Skip to main content
SpringerLink
Log in

Effect of 7, 8-dihydroxyflavone on the up-regulation of Nrf2-mediated heme oxygenase-1 expression in hamster lung fibroblasts

  • Published:
In Vitro Cellular & Developmental Biology - Animal Aims and scope Submit manuscript

Abstract

The cytoprotective mechanism of 7, 8-dihydroxyflavone (DHF) against oxidative stress-induced cell damage with respect to its stimulatory effect on the expression of heme oxygenase-1 (HO-1), a potent antioxidant enzyme, was investigated in the present study. Up-regulation of HO-1 expression by DHF was both dose and time dependent in lung fibroblast V79-4 cells. DHF also increased the protein expression level of the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), and induced the translocation of Nrf2 from the cytosol into the nucleus, leading to elevated HO-1 expression. The siNrf2 RNA-transfection attenuated HO-1 expression induced by DHF treatment. In addition, DHF induced the activation of extracellular signal-regulated kinase (ERK), while U0126 (a specific pharmacological inhibitor of ERK kinase) abrogated DHF-activated Nrf2 and HO-1 expression. This suggests that DHF increased the levels of Nrf2 and HO-1 via ERK-dependent pathways. Furthermore, DHF significantly prevented the reduction of cell viability in response to oxidative stress; however, U0126 attenuated the protective effect of DHF. Taken together, these results demonstrate that DHF protected cells from oxidative stress via the activation of an ERK/Nrf2/HO-1 signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.

Similar content being viewed by others

References

  • Alam J, Cook JL (2003) Transcriptional regulation of the heme oxygenase-1 gene via the stress response element pathway. Curr Pharm Des 9:2499–2511

    Article  CAS  PubMed  Google Scholar 

  • Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mtchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47:936–942

    CAS  PubMed  Google Scholar 

  • Cheng AS, Cheng YH, Chiou CH, Chang TL (2012) Resveratrol upregulates Nrf2 expression to attenuated methylglyoxal-induced insulin resistance in Hep G2 cells. J Agric Food Chem 60:9180–9187

    Article  CAS  PubMed  Google Scholar 

  • Choi AM, Alam J (1996) Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15:9–19

    Article  CAS  PubMed  Google Scholar 

  • Dinkova-Kostova AT, Holtzclaw WD, Wakabayashi N (2005) Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry 44:6889–6899

    Article  CAS  PubMed  Google Scholar 

  • Ewing JF, Maines MD (1991) Rapid induction of heme oxygenase 1 mRNA and protein by hyperthermia in rat brain: heme oxygenase 2 is not a heat shock protein. Proc Natl Acad Sci U S A 88:5364–5368

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fetisova EK, Avetisyan AV, Izyumov DS, Korotetskaya MV, Chemyak BV, Skulachev VP (2010) Mitochondria-targeted antioxidant SkQR1 selectively protects MDR (Pgp 170)-negative cells against oxidative stress. FEBS Lett 584:562–566

    Article  CAS  PubMed  Google Scholar 

  • Granado-Serrano AB, Martín MA, Haegeman G, Goya L, Bravo L, Ramos S (2010) Epicatechin induces NF-kappaB, activator protein-1 (AP-1) and nuclear transcription factor erythroid 2p45-related factor-2 (Nrf2) via phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and extracellular regulated kinase (ERK) signalling in HepG2 cells. Br J Nutr 103:168–179

    Article  CAS  PubMed  Google Scholar 

  • Ismail NS, Pravda EA, Li D, Shih SC, Dallabrida SM (2010) Angiopoietin-1 reduces H2O2-induced increases in reactive oxygen species and oxidative damage to skin cells. J Invest Dermatol 130:1307–1317

    Article  CAS  PubMed  Google Scholar 

  • Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Keum YS (2012) Regulation of Nrf2-Mediated Phase II Detoxification and Anti-oxidant Genes. Biomol Ther 20:144–151

    Article  CAS  Google Scholar 

  • Keyse SM, Tyrrell RM (1989) Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodiumarsenite. Proc Natl Acad Sci USA 86:99–103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim KC, Kang KA, Zhang R, Piao MJ, Kim GY, Kang MY, Lee SJ, Lee NH, Surh YJ, Hyun JW (2010) Up-regulation of Nrf2-mediated heme oxygenase-1 expression by eckol, a phlorotannin compound, through activation of Erk and PI3K/Akt. Int J Biochem Cell Biol 42:297–305

    Article  CAS  PubMed  Google Scholar 

  • Kitamura Y, Umemura T, Kanki K, Kodama Y, Kitamoto S, Saito K, Itoh K, Yamamoto M, Masegi T, Nishikawa A, Hirose M (2007) Increased susceptibility to hepatocarcinogenicity of Nrf2-deficient mice exposed to 2-amino-3-methylimidazo[4,5-f]quinoline. Cancer Sci 98:19–24

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi M, Yamamoto M (2005) Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal 7:385–394

    Article  CAS  PubMed  Google Scholar 

  • Leonq PK, Chiu PY, Chen N, Leunq H, Ko KM (2011) Schisandrin B elicits a glutathione antioxidant response and protects against apoptosis via the redox-sensitive ERK/Nrf2 pathway in AML12 hepatocytes. Free Radic Res 45:483–495

    Article  Google Scholar 

  • Li MH, Cha YN, Surh YJ (2006) Peroxynitrite induces HO-1 expression via PI3K/Akt-dependent activation of NF-E2-related factor 2 in PC12 cells. Free Radic Biol Med 41:1079–1091

    Google Scholar 

  • Loboda A, Rojczyk-Golebiewska E, B. BB-C, Zaprutko L, Jozkowicz A, Dulak J (2012) Targeting Nrf2-Mediated Gene Transcription by Triterpenoids and Their Derivatives. Biomol Ther 20:499–505

