Redox homeostasis dysregulation in noise-induced hearing loss: oxidative stress and antioxidant treatment

Yuhang Zhou1,2, Chaoyou Fang3, Ling Yuan3, Mengchen Guo4, Xinyi Xu5, Anwen Shao6, Anke Zhang6, Danyang Zhou1
1Health Management Center, Tongde Hospital of Zhejiang Province, Hangzhou, China
2The First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
3Department of Neurosurgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
4Department of Dermatology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
5School of Medicine, Ningbo University, Ningbo, China
6Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

Tóm tắt

Noise exposure is an important cause of acquired hearing loss. Studies have found that noise exposure causes dysregulated redox homeostasis in cochlear tissue, which has been recognized as a signature feature of hearing loss. Oxidative stress plays a pivotal role in many diseases via very complex and diverse mechanisms and targets. Reactive oxygen species are products of oxidative stress that exert toxic effects on a variety of physiological activities and are considered significant in noise-induced hearing loss (NIHL). Endogenous cellular antioxidants can directly or indirectly counteract oxidative stress and regulate intracellular redox homeostasis, and exogenous antioxidants can complement and enhance this effect. Therefore, antioxidant therapy is considered a promising direction for NIHL treatment. However, drug experiments have been limited to animal models of NIHL, and these experiments and related observations are difficult to translate in humans; therefore, the mechanisms and true effects of these drugs need to be further analyzed. This review outlines the effects of oxidative stress in NIHL and discusses the main mechanisms and strategies of antioxidant treatment for NIHL.

