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

  • Authors:
    • Ji Sook Kang
    • Il-Whan Choi
    • Min Ho Han
    • Gi-Young Kim
    • Su Hyun Hong
    • Cheol Park
    • Hye Jin Hwang
    • Cheol Min Kim
    • Byung Woo Kim
    • Yung Hyun Choi
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  • Published online on: June 22, 2015     https://doi.org/10.3892/ijmm.2015.2256
  • Pages: 501-510
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Abstract

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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August-2015
Volume 36 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Kang JS, Choi I, Han MH, Kim G, Hong SH, Park C, Hwang HJ, Kim CM, Kim BW, Choi YH, Choi YH, et al: 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. Int J Mol Med 36: 501-510, 2015.
APA
Kang, J.S., Choi, I., Han, M.H., Kim, G., Hong, S.H., Park, C. ... Choi, Y.H. (2015). 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. International Journal of Molecular Medicine, 36, 501-510. https://doi.org/10.3892/ijmm.2015.2256
MLA
Kang, J. S., Choi, I., Han, M. H., Kim, G., Hong, S. H., Park, C., Hwang, H. J., Kim, C. M., Kim, B. W., Choi, Y. H."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". International Journal of Molecular Medicine 36.2 (2015): 501-510.
Chicago
Kang, J. S., Choi, I., Han, M. H., Kim, G., Hong, S. H., Park, C., Hwang, H. J., Kim, C. M., Kim, B. W., Choi, Y. H."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". International Journal of Molecular Medicine 36, no. 2 (2015): 501-510. https://doi.org/10.3892/ijmm.2015.2256