    Google Scholar 

  • Ma ZC, Hong Q, Wang YG, Liang QD, Tan HL, Xiao CR, Tang XL, Shao S, Zhou SS, Gao Y (2011) Ferulic acid induces heme oxygenase-1 via activation of ERK and Nrf2. Drug Discov Ther 5:299–305

    CAS  PubMed  Google Scholar 

  • Okayama Y (2005) Oxidative stress in allergic and inflammatory skin disease. Curr Drug Targets Inflamm Allergy 4:517–519

    Article  CAS  PubMed  Google Scholar 

  • Otterbein LE, Soares MP, Yamashita K, Bach FH (2003) Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 24:449–455

    Google Scholar 

  • Ozgen U, Mavi A, Terzi Z, Kazaz C, Asci A, Kaya Y, Secen H (2011) Relationship between chemical structure and antioxidant activity of luteolin and its glycosides isolated from Thymus sipyleus subsp. sipyleus var. sipyleus. Rec Nat Prod 5:12–21

    CAS  Google Scholar 

  • Park HY, Kim GY, Hyun JW, Hwang HJ, Kim ND, Kim BW, Choi YH (2012) 7,8-Dihydroxyflavone exhibits anti-inflammatory properties by downregulating the NF-KB andMAPK signaling pathways in lipopolysaccharide-treated RAW 264.7 cells. Int J Mol Med 29:1146–1152

    CAS  PubMed  Google Scholar 

  • Ryter SW, Choi AM (2002) Heme oxygenase-1: molecular mechanisms of gene expression in oxygen-related stress. Antioxid Redox Signal 4:625–632

    Article  CAS  PubMed  Google Scholar 

  • Ryu MJ, Kang KA, Piao MJ, Kim KC, Zheng J, Yao CW, Cha JW, Chung HS, Kim SC, Jung E, Park D, Chae S, Hyun JW (2014) 7, 8-Dihydroxyflavone protects human keratinocytes against oxidative stress-induced cell damage via the ERK and PI3K/Akt-mediated Nrf2/HO-1 signaling pathways. Int J Mol Med 33:964–970

    Google Scholar 

  • Spencer JP (2008) Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance. Proc Nutr Soc 67:238–252

    Article  CAS  PubMed  Google Scholar 

  • Sun GB, Sun X, Wang M, Ye JX, Si JY, Xu HB, Meng XB, Qin M, Sun J, Wang HW, Sun XB (2010) Oxidative stress suppression by luteolin-induced heme oxygenase-1 expression. Toxicol Appl Phrmacol 265:229–240

    Article  Google Scholar 

  • Tu YP, Chuang SJ, Chen SC, Liu YH, Chen CF, Hour TC (2011) Simvastatin induces the expression of heme oxygenase-1 against ischemia-reperfusion injury on the testes in rats. Toxical Lett 207:242–250

    Article  CAS  Google Scholar 

  • Xiao J, Ni X, Kai G, Chen X (2013) A review on structure–activity relationship of dietary polyphenols inhibiting α-amylase. Crit Rev Food Sci Nutr 53:497–506

    Article  CAS  PubMed  Google Scholar 

  • Yang YC, Lii CK, Lin AH, Yeh YW, Yao HT, Li CC, Liu KL, Chen HW (2011) Induction of glutathione synthesis and heme oxygenase 1 by the flavonoids butein and phloretin is mediated through the ERK/Nrf2 pathway and protects against oxidative stress. Free Radic Biol Med 51:2073–2081

    Article  CAS  PubMed  Google Scholar 

  • Yao KS, O'Dwyer PJ (2003) Role of the AP-1 element and redox factor-1 (Ref-1) in mediating transcriptional induction of DT-diaphorase gene expression by oltipraz: a target for chemoprevention. Biochem Pharmacol 66:15–23

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Khor TO, Cheung KL, Li W, Wu TY, Huang Y, Foster BA, Kan YW, Kong AN (2010) Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP mice. PLoS One 5:e8579

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhang R, Kang KA, Piao MJ, Ko DO, Wang ZH, Chang WY, You HJ, Lee IK, Kim BJ, Kang SS, Hyun JW (2009) Preventive effect of 7,8-dihydroxyflavone against oxidative stress induced genotoxicity. Biol Pharm Bull 32:166–171

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by a research grant from Jeju National University Hospital.

Author information

Authors and Affiliations

  1. Food and Nutrition, Duksung Women’s University, Seoul, 132-714, Republic of Korea

    Min Ju Ryu & Ha Sook Chung

  2. School of Medicine, Jeju National University, Jeju, 690-756, Republic of Korea

    Kyoung Ah Kang, Mei Jing Piao, Ki Cheon Kim, Jian Zheng, Cheng Wen Yao, Ji Won Cha, Chang Lim Hyun, Jong Cook Park, Suk Ju Cho & Jin Won Hyun

Authors
  1. Min Ju Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyoung Ah Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mei Jing Piao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ki Cheon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheng Wen Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ji Won Cha
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chang Lim Hyun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ha Sook Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jong Cook Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Suk Ju Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jin Won Hyun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Suk Ju Cho or Jin Won Hyun.

Additional information

Editor: T. Okamoto

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ryu, M.J., Kang, K.A., Piao, M.J. et al. Effect of 7, 8-dihydroxyflavone on the up-regulation of Nrf2-mediated heme oxygenase-1 expression in hamster lung fibroblasts. In Vitro Cell.Dev.Biol.-Animal 50, 549–554 (2014). https://doi.org/10.1007/s11626-014-9735-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11626-014-9735-4

Keywords

Search

Navigation