Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a major pungent ingredient of red pepper, is reported to have antimutagenic and anticarcinogenic properties. However, the mechanisms underlying its chemoprotective effects remain largely unresolved. In the present study, we found that capsaicin induced expression of heme oxygenase-1 (HO-1) in HepG2 cells. Capsaicin treatment resulted in a transient increase in the phosphorylation of Akt and subsequently nuclear translocation of NF-E2-related factor 2 (Nrf2), enhancing its binding to antioxidant response element (ARE). HepG2 cells treated with capsaicin exhibited increased production of reactive oxygen species (ROS). Prior exposure of cells to N-acetyl-L -cysteine blocked not only the ROS production but also the nuclear translocation of Nrf2 and its ARE binding, as well as HO-1 induction by capsaicin. Immunoblot analysis showed that whereas the level of HO-1 protein was elevated, that of NAD(P)H:quinone oxidoreductase (NQO1) was decreased after the treatment with capsaicin or the inhibitor of NQO1, dicumarol. We hypothesize that quinone metabolites or other reactive forms of capsaicin may bind covalently to NQO1 and thereby inhibit its activity, leading to production of ROS. This, in turn, would trigger the activation of Akt via phosphorylation, increase the nuclear translocation and ARE binding of Nrf2, and upregulate the expression of HO-1.

H. pylori-induced STAT3 activation is mediated, at least in part, through ROS-induced upregulation of IL-6 expression. These findings provide a novel molecular mechanism responsible for H. pylori-induced gastritis and gastric carcinogenesis.

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Induction of heme oxygenase-1 (HO-1) represents an important cellular adaptive survival response to oxidative stress and other toxic insults. In the present study, HepG2 cells grown in glucose-free media underwent apoptotic cell death, but they exhibited elevated expression of HO-1 before apoptosis manifested. Treatment of HepG2 cells with SnCl₂, a HO-1 inducer, rescued these cells from glucose deprivation-induced apoptosis, while inhibition of the HO activity with zinc protoporphyrin IX exacerbated apoptosis under the same condition. HepG2 cells transfected with a dominant negative Nrf2 were more vulnerable to glucose deprivation-induced apoptosis compared to cells transfected with empty vector alone. To confirm the involvement of Nrf2 in the induction of HO-1 caused by glucose deprivation, we used embryonic fibroblasts prepared from nrf2⁻(/)⁻, nrf2(+/)⁻, and nrf2(+/+) embryos. Compared to the wild-type and the nrf2(+/)⁻ embryonic fibroblasts, nrf2⁻(/)⁻ cells were less prone to induce HO-1 expression upon glucose deprivation. Exposure of HepG2 cells to glucose-deprived media resulted in an elevated accumulation of reactive oxygen species (ROS). Pretreatment with N-acetylcysteine prevented the glucose deprivation-induced ROS accumulation and also the HO-1 expression. In conclusion, the Nrf2-mediated HO-1 upregulation upon glucose deprivation is mediated by ROS in HepG2 cells, and responsible for the adaptive survival response.