a lignan isolated from Rubia philippinensis, through the activation of p38

“…3A–C). HO-1 plays its antioxidant role by converting heme into the powerful pro-oxidant biliverdin and finally a strong antioxidant bilirubin34. Several nutrients with benefits related to oxidative stress, such as curcumin, caffeic acid ester, eckol, and hydroxytyrosol, have been reported to induce HO-1 expression35.…”

Norbixin Protects Retinal Pigmented Epithelium Cells and Photoreceptors against A2E-Mediated Phototoxicity In Vitro and In Vivo

“…There is indeed good evidence that Nrf2 is involved in the protection of RPE against degeneration [89]. Nfr2 activation was described for lutein [90,91], zeaxanthin [92], astaxanthin [93] and bixin [77], but these effects were not always observed with RPE cells, so they may require confirmation using appropriate target cells.…”

APR3 modulates oxidative stress and mitochondrial function in ARPE‐19 cells

“…Supernatants were centrifuged at 17,000 g for 15 min at 4°C, and mitochondrial pellets were resuspended in 100 ml of isotonic buffer (210 mM mannitol, 70 mM sucrose, 5 mM Tris base, 1 mM EDTA×2Na, pH 7.5). Assays for NADHubiquinone reductase (complex I), succinate-CoQ oxidoreductase (complex II), ubiquinol cytochrome c reductase (complex III), cytochrome c oxidase (complex IV), and Mg 2+ -ATPase (complex V) activities were performed according to previously described methods (9).…”

“…Previous studies have indicated that the pathogenesis of AMD is strongly associated with chronic oxidative stress and inflammation, which ultimately lead to protein damage and aggregation and to degeneration of RPE cells (7). As the major component of the antioxidant defense system, nuclear factor (erythroidderived 2)-like 2 (Nrf2) has been suggested to play a vital role in protecting RPE cells through modulating phase II enzymes (8)(9)(10). Nrf2 is a major regulator that binds to antioxidant response elements and regulates the antioxidant response (11,12).…”