Survival Response by HO-1 and Its Products 201 Fig. 3. Cytoprotective HO-1 expression by curcumin through MAPK-dependent Nrf2 activation in HepG2 cells. (A) Structure of cur- cumin. (B, C, D and E) Cells were treated with indicated concentrations of curcumin for indicated time periods in the absence or presence of inhibitors for MAPK pathways, and Western blotting analysis for HO-1 expression and phosphorylation of ERK, p38 MAPK and JNK and fluorescence microscopic examination for Nrf2-nuclear translocation by using green-fluorescence dye conjugated to Nrf2 antibody were performed as previously described [40]. (F) Cells were pre-incubated for 12 h with 10 µ M of curcumin, and exposed for 6 h to 30 µ M of ter-butylhydroperoxide in the absence or presence of 20 µ M of zinc protoporphyrin IX. induce X-box binding protein-1 (Xbp-1) expression and activating transcription factor 6 (ATF6) cleavage. Instead, CO prevented Xbp-1 expression and ATF6 cleavage induced by endoplasmic reticulum (ER) stress inducers such as tunicamycin. They also demonstrated that CO rendered endothelial cells resistant to ER stress, which is potentially therapeutic in vascular diseases associated with ER stress. CO prevented endothelial apoptosis triggered by ER stress inducers through the suppression of C/EBP homologous protein (CHOP) expression, which was associated with its activation of p38 MAPK. The endogenous CO produced from HO-1 was also cytoprotective against ER stress through CHOP suppression. Conclusion Growing evidence supports HO-1 as an ‘omnipotent’ protein that, when expressed in a variety of disease states, exerts numerous activities that offer tissue protection. The precise underlying mechanisms for HO-1-based protection are not yet completely understood, but appear to involve the effects of by-products of HO-1 activity on intracellular signaling pathways. Overall, the ultimate goal of most research in HO-1 is to find a therapeutic use, and there could be several approaches to this issue. Transfer of HO-1 gene Vol. 42, No. 3, 2008 and administration of the reaction products of HO-1 have been attempted in animals with promising results, but not in human studies, probably due to potentially injurious effects. However, it is worth mentioning that several dietary anti- oxidants, of which safety is well characterized in humans, can induce HO-1 expression in a variety of cell types, and this may be a mechanism for their beneficial effects in several diseases. Further studies are required to investigate the effects of other dietary antioxidants and examine the signaling pathways involved in HO-1 expression. Acknowledgement This work was supported by (2006). Abbreviations Wonkwang University HO-1, heme oxygenase-1; BR, bilirubin; BV, biliverdin; NO, nitric oxide; Nrf2, nuclear factor E2-related factor 2; MAPK, mitogen-activated protein kinase; ERK, extra- cellular signal regulated kinase; JNK, c-Jun NH2-terminal kinase; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; cGMP, cyclic guanine monophosphate; CORM, CO-releasing molecule; PERK, protein kinase R-like endo-