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Research article
Bioactive Compounds and Chemical Biology
Naringenin Exerts Cytoprotective Effect Against Paraquat-Induced Toxicity in Human Bronchial Epithelial BEAS-2B Cells Through NRF2 Activation
Department of Microbiology, School of Medicine, Soonchunhyang University, Cheonan 330-090, Republic of Korea
Received: February 3, 2014; Accepted: February 24, 2014
J. Microbiol. Biotechnol. 2014; 24(5): 605-613
Published May 28, 2014 https://doi.org/10.4014/jmb.1402.02001
Copyright © The Korean Society for Microbiology and Biotechnology.
Abstract
We have previously shown that paraquat (PQ)-induced oxidative stress causes dramatic
damage in various human cell lines. Naringenin (NG) is an active flavanone, which has been
reported to have beneficial bioactivities, including antioxidative, anti-inflammatory, and
antitumorigenic activities, with a relatively low toxicity to normal cells. In this study, we
intended to assess the cytoprotective effect of NG against PQ-induced toxicity in the human
bronchial epithelial BEAS-2B cell line. Co-treatment with NG in PQ-treated BEAS-2B cells can
reduce PQ-induced cellular toxicity. NG can also decrease the generation of intracellular ROS
caused by PQ treatment. We also observed that treatment with NG in PQ-exposed BEAS-2B
cells can significantly induce the expression of antioxidant-related genes, including GPX2,
GPX3, GPX5, and GPX7. NG co-treatment can also activate the NRF2 transcription factor and
promote its nuclear translocation. In addition, NG co-treatment can induce the expression of
NRF2-downstream target genes such as that of heme oxygenase-1 (HO-1) and NAD(P)H:quinone
oxidoreductase 1 (NQO1). A small interfering RNA study revealed that the knockdown of
NRF2 can abrogate NG-mediated protection of the cells from PQ-induced cellular toxicity. We
propose that NG effectively alleviates PQ-induced cytotoxicity in human bronchial epithelial
BEAS-2B cells through the NRF2-regulated antioxidant defense pathway, and NG might be a
good therapeutic candidate molecule in oxidative stress-related diseases.
Keywords
Naringenin, Paraquat, Antioxidant-related genes, Nrf2, Human bronchial epithelial BEAS-2B cells
References
- Bus JS, Gibson JE. 1984. Paraquat: model for oxidantinitiated toxicity. Environ. Health Perspect. 55: 37-46.
- Carre P, Leophonte P. 1993. [Cytokines and pulmonary fibroses]. Rev. Mal. Respir. 10: 193-207.
- Chabory E, Damon C, Lenoir A, Kauselmann G, Kern H, Zevnik B, et al. 2009. Epididymis seleno-independent glutathione peroxidase 5 maintains sperm DNA integrity in mice. J. Clin. Invest. 119: 2074-2085.
- Chan K, Han XD, Kan YW. 2001. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc. Natl. Acad. Sci. USA 98: 4611-4616.
- Cui L, Zhang ZH, Sun E, Jia XB. 2012. Effect of betacyclodextrin complexation on solubility and enzymatic conversion of naringin. Int. J. Mol. Sci. 13: 14251-14261.
- Gopinath K, Sudhandiran G. 2012. Naringin modulates oxidative stress and inflammation in 3-nitropropionic acidinduced neurodegeneration through the activation of nuclear factor-erythroid 2-related factor-2 signalling pathway. Neuroscience 227: 134-143.
- Hao Q, Lu X, Liu N, Xue X, Li M, Zhang C, et al. 2013. Posttranscriptional deregulation of Src due to aberrant miR34a and miR203 contributes to gastric cancer development. BMB Rep. 46: 316-321.
- Hermenean A, Ardelean A, Stan M, Herman H, Mihali CV, Costache M, Dinischiotu A. 2013. Protective effects of naringenin on carbon tetrachloride-induced acute nephrotoxicity in mouse kidney. Chem. Biol. Interact. 205: 138-147.
- Higgins LG, Kelleher MO, Eggleston IM, Itoh K, Yamamoto M, Hayes JD. 2009. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents. Toxicol. Appl. Pharmacol. 237: 267280.
- Hong GL, Liu JM, Zhao GJ, Wang L, Liang G, Wu B, et al. 2013. The reversal of paraquat-induced mitochondria-mediated apoptosis by cycloartenyl ferulate, the important role of Nrf2 pathway. Exp. Cell Res. 319: 2845-2855.
- Jeong WS, Jun M, Kong AN. 2006. Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. Antioxid. Redox Signal. 8: 99-106.
- Jung KA, Kwak MK. 2010. The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules 15: 7266-7291.
- Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M. 1999. Quantitation of flavonoid constituents in citrus fruits. J. Agric. Food Chem. 47: 3565-3571.
