Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery
Valsala Haridas, … , Zbigniew Walaszek, Jordan U. Gutterman
Valsala Haridas, … , Zbigniew Walaszek, Jordan U. Gutterman
Published January 1, 2004
Citation Information: J Clin Invest. 2004;113(1):65-73. https://doi.org/10.1172/JCI18699.
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Article Oncology

Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery

Abstract

Avicins are proapoptotic and anti-inflammatory triterpene electrophiles isolated from an Australian desert tree, Acacia victoriae. The presence of two α,β 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.

Authors

Valsala Haridas, Margaret Hanausek, Goshi Nishimura, Holly Soehnge, Amos Gaikwad, Maciej Narog, Erick Spears, Robert Zoltaszek, Zbigniew Walaszek, Jordan U. Gutterman

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Figure 1

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Nuclear localization of Nrf2 and activation of ARE-mediated gene express...
Nuclear localization of Nrf2 and activation of ARE-mediated gene expression. (a) Hep G2 cells transfected with EGFP-Nrf2 were either untreated or treated with avicin D (2 μg/ml) for 1 hour at 37°C. Nuclear localization of Nrf2 was studied by fluorescence microscopy (H&E staining; ×400). (b) Hep G2 cells were treated with avicin D (2 μg/ml) for 0–4 hours at 37°C. Western blot analysis of cytoplasmic and nucleaE-LUC plasmid, and LUC activity was measured as described in Methods. Dose response of ARE activation was studied using 0–2 μg/ml of avicin D for 2 hours at 37°C (c), and kinetics of ARE activation was studied using 2 μg/ml of avicin D for 0–16 hours at 37°C (d). (e) Effect of DTT (100 μM) on ARE activation was studied by application of DTT to cells for 2 hours, before, after, or along with avicin D (2 μg/ml).