Eckol Enhances Heme Oxygenase-1 Expression through Activation of Nrf2/JNK Pathway in HepG2 Cells

Jun, Young-Jin; Lee, Min-Sup; Shin, Tai-Sun; Yoon, Na-Young; Kim, Jihoe; Kim, Hyeung‐Rak

doi:10.3390/molecules191015638

Cited by 51 publications

(42 citation statements)

References 35 publications

(44 reference statements)

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“…A number of studies have suggested that diverse protein kinases are involved in the signals that trigger Nrf2-Keap1 dissociation and the phosphorylation of Nrf2, as well as the antioxidant-induced activation of the Nrf2/HO-1 signaling pathway. For example, the phenolic glucoside gastrodin stimulated HO-1 expression through the activation of the p38 MAPK/Nrf2 signaling pathway (39), the flavonoid sulfuretin upregulation of the activity of HO-1 through the JNK/ERK/Nrf2 signaling pathway (40), the eckol induction of Nrf2-dependent HO-1 expression through the JNK and PI3K/Akt signaling pathways (41), and the induction of expression of HO-1 by prenylated flavone cudraflavone B mediated through the PI3K/Akt pathway (42). These findings prove that the role of each pathway in the activation of Nrf2/HO-1 signaling, and their molecular targets, may be specific to the stimulus and cell type.…”

Section: Discussionmentioning

confidence: 99%

The cytoprotective effects of 7,8-dihydroxyflavone against oxidative stress are mediated by the upregulation of Nrf2-dependent HO-1 expression through the activation of the PI3K/Akt and ERK pathways in C2C12 myoblasts

Kang

Choi

Han

et al. 2015

International Journal of Molecular Medicine

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Recent studies have demonstrated that 7,8-dihydroxyflavone (7,8-DHF), a newly identified tyrosine kinase receptor B agonist, is a potent antioxidant agent. The present study was designed to confirm the cytoprotective effects of 7,8-DHF against oxidative stress-induced cellular damage and to further elucidate the underlying mechanisms in C2C12 myoblasts. We found that 7,8-DHF attenuated hydrogen peroxide (H2O2)-induced growth inhibition and exhibited scavenging activity against intracellular reactive oxygen species (ROS) that were induced by H2O2. We also observed that 7,8-DHF significantly attenuated H2O2-induced comet tail formation, and decreased the phosphorylation levels of the histone, H2AX, as well as the number of Annexin V-positive cells, suggesting that 7,8-DHF prevents H2O2-induced DNA damage and cell apoptosis. Furthermore, 7,8-DHF increased the levels of heme oxygenase-1 (HO-1), which is a potent antioxidant enzyme associated with the induction and phosphorylation of nuclear factor-erythroid 2-related factor 2 (Nrf2), as well as the translocation of Nrf2 from the cytosol to the nucleus. However, the protective effects of 7,8-DHF against H2O2 -induced ROS generation and growth inhibition were significantly diminished by zinc protoporphyrin IX, an HO-1 competitive inhibitor. Moreover, the potential of 7,8-DHF to mediate HO-1 induction and protect the cells against H2O2 -mediated growth inhibition was abrogated by transient transfection with Nrf2-specific small interfering RNA (siRNA). In addition, 7,8-DHF induced the activation of Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K), and also that of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), while specific inhibitors of PI3K and ERK, but not a p38 MAPK inhibitor, abolished the 7,8-DHF induced HO-1 upregulation and Nrf2 induction and phosphorylation. Collectively, these results demonstrate that 7,8-DHF augments the cellular antioxidant defense capacity through activation of the Nrf2/HO-1 pathway, which also involves the activation of the PI3K/Akt and ERK pathways, thereby protecting C2C12 myoblasts from H2O2-induced oxidative cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

The cytoprotective effects of 7,8-dihydroxyflavone against oxidative stress are mediated by the upregulation of Nrf2-dependent HO-1 expression through the activation of the PI3K/Akt and ERK pathways in C2C12 myoblasts

Kang

Choi

Han

et al. 2015

International Journal of Molecular Medicine

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“…Polyphenols protect against oxidative stress by eliminating free radicals (53). Oxidative stress is attenuated by eckol via the upregulation of transcription factors including nuclear respiratory factor (NRF) and Forkhead box O3a, which directly regulate the ROS-scavenging enzymes HO-1 and MnSOD via NRF2/JNK, ERK, PI3K/AKT, and AMPK signaling pathways (26,54,55). Consistent with these ndings, we showed that eckol alleviates H 2 O 2 -induced oxidative stress by stimulating the expression of HO-1 and MnSOD via PI3K/AKT, P38, and AMPK signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Eckol alleviates intestinal dysfunction during suckling-to-weaning transition via modulation of PDX1 and HBEGF