- Kim YS, Zerin T, Song HY. 2013. Antioxidant action of ellagic acid ameliorates paraquat-induced A549 cytotoxicity. Biol. Pharm. Bull. 36: 609-615.
- Li H, Wu S, Wang Z, Lin W, Zhang C, Huang B. 2012. Neuroprotective effects of tert-butylhydroquinone on paraquatinduced dopaminergic cell degeneration in C57BL/6 mice and in PC12 cells. Arch. Toxicol. 86: 1729-1740.
- Ma Q, Battelli L, Hubbs AF. 2006. Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am. J. Pathol. 168: 1960-1974.
- Ma Q, He X. 2012. Molecular basis of electrophilic and oxidative defense: promises and perils of Nrf2. Pharmacol. Rev. 64: 1055-1081.
- Pietta PG. 2000. Flavonoids as antioxidants. J. Nat. Prod. 63:1035-1042.
- Podder B, Kim YS, Zerin T, Song HY. 2012. Antioxidant effect of silymarin on paraquat-induced human lung adenocarcinoma A549 cell line. Food Chem. Toxicol. 50: 32063214.
- Renugadevi J, Prabu SM. 2009. Naringenin protects against cadmium-induced oxidative renal dysfunction in rats. Toxicology 256: 128-134.
- Rice-Evans CA, Miller NJ, Paganga G. 1996. Structureantioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med. 20: 933-956.
- Sabarinathan D, Mahalakshmi P, Vanisree AJ. 2011. Naringenin, a flavanone, inhibits the proliferation of cerebrally implanted C6 glioma cells in rats. Chem. Biol. Interact. 189: 26-36.
- Surh YJ, Kundu JK, Na HK. 2008. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med. 74: 1526-1539.
- Vale JA, Meredith TJ, Buckley BM. 1987. Paraquat poisoning:clinical features and immediate general management. Hum. Toxicol. 6: 41-47.
- Yin J, Zhang H, Ye J. 2008. Traditional Chinese medicine in treatment of metabolic syndrome. Endocr. Metab. Immune Disord. Drug Targets 8: 99-111.
- Zerin T, Kim YS, Hong SY, Song HY. 2013. Quercetin reduces oxidative damage induced by paraquat via modulating expression of antioxidant genes in A549 cells. J. Appl. Toxicol. 33: 1460-1467.
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Research article
J. Microbiol. Biotechnol. 2014; 24(5): 605-613
Published online May 28, 2014 https://doi.org/10.4014/jmb.1402.02001
Copyright © The Korean Society for Microbiology and Biotechnology.
Naringenin Exerts Cytoprotective Effect Against Paraquat-Induced Toxicity in Human Bronchial Epithelial BEAS-2B Cells Through NRF2 Activation
Biswajit Podder 1, Ho-Yeon Song 1 and Yong-Sik Kim 1*
Department of Microbiology, School of Medicine, Soonchunhyang University, Cheonan 330-090, Republic of Korea
Received: February 3, 2014; Accepted: February 24, 2014
Abstract
We have previously shown that paraquat (PQ)-induced oxidative stress causes dramatic
damage in various human cell lines. Naringenin (NG) is an active flavanone, which has been
reported to have beneficial bioactivities, including antioxidative, anti-inflammatory, and
antitumorigenic activities, with a relatively low toxicity to normal cells. In this study, we
intended to assess the cytoprotective effect of NG against PQ-induced toxicity in the human
bronchial epithelial BEAS-2B cell line. Co-treatment with NG in PQ-treated BEAS-2B cells can
reduce PQ-induced cellular toxicity. NG can also decrease the generation of intracellular ROS
caused by PQ treatment. We also observed that treatment with NG in PQ-exposed BEAS-2B
cells can significantly induce the expression of antioxidant-related genes, including GPX2,
GPX3, GPX5, and GPX7. NG co-treatment can also activate the NRF2 transcription factor and
promote its nuclear translocation. In addition, NG co-treatment can induce the expression of
NRF2-downstream target genes such as that of heme oxygenase-1 (HO-1) and NAD(P)H:quinone
oxidoreductase 1 (NQO1). A small interfering RNA study revealed that the knockdown of
NRF2 can abrogate NG-mediated protection of the cells from PQ-induced cellular toxicity. We
propose that NG effectively alleviates PQ-induced cytotoxicity in human bronchial epithelial
BEAS-2B cells through the NRF2-regulated antioxidant defense pathway, and NG might be a
good therapeutic candidate molecule in oxidative stress-related diseases.
Keywords: Naringenin, Paraquat, Antioxidant-related genes, Nrf2, Human bronchial epithelial BEAS-2B cells
References
- Bus JS, Gibson JE. 1984. Paraquat: model for oxidantinitiated toxicity. Environ. Health Perspect. 55: 37-46.
