Preconditioning by sesquiterpene lactone enhances H2O2-induced Nrf2/ARE activation.
The Nrf2/ARE pathway plays a pivotal role in chemoprevention and neuroprotection. Here, we report that sesquiterpene lactones extracted from Calea urticifolia and feverfew increased enhancer activity of the ARE. ARE activation was dependent on the number of alpha,beta-unsaturated carbonyl groups each compound bears and calealactone A (CL-A) harboring 3 of those was the most potent ARE inducer. At subtoxic doses, CL-A induced expression of heme oxygenase-1 (HO-1) gene, one of ARE target genes, through activation of the Nrf2/ARE pathway involving transient ROS generation and activation of PI3-K/Akt and MAPK pathways. Interestingly, H(2)O(2)-induced ARE activation and HO-1 induction were potentiated by pretreatment with CL-A at lower concentrations, at which Nrf2/ARE activation by the compound was minimal. These results suggest a possibility that preconditioning by sesquiterpene lactone may enhance activation of the Nrf2/ARE pathway and induction of phase II detoxification/antioxidant enzymes upon oxidative stress, thereby resulting in increased resistance to oxidative damage.
Umemura
Ken
K
Department of Longevity and Aging Research, Gifu International Institute of Biotechnology, 1-1 Naka-fudogaoka, Kakamigahara, Gifu 504-0838, Japan.
Itoh
Tomohiro
T
Hamada
Nanako
N
Fujita
Yasunori
Y
Akao
Yukihiro
Y
Nozawa
Yoshinori
Y
Matsuura
Nobuyasu
N
Iinuma
Munekazu
M
Ito
Masafumi
M
D000818:Animals; D000975:Antioxidants / Q000502:physiology*; D019659:Asteraceae / Q000737:chemistry; D004742:Enhancer Elements, Genetic; D017930:Genes, Reporter; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D020218:Response Elements / Q000502:physiology*; D012717:Sesquiterpenes / Q000494:pharmacology*
D000975:Antioxidants; D007783:Lactones; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D012717:Sesquiterpenes; C527645:calealactone A; C002669:parthenolide; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat