Fragrant Unsaturated Aldehydes Elicit Activation of the Keap1/Nrf2 System Leading to the Upregulation of Thioredoxin Expression and Protection Against Oxidative Stress

摘要

Thioredoxin, a key molecule in redox regulation, and many redox enzymes are regulated through the antioxi-dant responsive element (ARE). To search for antioxidative constituents, we screened extracts from vegetables and found that the extracts of Perilla frutescens and Artemisia princeps have potent thioredoxin-inducing activities. By activity-guided purification of Perilla frutescens extracts, we identified perillaldehyde as a novel thioredoxin inducer. Fragrant unsaturated aldehydes, such as frans-cinnamaldehyde, safranal, 2,4-octadienal, citral, trans-2, cis-6-nonadienal, and frans-2-hexenal showed the ability to activate ARE. Perillaldehyde-induced activation through the ARE was suppressed by the overexpression of wild-type Keapl, whereas sulforaphane-induced activation seemed to be partially suppressed. Mutant Keapl (R272A/K287A or C273A/C288A) did not suppress this activation. Pretreatment with perillaldehyde reduced the H_2O_2-induced cytotoxicity. Thus, we show that fragrant unsaturated aldehydes from edible plants are novel thioredoxin inducers and ARE activators and may be beneficial for protection against oxidative stress-induced cellular damage. These results also suggest that perillaldehyde activates the Nrf2-Keapl system and that the lysine and arginine residues juxtaposed to the critical cysteine residues of Keapl are required for signal sensing.