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Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2004 Jan; Vol. 113 (1), pp. 65-73. - Publication Year :
- 2004
-
Abstract
- Avicins are proapoptotic and anti-inflammatory triterpene electrophiles isolated from an Australian desert tree, Acacia victoriae. The presence of two alpha,beta unsaturated carbonyl groups (Michael reaction sites) in the side chain of the avicin molecule prompted us to study its effects on NF-E2-related factor 2 (Nrf2), a redox-regulated transcription factor that controls the expression of a battery of detoxification and antioxidant proteins via its binding to antioxidant response element (ARE). Avicin D-treated Hep G2 cells showed translocation of Nrf2 into the nucleus and a time-dependent increase in ARE activity. These properties were sensitive to DTT, suggesting that avicins affect one or more critical cysteine residues, probably on the Keap1 molecule. Downstream of ARE, an activation of a battery of stress-induced proteins occurred. The implications of these findings were evaluated in vivo in mouse skin exposed to an ancient stressor, UV light. Avicins inhibited epidermal hyperplasia, reduced p53 mutation, enhanced apoptosis, decreased generation of 8-hydroxy-2'-deoxyguanosine, and enhanced expression of NADPH:quinone oxidoreductase 1 and heme oxygenase-1. These data, combined with our earlier published work, demonstrate that avicins represent a new class of plant stress metabolites capable of activating stress adaptation and suppressing proinflammatory components of the innate immune system in human cells by redox regulation. The relevance for treatment of clinical diseases in which stress responses are dysfunctional or deficient is discussed.
- Subjects :
- Carcinoma, Hepatocellular
Dithiothreitol pharmacology
Gene Expression Regulation, Neoplastic genetics
Glutathione metabolism
Glutathione Peroxidase metabolism
Glutathione Transferase metabolism
Humans
Kinetics
Liver Neoplasms
Recombinant Proteins metabolism
Transfection
Tumor Cells, Cultured
Apoptosis drug effects
Gene Expression Regulation, Neoplastic drug effects
Saponins pharmacology
Triterpenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 113
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 14702110
- Full Text :
- https://doi.org/10.1172/JCI18699