Lee

Kim

2020

Preprint

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Background Maintaining intestinal health in livestock is critical during weaning. Although intestinal dysfunction during this period can be alleviated by phlorotannins including eckol, the precise mechanisms are not fully understood. We addressed this question by evaluating changes in gene expression and intestinal function after treatment with eckol during the suckling-to-weaning transition. The biological roles of differentially expressed genes in intestinal development were investigated by assessing intestinal wound healing and barrier function and associated signaling pathways, along with oxidative stress levels. Results We identified 890 differentially expressed genes in the intestine whose expression was altered by eckol treatment including pancreatic and duodenal homeobox (PDX)1, which directly regulate the expression of heparin-binding epidermal growth factor-like growth factor (HBEGF) to preserve intestinal barrier function and promote wound healing via phosphoinositide 3-kinase (PI3K)/AKT and P38 signaling. Additionally, eckol alleviated H2O2-induced oxidative stress via PI3K/AKT, P38, and 5' AMP-activated protein kinase signaling, improved growth, and reduced oxidative stress and intestinal permeability in pigs during weaning. Conclusions Eckol modulates intestinal barrier function, wound healing, and oxidative stress via PDX/HBEGF and improves growth during the suckling-to-weaning transition, suggesting that it can be used as a feed supplement to preserve intestinal function during this process in pigs and other livestock.

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“…The phenolic glucoside, gastrodin, has also been shown to stimulate HO-1 expression through the activation of the p38 MAPK/Nrf2 signaling pathway (38). In addition, eckol, a phlorotannin isolated from brown algae, has been shown to induce Nrf2-dependent HO-1 expression through the JNK and PI3K/Akt signaling pathways (39). These findings suggest that the role of each pathway in the activation of Nrf2/HO-1 signaling, and their molecular targets, may be specific to the stimulus and cell type.…”

Section: Discussionmentioning

confidence: 99%

An exploration of the antioxidant effects of garlic saponins in mouse-derived C2C12 myoblasts

Kang

Kim

et al. 2015

International Journal of Molecular Medicine

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In this study, we aimed to confirm the protective effects of garlic saponins against oxidative stress-induced cellular damage and to further elucidate the underlying mechanisms in mouse-derived C2C12 myoblasts. Relative cell viability was determined by 3-(4.5-dimethylthiazol-2-yl)-2.5 diphenyltetrazolium bromide assay. Comet assay was used to measure DNA damage and oxidative stress was determined using 2',7'-dichlorofluorescein diacetate to measure intracellular reactive oxygen species (ROS) generation. Western blot analysis and small interfering RNA (siRNA)-based knockdown were used in order to investigate the possible molecular mechanisms. Our results revealed that garlic saponins prevented hydrogen peroxide (H2O2)-induced growth inhibition and exhibited scavenging activity against intracellular ROS. We also observed that garlic saponins prevented H2O2-induced comet tail formation and decreased the phosphorylation levels of γH2AX expression, suggesting that they can prevent H2O2-induced DNA damage. In addition, garlic saponins increased the levels of heme oxygenase-1 (HO-1), a potent antioxidant enzyme associated with the induction and phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the translocation of Nrf2 from the cytosol into the nucleus. However, the protective effects of garlic saponins on H2O2-induced ROS generation and growth inhibition were significantly reduced by zinc protoporphyrin Ⅸ, an HO-1 competitive inhibitor. In addition, the potential of garlic saponins to mediate HO-1 induction and protect against H2O2‑mediated growth inhibition was adversely affected by transient transfection with Nrf2-specific siRNA. Garlic saponins activated extracellular signal‑regulated kinase (ERK) signaling, whereas a specific ERK inhibitor was able to inhibit HO-1 upregulation, as well as Nrf2 induction and phosphorylation. Taken together, the findings of our study suggest that garlic saponins activate the Nrf2/HO-1 pathway by enabling ERK to contribute to the induction of phase Ⅱ antioxidant and detoxifying enzymes, including HO-1 in C2C12 cells.

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Eckol Enhances Heme Oxygenase-1 Expression through Activation of Nrf2/JNK Pathway in HepG2 Cells

Cited by 51 publications

References 35 publications

The cytoprotective effects of 7,8-dihydroxyflavone against oxidative stress are mediated by the upregulation of Nrf2-dependent HO-1 expression through the activation of the PI3K/Akt and ERK pathways in C2C12 myoblasts

The cytoprotective effects of 7,8-dihydroxyflavone against oxidative stress are mediated by the upregulation of Nrf2-dependent HO-1 expression through the activation of the PI3K/Akt and ERK pathways in C2C12 myoblasts

Eckol alleviates intestinal dysfunction during suckling-to-weaning transition via modulation of PDX1 and HBEGF

An exploration of the antioxidant effects of garlic saponins in mouse-derived C2C12 myoblasts

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