Abstract
This study investigated the protective mechanisms of triphlorethol-A, isolated from Ecklonia cava, against oxidative stress-induced DNA base damage, especially 8-oxoguanine (8-oxoG), in Chinese hamster lung fibroblast V79-4 cells. 8-Oxoguanine DNA glycosylase-1 (OGG1) plays an important role in the removal of 8-oxoG during the cellular response to DNA base damage. Triphlorethol-A significantly decreased the levels of 8-oxoG induced by H2O2, and this correlated with increases in OGG1 mRNA and OGG1 protein levels. Furthermore, siOGG1-transfected cell attenuated the protective effect of triphlorethol-A against H2O2 treatment. Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcription factor for OGG1, and Nrf2 combines with small Maf proteins in the nucleus to bind to antioxidant response elements (ARE) in the upstream promoter region of the OGG1 gene. Triphlorethol-A restored the expression of nuclear Nrf2, small Maf protein, and the Nrf2-Maf complex, all of which were reduced by oxidative stress. Furthermore, triphlorethol-A increased Nrf2 binding to ARE sequences and the resulting OGG1 promoter activity, both of which were also reduced by oxidative stress. The levels of the phosphorylated forms of Akt kinase, downstream of phosphatidylinositol 3-kinase (PI3K), and Erk, which are regulators of OGG1, were sharply decreased by oxidative stress, but these decreases were prevented by triphlorethol-A. Specific PI3K, Akt, and Erk inhibitors abolished the cytoprotective effects of triphlorethol-A, suggesting that OGG1 induction by triphlorethol-A involves the PI3K/Akt and Erk pathways. Taken together, these data indicate that by activating the DNA repair system, triphlorethol-A exerts protective effects against DNA base damage induced by oxidative stress.
Highlights
Single bases within a DNA strand can be chemically damaged by deamination, oxidation, or alkylation through a variety of mechanisms [1]
We previously reported that optimal dose of triphlorethol-A which protected V79-4 cells against oxidative stress was 30 μM [24]
In cells treated with H2O2, triphlorethol-A restored Oxoguanine DNA glycosylase-1 (OGG1) expression via up-regulation of Nuclear factor erythroid 2–related factor 2 (Nrf2) and activity of the OGG1 promoter
Summary
Single bases within a DNA strand can be chemically damaged by deamination, oxidation, or alkylation through a variety of mechanisms [1]. Our recent study showed that triphlorethol-A increases heme oxygenase-1 activity by elevating the transcriptional activity of Nrf2 [21], and ameliorates the effects of formaldehyde on non-homologous end joining and BER capacity [22]. This compound enhances the activities of the antioxidant system and inhibits cellular damage against ultraviolet B rays, thereby protecting human keratinocytes against. Ultraviolet B radiation [23] In light of these observations, our current study focused on the ability of triphlorethol-A to protect cells against H2O2-induced DNA base damage and investigated the molecular mechanisms underlying this protective effect
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