Protective Effect of Phloroglucinol on Oxidative Stress-Induced DNA Damage and Apoptosis through Activation of the Nrf2/HO-1 Signaling Pathway in HaCaT Human Keratinocytes.

Cheol Park,Heui-Soo Kim,You-Jin Jeon,Yung Hyun Choi,Suhkmann Kim,Hee-Jae Cha,Su Hyun Hong,Byung Woo Kim,Gi-Young Kim

doi:10.3390/md17040225

Abstract

Phloroglucinol (PG) is a component of phlorotannins, which are abundant in marine brown alga species. Recent studies have shown that PG is beneficial in protecting cells from oxidative stress. In this study, we evaluated the protective efficacy of PG in HaCaT human skin keratinocytes stimulated with oxidative stress (hydrogen peroxide, H2O2). The results showed that PG significantly inhibited the H2O2-induced growth inhibition in HaCaT cells, which was associated with increased expression of heme oxygenase-1 (HO-1) by the activation of nuclear factor erythroid 2-related factor-2 (Nrf2). PG remarkably reversed H2O2-induced excessive ROS production, DNA damage, and apoptosis. Additionally, H2O2-induced mitochondrial dysfunction was related to a decrease in ATP levels, and in the presence of PG, these changes were significantly impaired. Furthermore, the increases of cytosolic release of cytochrome c and ratio of Bax to Bcl-2, and the activation of caspase-9 and caspase-3 by the H2O2 were markedly abolished under the condition of PG pretreatment. However, the inhibition of HO-1 function using zinc protoporphyrin, a HO-1 inhibitor, markedly attenuated these protective effects of PG against H2O2. Overall, our results suggest that PG is able to protect HaCaT keratinocytes against oxidative stress-induced DNA damage and apoptosis through activating the Nrf2/HO-1 signaling pathway.

Highlights

Reactive oxygen species (ROS) act as important regulatory molecules of the intracellular signaling system for physiological responses
Despite the fact that skin has efficient mechanisms to defend against oxidative stress, accumulation of ROS overwhelming the protection from ultraviolet B (UVB) exposure has been shown to have a decisive influence on skin cell damage, including keratinocytes
We investigated whether PG is effective in preventing oxidative stress-induced cytotoxicity through nuclear factor erythroid 2-related factor-2 (Nrf2)-mediated heme oxygenase-1 (HO-1) activation in HaCaT keratinocytes

Summary

Introduction

Reactive oxygen species (ROS) act as important regulatory molecules of the intracellular signaling system for physiological responses. Excessive production of ROS beyond the antioxidant capacity of cells can cause irreversible severe oxidative damage to the cells [1,2]. Inaccurate accumulation of ROS by oxidative stress has been recognized as one of the mechanisms that lead to apoptosis following DNA damage associated with mitochondrial dysfunction [8,9]. These observations suggest that antioxidant supplementation can maintain normal skin cell function by preventing free radical accumulation through the activation of signaling pathways that block ROS production

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