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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. 2015 Aug; 36(2):501-10.IJ

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.

Authors+Show Affiliations

Blue-Bio Industry RIC and Anti-Aging Research Center, Dongeui University, Busan 614-714, Republic of Korea.Department of Microbiology, College of Medicine, Inje University, Busan 608-756, Republic of Korea.Blue-Bio Industry RIC and Anti-Aging Research Center, Dongeui University, Busan 614-714, Republic of Korea.Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea.Department of Biochemistry, Dongeui University College of Korean Medicine, Busan 614-052, Republic of Korea.Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan 614-714, Republic of Korea.Blue-Bio Industry RIC and Anti-Aging Research Center, Dongeui University, Busan 614-714, Republic of Korea.Department of Biochemistry, Busan National University College of Medicine, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea.Blue-Bio Industry RIC and Anti-Aging Research Center, Dongeui University, Busan 614-714, Republic of Korea.Blue-Bio Industry RIC and Anti-Aging Research Center, Dongeui University, Busan 614-714, Republic of Korea.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26096841

Citation

Kang, Ji Sook, 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." International Journal of Molecular Medicine, vol. 36, no. 2, 2015, pp. 501-10.
Kang JS, Choi IW, Han MH, 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. 2015;36(2):501-10.
Kang, J. S., Choi, I. W., Han, M. H., Kim, G. Y., Hong, S. H., Park, C., Hwang, H. J., Kim, C. M., Kim, B. W., & 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(2), 501-10. https://doi.org/10.3892/ijmm.2015.2256
Kang JS, 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. 2015;36(2):501-10. PubMed PMID: 26096841.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Kang,Ji Sook, AU - Choi,Il-Whan, AU - Han,Min Ho, AU - Kim,Gi-Young, AU - Hong,Su Hyun, AU - Park,Cheol, AU - Hwang,Hye Jin, AU - Kim,Cheol Min, AU - Kim,Byung Woo, AU - Choi,Yung Hyun, Y1 - 2015/06/22/ PY - 2015/03/08/received PY - 2015/06/10/accepted PY - 2015/6/23/entrez PY - 2015/6/23/pubmed PY - 2016/3/31/medline SP - 501 EP - 10 JF - International journal of molecular medicine JO - Int J Mol Med VL - 36 IS - 2 N2 - 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. SN - 1791-244X UR - https://www.unboundmedicine.com/medline/citation/26096841/The_cytoprotective_effects_of_78_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_ L2 - http://www.spandidos-publications.com/ijmm/36/2/501 DB - PRIME DP - Unbound Medicine ER -