Abstract
Cardiovascular diseases are the major health concern and the leading cause of death. Numerous studies have shown that oxidative stress stimuli have been incriminated in the pathogenesis of both acute and chronic heart disease. Though it is well known that bioflavonoids protect cells against reactive oxygen species (ROS)-induced damage, the molecular mechanisms involved are uncertain. Understanding the possible intracellular signaling pathways triggered by flavonoids will help to overcome the cardiac diseases resulting from oxidative stress. In the present study, we investigated whether naringenin (NGN) supplementation would improve the antioxidant defence under oxidative stress through the activation of Nrf2 signaling in cultured cardiomyoblast. NGN pretreatment significantly reduced stress-mediated apoptotic cell death and lipid peroxidation and showed increased level of reduced glutathione in H2O2-treated cardiomyoblast. In addition, NGN inhibited the production of NO and trigged the synthesis of antioxidant marker enzymes. Gene expression studies revealed that NGN upregulated the transcription of Akt and downregulated NF-κB and Caspase 3 genes. Notably, transcription of Nrf2 and its target genes was also upregulated. Taken together, the present study revealed that NGN elicits potent cytoprotective effect against oxidative stress by regulating Nrf2 and its target genes. In conclusion, the present work suggests that improving Nrf2 signaling by NGN supplementation would be a rational approach to facilitate ROS detoxification by augmenting both expression and activity of phase II detoxification enzymes for the alleviation of cardiac complications.
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References
Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–127
Akhlaghi M, Bandy B (2009) Mechanisms of flavonoid protection against myocardial ischemia–reperfusion injury. J Mol Cell Cardiol 46:309–317
Alía M, Ramos S, Mateos R et al (2006) Quercetin protects human hepatoma HepG2 against oxidative stress induced by tert-butyl hydroperoxide. Toxicol Appl Pharmacol 212:110–118
Andreadi CK, Howells LM, Atherfold PA, Manson MM (2006) Involvement of Nrf2, p38, B-Raf, and nuclear factor-kappaB, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols. Mol Pharmacol 69:1033–1040
Banning A, Deubel S, Kluth D, Zhou Z, Brigelius-Flohe R (2005) The GI-GPx gene is a target for Nrf2. Mol Cell Biol 25:4914–4923
Chen CY, Jang JH, Li MH, Surh YJ (2005) Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells. Biochem Biophys Res Commun 331:993–1000
Dhalla NS, Temsah RM, Netticadan T (2000) Role of oxidative stress in cardiovascular diseases. J Hypertens 18:655–673
Flohe L, Gunzler WA (1984) Assays of glutathione peroxidase. Methods Enzymol 105:114–119
Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases the first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139
Kimes BW, Brandt BL (1976) Properties of a clonal muscle cell line from rat heart. Exp Cell Res 98:367–381
Liu L, Xu D, Cheng Y (2008) Distinct effects of naringenin and hesperetin on nitric oxide production from endothelial cells. J Agric Food Chem 56:824–829
Madamanchi NR, Vendrov A, Runge MS (2005) Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 25:29–38
Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK (2006) Enhanced therapeutic potential of naringenin-phospholipid complex in rats. J Pharm Pharmacol 58:1227–1233
Mann GE, Rowlands DJ, Li FY, de Winter P, Siow RC (2007) Activation of endothelial nitric oxide synthase by dietary isoflavones: role of NO in Nrf2-mediated antioxidant gene expression. Cardiovasc Res 75:261–274
Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta 528:67–78
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Ramprasath T, Kumar PH, Puhari SS, Murugan PS, Vasudevan V, Selvam GS (2012) l-Arginine ameliorates cardiac left ventricular oxidative stress by Upregulating eNOS and Nrf2 target genes in alloxan-induced hyperglycemic rats. Biochem Biophys Res Commun 428:389–394
Ramprasath T, Murugan PS, Kalaiarasan E, Gomathi P, Rathinavel A, Selvam GS (2012) Genetic association of glutathione peroxidase-1 (GPx-1) and NAD(P)H:quinoneoxidoreductase 1(NQO1) variants and their association of CAD in patients with type-2 diabetes. Mol Cell Biochem 361:143–150
Ramprasath T, Murugan PS, Prabakaran AD, Gomathi P, Rathinavel A, Selvam GS (2011) Potential risk modifications of GSTT1, GSTM1 and GSTP1 (glutathione-S-transferases) variants and their association to CAD in patients with type-2 diabetes. Biochem Biophys Res Commun 407:49–53
Ramprasath T, Selvam GS (2013) Potential impact of genetic variants in Nrf2 regulated antioxidant genes and risk prediction of diabetes and associated cardiac complications. Curr Med Chem 20:4680–4693
Renugadevi J, Prabu SM (2009) Naringenin protects against cadmium induced oxidative renal dysfunction in rats. Toxicology 256:128–134
Renugadevi J, Prabu SM (2010) Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin. Exp Toxicol Pathol 62:171–181
Rushworth SA, Ogborne RM, Charalambos CA, O’Connell MA (2006) Role of protein kinase C delta in curcumin-induced anti-oxidant response element- mediated gene expression in human monocytes. Biochem Biophys Res Commun 341:1007–1016
Yang J, Li Q, Zhou XD, Kolosov VP, Perelman JM (2011) Naringenin attenuates mucous hypersecretion by modulating reactive oxygen species production and inhibiting NF-κB activity via EGFR-PI3K-Akt/ERK MAPKinase signaling in human airway epithelial cells. Mol Cell Biochem 351:29–40
Acknowledgments
T. Ramprasath expresses his gratitude to the Council for Scientific and Industrial Research (CSIR) for the award of CSIR-Senior Research Fellowship. Authors acknowledge University Grants Commission (UGC), New Delhi, India for the financial support through CEGS, NRCBS, CAS, and UPE and DST-PURSE and Department of Biotechnology (DBT) for the IPLS program.
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Ramprasath, T., Senthamizharasi, M., Vasudevan, V. et al. Naringenin confers protection against oxidative stress through upregulation of Nrf2 target genes in cardiomyoblast cells. J Physiol Biochem 70, 407–415 (2014). https://doi.org/10.1007/s13105-014-0318-3
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DOI: https://doi.org/10.1007/s13105-014-0318-3