Naringenin Exerts Anti-inflammatory Effects in Paraquat-Treated SH-SY5Y Cells Through a Mechanism Associated with the Nrf2/HO-1 Axis
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Naringenin (NGN; 5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one; C15H12O5), a flavanone, is found in citrus fruits and has been viewed as an antioxidant and anti-inflammatory agent. NGN is a potent inducer of the nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulates the expression of heme oxygenase-1 (HO-1), an enzyme exhibiting both antioxidant and anti-inflammatory effects. The complete mechanism by which NGN exerts anti-inflammatory actions is not completely understood yet. Therefore, we investigated here whether NGN would be able to reduce the inflammation induced by paraquat (PQ) in SH-SY5Y cells. Additionally, we analyzed the mechanism associated with the NGN-induced anti-inflammatory effect. We found that a pretreatment with NGN at 80 µM for 2 h decreased the levels of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in PQ-treated SH-SY5Y cells. The production of nitric oxide (NO·) and levels of cyclooxygenase-2 (COX-2) and of the inducible isoform of nitric oxide synthase (iNOS) were downregulated by NGN in the cells exposed to PQ. Moreover, NGN downregulated the activation of the nuclear factor-κB (NF-κB) in PQ-treated cells. The anti-apoptotic and anti-inflammatory effects promoted by NGN were abolished by ZnPP IX (a specific inhibitor of HO-1) or by knockdown of Nrf2 by small interfering RNA (siRNA). Therefore, NGN induced anti-inflammatory effects in PQ-treated SH-SY5Y cells by a mechanism associated with the Nrf2/HO-1 signaling pathway.
KeywordsNaringenin Anti-inflammatory Nrf2 Heme oxygenase-1 Nuclear factor-κB
This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de Mato Grosso (FAPEMAT).
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Conflict of interest
The authors declare that they have no conflict of interest.
- 5.Ramprasath T, Senthamizharasi M, Vasudevan V, Sasikumar S, Yuvaraj S, Selvam GS (2014) Naringenin confers protection against oxidative stress through upregulation of Nrf2 target genes in cardiomyoblast cells. J Physiol Biochem 70:407–415. https://doi.org/10.1007/s13105-014-0318-3 CrossRefPubMedGoogle Scholar
- 6.Manchope MF, Calixto-Campos C, Coelho-Silva L, Zarpelon AC, Pinho-Ribeiro FA, Georgetti SR, Baracat MM, Casagrande R, Verri WA Jr (2016) Naringenin Inhibits superoxide anion-induced inflammatory pain: role of oxidative stress, cytokines, Nrf-2 and the NO-cGMP-PKG-KATP channel signaling pathway. PLoS ONE 11:e0153015. https://doi.org/10.1371/journal.pone.0153015 CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Calabrese V, Cornelius C, Mancuso C, Pennisi G, Calafato S, Bellia F, Bates TE, Giuffrida Stella AM, Schapira T, Dinkova Kostova AT, Rizzarelli E (2008) Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity. Neurochem Res 33:2444–2471. https://doi.org/10.1007/s11064-008-9775-9 CrossRefPubMedGoogle Scholar
- 9.Nakagami Y (2016) Nrf2 is an attractive therapeutic target for retinal diseases. Oxid Med Cell Longev 2016:7469326Google Scholar
- 13.Taki-Nakano N, Ohzeki H, Kotera J, Ohta H (2014) Cytoprotective effects of 12-oxo phytodienoic acid, a plant-derived oxylipin jasmonate, on oxidative stress-induced toxicity in human neuroblastoma SH-SY5Y cells. Biochim Biophys Acta 1840:3413–3422. https://doi.org/10.1016/j.bbagen.2014.09.003 CrossRefPubMedGoogle Scholar
- 24.Villa V, Thellung S, Bajetto A, Gatta E, Robello M, Novelli F, Tasso B, Tonelli M, Florio T (2016) Novel celecoxib analogues inhibit glial production of prostaglandin E2, nitric oxide, and oxygen radicals reverting the neuroinflammatory responses induced by misfolded prion protein fragment 90–231 or lipopolysaccharide. Pharmacol Res 113:500–514. https://doi.org/10.1016/j.phrs.2016.09.010 CrossRefPubMedGoogle Scholar
- 28.Arias-Salvatierra D, Silbergeld EK, Acosta-Saavedra LC, Calderon-Aranda ES (2011) Role of nitric oxide produced by iNOS through NF-κB pathway in migration of cerebellar granule neurons induced by Lipopolysaccharide. Cell Signal 23:425–435. https://doi.org/10.1016/j.cellsig.2010.10.017 CrossRefPubMedGoogle Scholar
- 30.Cao H, Yu R, Choi Y, Ma ZZ, Zhang H, Xiang W, Lee DY, Berman BM, Moudgil KD, Fong HH, van Breemen RB (2010) Discovery of cyclooxygenase inhibitors from medicinal plants used to treat inflammation. Pharmacol Res 61:519–524. https://doi.org/10.1016/j.phrs.2010.02.007 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.de Oliveira MR, Ferreira GC, Schuck PF (2016) Protective effect of carnosic acid against paraquat-induced redox impairment and mitochondrial dysfunction in SH-SY5Y cells: role for PI3K/Akt/Nrf2 pathway. Toxicol In Vitro 32:41–54. https://doi.org/10.1016/j.tiv.2015.12.005 CrossRefPubMedGoogle Scholar
- 38.Ortiz-Ortiz MA, Morán JM, González-Polo RA, Niso-Santano M, Soler G, Bravo-San Pedro JM, Fuentes JM (2009) Nitric oxide-mediated toxicity in paraquat-exposed SH-SY5Y cells: a protective role of 7-nitroindazole. Neurotox Res 16:160–173. https://doi.org/10.1007/s12640-009-9065-6 CrossRefPubMedGoogle Scholar
- 42.de Oliveira MR, Ferreira GC, Schuck PF, Dal Bosco SM (2015) Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Chem Biol Interact 242:396–406. https://doi.org/10.1016/j.cbi.2015.11.003 CrossRefPubMedGoogle Scholar
- 43.Scapagnini G, Vasto S, Abraham NG, Caruso C, Zella D, Fabio G (2011) Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. Mol Neurobiol 44:192–201. https://doi.org/10.1007/s12035-011-8181-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Rehman MU, Tahir M, Khan AQ, Khan R, Lateef A, Oday-O-Hamiza, Qamar W, Ali F, Sultana S (2013) Chrysin suppresses renal carcinogenesis via amelioration of hyperproliferation, oxidative stress and inflammation: plausible role of NF-κB. Toxicol Lett 216:146–158. https://doi.org/10.1016/j.toxlet.2012.11.013 CrossRefPubMedGoogle Scholar
- 51.Hua FZ, Ying J, Zhang J, Wang XF, Hu YH, Liang YP, Liu Q, Xu GH (2016) Naringenin pre-treatment inhibits neuroapoptosis and ameliorates cognitive impairment in rats exposed to isoflurane anesthesia by regulating the PI3/Akt/PTEN signalling pathway and suppressing NF-κB-mediated inflammation. Int J Mol Med 38:1271–12780. https://doi.org/10.3892/ijmm.2016.2715 CrossRefPubMedGoogle Scholar
- 53.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. https://doi.org/10.1007/s11010-010-0708-y CrossRefPubMedGoogle Scholar