Fragrant unsaturated aldehydes elicit activation of the Keap1/Nrf2 system leading to the upregulation of thioredoxin expression and protection against oxidative stress.
Thioredoxin, a key molecule in redox regulation, and many redox enzymes are regulated through the antioxidant 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 trans-cinnamaldehyde, safranal, 2,4-octadienal, citral, trans-2, cis-6-nonadienal, and trans-2-hexenal showed the ability to activate ARE. Perillaldehyde-induced activation through the ARE was suppressed by the overexpression of wild-type Keap1, whereas sulforaphane-induced activation seemed to be partially suppressed. Mutant Keap1 (R272A/K287A or C273A/C288A) did not suppress this activation. Pretreatment with perillaldehyde reduced the H(2)O(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-Keap1 system and that the lysine and arginine residues juxtaposed to the critical cysteine residues of Keap1 are required for signal sensing.
Masutani
Hiroshi
H
Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan. hmasutan@virus.kyoto-u.ac.jp
Otsuki
Ryoko
R
Yamaguchi
Yoshimi
Y
Takenaka
Masahiro
M
Kanoh
Nobue
N
Takatera
Koji
K
Kunimoto
Yuji
Y
Yodoi
Junji
J
D000447:Aldehydes / Q000494:pharmacology*; D001483:Base Sequence; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D010936:Plant Extracts / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013879:Thioredoxins / Q000378:metabolism*; D015854:Up-Regulation
D000447:Aldehydes; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010936:Plant Extracts; D013879:Thioredoxins