- Carre P, Leophonte P. 1993. [Cytokines and pulmonary fibroses]. Rev. Mal. Respir. 10: 193-207.
- Chabory E, Damon C, Lenoir A, Kauselmann G, Kern H, Zevnik B, et al. 2009. Epididymis seleno-independent glutathione peroxidase 5 maintains sperm DNA integrity in mice. J. Clin. Invest. 119: 2074-2085.
- Chan K, Han XD, Kan YW. 2001. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc. Natl. Acad. Sci. USA 98: 4611-4616.
- Cui L, Zhang ZH, Sun E, Jia XB. 2012. Effect of betacyclodextrin complexation on solubility and enzymatic conversion of naringin. Int. J. Mol. Sci. 13: 14251-14261.
- Gopinath K, Sudhandiran G. 2012. Naringin modulates oxidative stress and inflammation in 3-nitropropionic acidinduced neurodegeneration through the activation of nuclear factor-erythroid 2-related factor-2 signalling pathway. Neuroscience 227: 134-143.
- Hao Q, Lu X, Liu N, Xue X, Li M, Zhang C, et al. 2013. Posttranscriptional deregulation of Src due to aberrant miR34a and miR203 contributes to gastric cancer development. BMB Rep. 46: 316-321.
- Hermenean A, Ardelean A, Stan M, Herman H, Mihali CV, Costache M, Dinischiotu A. 2013. Protective effects of naringenin on carbon tetrachloride-induced acute nephrotoxicity in mouse kidney. Chem. Biol. Interact. 205: 138-147.
- Higgins LG, Kelleher MO, Eggleston IM, Itoh K, Yamamoto M, Hayes JD. 2009. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents. Toxicol. Appl. Pharmacol. 237: 267280.
- Hong GL, Liu JM, Zhao GJ, Wang L, Liang G, Wu B, et al. 2013. The reversal of paraquat-induced mitochondria-mediated apoptosis by cycloartenyl ferulate, the important role of Nrf2 pathway. Exp. Cell Res. 319: 2845-2855.
- Jeong WS, Jun M, Kong AN. 2006. Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. Antioxid. Redox Signal. 8: 99-106.
- Jung KA, Kwak MK. 2010. The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules 15: 7266-7291.
- Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M. 1999. Quantitation of flavonoid constituents in citrus fruits. J. Agric. Food Chem. 47: 3565-3571.
- Kim YS, Zerin T, Song HY. 2013. Antioxidant action of ellagic acid ameliorates paraquat-induced A549 cytotoxicity. Biol. Pharm. Bull. 36: 609-615.
- Li H, Wu S, Wang Z, Lin W, Zhang C, Huang B. 2012. Neuroprotective effects of tert-butylhydroquinone on paraquatinduced dopaminergic cell degeneration in C57BL/6 mice and in PC12 cells. Arch. Toxicol. 86: 1729-1740.
- Ma Q, Battelli L, Hubbs AF. 2006. Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am. J. Pathol. 168: 1960-1974.
- Ma Q, He X. 2012. Molecular basis of electrophilic and oxidative defense: promises and perils of Nrf2. Pharmacol. Rev. 64: 1055-1081.
- Pietta PG. 2000. Flavonoids as antioxidants. J. Nat. Prod. 63:1035-1042.
- Podder B, Kim YS, Zerin T, Song HY. 2012. Antioxidant effect of silymarin on paraquat-induced human lung adenocarcinoma A549 cell line. Food Chem. Toxicol. 50: 32063214.
- Renugadevi J, Prabu SM. 2009. Naringenin protects against cadmium-induced oxidative renal dysfunction in rats. Toxicology 256: 128-134.
- Rice-Evans CA, Miller NJ, Paganga G. 1996. Structureantioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med. 20: 933-956.
- Sabarinathan D, Mahalakshmi P, Vanisree AJ. 2011. Naringenin, a flavanone, inhibits the proliferation of cerebrally implanted C6 glioma cells in rats. Chem. Biol. Interact. 189: 26-36.
- Surh YJ, Kundu JK, Na HK. 2008. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med. 74: 1526-1539.
- Vale JA, Meredith TJ, Buckley BM. 1987. Paraquat poisoning:clinical features and immediate general management. Hum. Toxicol. 6: 41-47.
- Yin J, Zhang H, Ye J. 2008. Traditional Chinese medicine in treatment of metabolic syndrome. Endocr. Metab. Immune Disord. Drug Targets 8: 99-111.
- Zerin T, Kim YS, Hong SY, Song HY. 2013. Quercetin reduces oxidative damage induced by paraquat via modulating expression of antioxidant genes in A549 cells. J. Appl. Toxicol. 33: 1460-1467.
