DescriptionThe induction of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)- antioxidant response elements (ARE)-mediated antioxidant enzymes provides a cellular defense against oxidative stress, a major drive of human diseases such as the tumor. Phytochemicals in folk medicine are widely being used as natural sources to develop novel therapeutics. Astaxanthin (AST) with potent antioxidant activity in combination with omega-3 fatty acid docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) at low concentration showed synergistic defense against oxidative stress via Nrf2-ARE pathway. The three natural chemicals alone and in combination elevated cellular GSH level, increased total antioxidant activity, induced mRNA expression of Nrf2 and its downstream genes in human HepG2-C8 cells. In addition, AST significantly decreased the methylation of GSTP1 promoter region and restored the expression of GSTP1, which is involved in detoxification and metabolism to prevent genome damage and cancer initiation. It suggests a correlation between the DNA methylation and GSTP1 expression in human prostate LNCaP cells. AST reduced protein expression and enzyme activity of the DNA methyltransferases (DNMTs). Moreover, we demonstrated that Nrf2 shows protective role in epidermis against inflammation and extracellular matrix (ECM) damage induced by the UVB-irradiation. As compared with the wildt-ype (WT) mice, Nrf2 knockout (KO) mice showed the increased protein expression of inflammatory markers, including P53, macrophage inflammatory protein-2 (MIP-2), and pro-matrix metalloproteinase-9 (pro-MMP-9). The protective effects of Nrf2 in response to the UVB-irradiation were mediated by increased HO-1 protein expression. Moreover, we conducted genome-wide analysis of DNA methylation in UVB- and DMBA-TPA induced mouse skin tumor models to identify genes and pathways with significant changes. The top-ranked genes and pathways will provide insight into the discovery of key genes in skin tumor initiation and progression so as to provide potential preventive biomarkers. Furthermore, we demonstrated that ursolic acid (UA), and sulforaphane (SFN) reduced in vivo skin carcinogenesis induced by UVB-irradiation. In conclusion, dietary natural chemicals alone or in combination attenuate oxidative stress, inflammation and even carcinogenesis through modulation of genetic and epigenetic events, and provide promising insights into cancer prevention.