Abstract
Eckol isolated from Ecklonia stolonifera was previously reported to exhibit cytoprotective activity with its intrinsic antioxidant activity in in vitro studies. In this study, we characterized the mechanism underlying the eckol-mediated the expression of heme oxygenase-1 (HO-1). Eckol suppressed the production of intracellular reactive oxygen species and increased glutathione level in HepG2 cells. Eckol treatment enhanced the expression of HO-1 at the both level of protein and mRNA in HepG2 cells. Enhanced expression of HO-1 by eckol was presumed to be the activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2) demonstrated by its nuclear translocation and increased transcriptional activity. c-Jun NH2-terminal kinases (JNKs) and PI3K/Akt contributed to Nrf2-mediated HO-1 expression. These results demonstrate that the eckol-mediated expression of HO-1 in HepG2 cells is regulated by Nrf2 activation via JNK and PI3K/Akt signaling pathways, suggesting that eckol may be used as a natural antioxidant and cytoprotective agent.
Highlights
Reactive oxygen species (ROS) are continuously produced in aerobic organisms as a natural by-product of oxygen metabolism and act as subcellular messengers in complex cellular processes, such as mitogenic signal transduction, gene expression, and regulation of cell proliferation
The result indicates that eckol activates the transcriptional activity of nuclear factor erythroid-derived 2-like 2 (Nrf2) via translocation into nucleus in HepG2 cells, suggesting the compound induces the expression of heme oxygenase-1 (HO-1) through the activation of Nrf2-antioxidant response element (ARE) signaling pathway
To further determine the upstream signaling pathway involved in eckol-mediated Nrf2 activation and induction of HO-1, we assessed the phosphorylation of MAPKs and Akt, which are signaling proteins involved in cellular protection against oxidative stress
Summary
Reactive oxygen species (ROS) are continuously produced in aerobic organisms as a natural by-product of oxygen metabolism and act as subcellular messengers in complex cellular processes, such as mitogenic signal transduction, gene expression, and regulation of cell proliferation. Exposure to the chemopreventive agents produces certain level of ROS, and causes mild oxidative stresses in cells [5] Such mild oxidative stresses are sufficient to initiate the intracellular signaling lead to the induction of phase II detoxification enzymes and antioxidant enzymes [6,7]. Due to the potential role of Nrf2-ARE signaling pathway in inducing antioxidant enzymes and protecting cells against oxidative damage, there are growing interests in the molecules that could activate this pathway [11]. A large number of studies have demonstrated that phytochemicals, such as resveratrol [12], curcumin [13], epigallocatechin-3-gallate [14], and eckol [7], have cytoprotective effects by enhancing Nrf2-ARE pathway-mediated antioxidant enzymes in in vitro and in vivo experiments. E. stolonifera and evaluated its cytoprotective properties and the underlying mechanism of the activation of Nrf signaling pathway in human hepatoma cell line (HepG2)
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