Tài liệu tham khảo

Kurabi A, Keithley EM, Housley GD, Ryan AF, Wong AC. Cellular mechanisms of noise-induced hearing loss. Hear Res. 2017;349:129–37. Lynch ED, Kil J. Compounds for the prevention and treatment of noise-induced hearing loss. Drug Discov Today. 2005;10(19):1291–8. Verbeek JH, Kateman E, Morata TC, Dreschler W, Sorgdrager B. Interventions to prevent occupational noise induced hearing loss. Cochrane Database Syst Rev. 2009;7(3):Cd006396. Fetoni AR, Paciello F, Rolesi R, Paludetti G, Troiani D. Targeting dysregulation of redox homeostasis in noise-induced hearing loss: oxidative stress and ROS signaling. Free Radic Biol Med. 2019;135:46–59. Liberman MC. Noise-induced hearing loss: permanent versus temporary threshold shifts and the effects of hair cell versus neuronal degeneration. Adv Exp Med Biol. 2016;875:1–7. Tikka C, Verbeek JH, Kateman E, Morata TC, Dreschler WA, Ferrite S. Interventions to prevent occupational noise-induced hearing loss. Cochrane Database Syst Rev. 2017;7(7):Cd006396. Nelson DI, Nelson RY, Concha-Barrientos M, Fingerhut M. The global burden of occupational noise-induced hearing loss. Am J Ind Med. 2005;48(6):446–58. Clark WW, Bohne BA. Effects of noise on hearing. JAMA. 1999;281(17):1658–9. Kujawa SG, Liberman MC. Adding insult to injury: cochlear nerve degeneration after “temporary” noise-induced hearing loss. J Neurosci: Off J Soc Neurosci. 2009;29(45):14077–85. Yan W, Liu W, Qi J, Fang Q, Fan Z, Sun G, Han Y, Zhang D, Xu L, Wang M, Li J, Chen F, Liu D, Chai R, Wang H. A Three-dimensional culture system with matrigel promotes purified spiral ganglion neuron survival and function in vitro. Mol Neurobiol. 2018;55(3):2070–84. Wu PZ, O’Malley JT, de Gruttola V, Liberman MC. Primary neural degeneration in noise-exposed human cochleas: correlations with outer hair cell loss and word-discrimination scores. J Neurosci: Off J Soc Neurosci. 2021;41(20):4439–47. Wang Y, Hirose K, Liberman MC. Dynamics of noise-induced cellular injury and repair in the mouse cochlea. J Assoc Res Otolaryngol: JARO. 2002;3(3):248–68. Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal. 2014;20(3):460–73. Li H, Song Y, He Z, Chen X, Wu X, Li X, Bai X, Liu W, Li B, Wang S, Han Y, Xu L, Zhang D, Li J, Chai R, Wang H, Fan Z. Meclofenamic acid reduces reactive oxygen species accumulation and apoptosis, inhibits excessive autophagy, and protects hair cell-like HEI-OC1 cells from cisplatin-induced damage. Front Cell Neurosci. 2018;12:139. Mizushima N, Levine B. Autophagy in human diseases. N Engl J Med. 2020;383(16):1564–76. Miao L, Zhang J, Yin L, Pu Y. Metabolomics analysis reveals alterations in cochlear metabolic profiling in mice with noise-induced hearing loss. Biomed Res Int. 2022;2022:9548316. Schwarz C, Stekovic S, Wirth M, Benson G, Royer P, Sigrist SJ, Pieber T, Dammbrueck C, Magnes C, Eisenberg T, Pendl T, Bohlken J, Köbe T, Madeo F, Flöel A. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging. 2018;10(1):19–33. Pekar T, Bruckner K, Pauschenwein-Frantsich S, Gschaider A, Oppliger M, Willesberger J, Ungersbäck P, Wendzel A, Kremer A, Flak W, Wantke F, Jarisch R. The positive effect of spermidine in older adults suffering from dementia : first results of a 3-month trial. Wien Klin Wochenschr. 2021;133(9–10):484–91. Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P. Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie. 2008;90(2):313–23. Yuan H, Wang X, Hill K, Chen J, Lemasters J, Yang SM, Sha SH. Autophagy attenuates noise-induced hearing loss by reducing oxidative stress. Antioxid Redox Signal. 2015;22(15):1308–24. Fujioka M, Okano H, Ogawa K. Inflammatory and immune responses in the cochlea: potential therapeutic targets for sensorineural hearing loss. Front Pharmacol. 2014;5:287. Fujioka M, Kanzaki S, Okano HJ, Masuda M, Ogawa K, Okano H. Proinflammatory cytokines expression in noise-induced damaged cochlea. J Neurosci Res. 2006;83(4):575–83. Tornabene SV, Sato K, Pham L, Billings P, Keithley EM. Immune cell recruitment following acoustic trauma. Hear Res. 2006;222(1–2):115–24. Wakabayashi K, Fujioka M, Kanzaki S, Okano HJ, Shibata S, Yamashita D, Masuda M, Mihara M, Ohsugi Y, Ogawa K, Okano H. Blockade of interleukin-6 signaling suppressed cochlear inflammatory response and improved hearing impairment in noise-damaged mice cochlea. Neurosci Res. 2010;66(4):345–52. Zhang G, Zheng H, Pyykko I, Zou J. The TLR-4/NF-κB signaling pathway activation in cochlear inflammation of rats with noise-induced hearing loss. Hear Res. 2019;379:59–68. Sai N, Shi X, Zhang Y, Jiang QQ, Ji F, Yuan SL, Sun W, Guo WW, Yang SM, Han WJ. Involvement of cholesterol metabolic pathways in recovery from noise-induced hearing loss. Neural Plast. 2020;2020:6235948. Paciello F, Di Pino A, Rolesi R, Troiani D, Paludetti G, Grassi C, Fetoni AR. Anti-oxidant and anti-inflammatory effects of caffeic acid: in vivo evidences in a model of noise-induced hearing loss. Food Chem Toxicol: Int J Publ Br Ind Biol Res Assoc. 2020;143:111555. Masuda M, Nagashima R, Kanzaki S, Fujioka M, Ogita K, Ogawa K. Nuclear factor-kappa B nuclear translocation in the cochlea of mice following acoustic overstimulation. Brain Res. 2006;1068(1):237–47. Vethanayagam RR, Yang W, Dong Y, Hu BH. Toll-like receptor 4 modulates the cochlear immune response to acoustic injury. Cell Death Dis. 2016;7(6):e2245. Jones DP. Redefining oxidative stress. Antioxid Redox Signal. 2006;8(9–10):1865–79. Sies H. Oxidative stress: a concept in redox biology and medicine. Redox Biol. 2015;4:180–3. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radical Biol Med. 2010;49(11):1603–16. Kattoor AJ, Pothineni NVK, Palagiri D, Mehta JL. Oxidative stress in atherosclerosis. Curr Atheroscler Rep. 2017;19(11):42. Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015;22(3):377–88. Giordano S, Darley-Usmar V, Zhang J. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol. 2014;2:82–90. Pal R, Bajaj L, Sharma J, Palmieri M, Di Ronza A, Lotfi P, Chaudhury A, Neilson J, Sardiello M, Rodney GG. NADPH oxidase promotes Parkinsonian phenotypes by impairing autophagic flux in an mTORC1-independent fashion in a cellular model of Parkinson’s disease. Sci Rep. 2016;6:22866. Zhang C, Li Q, Chen M, Lu T, Min S, Li S. The role of oxidative stress in the susceptibility of noise-impaired cochleae to synaptic loss induced by intracochlear electrical stimulation. Neuropharmacology. 2021;196:108707. Fetoni AR, De Bartolo P, Eramo SL, Rolesi R, Paciello F, Bergamini C, Fato R, Paludetti G, Petrosini L, Troiani D. Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: cochlear and cortical responses after an increase in antioxidant defense. J Neurosci: Off J Soc Neurosci. 2013;33(9):4011–23. Kopke RD, Coleman JK, Liu J, Campbell KC, Riffenburgh RH. Candidate’s thesis: enhancing intrinsic cochlear stress defenses to reduce noise-induced hearing loss. Laryngoscope. 2002;112(9):1515–32. Tretter V, Hochreiter B, Zach ML, Krenn K, Klein KU. Understanding cellular redox homeostasis: a challenge for precision medicine. Int J Mol Sci. 2021;23(1):106. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24(5):981–90. Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21(7):363–83. Benham AM. Endoplasmic reticulum redox pathways: in sickness and in health. FEBS J. 2019;286(2):311–21. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol: CB. 2014;24(10):R453–62. Hamanaka RB, Weinberg SE, Reczek CR, Chandel NS. The mitochondrial respiratory chain is required for organismal adaptation to hypoxia. Cell Rep. 2016;15(3):451–9. Blacker TS, Duchen MR. Investigating mitochondrial redox state using NADH and NADPH autofluorescence. Free Radic Biol Med. 2016;100:53–65. Lee HC, Wei YH. Mitochondria and aging. Adv Exp Med Biol. 2012;942:311–27. Adam-Vizi V. Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources. Antioxid Redox Signal. 2005;7(9–10):1140–9. Böttger EC, Schacht J. The mitochondrion: a perpetrator of acquired hearing loss. Hear Res. 2013;303:12–9. Spoendlin H. Primary structural changes in the organ of Corti after acoustic overstimulation. Acta Otolaryngol. 1971;71(2):166–76. Chen FQ, Zheng HW, Hill K, Sha SH. Traumatic noise activates Rho-family GTPases through transient cellular energy depletion. J Neurosci: Off J Soc Neurosci. 2012;32(36):12421–30. Henderson D, Bielefeld EC, Harris KC, Hu BH. The role of oxidative stress in noise-induced hearing loss. Ear Hear. 2006;27(1):1–19. Sipos I, Tretter L, Adam-Vizi V. Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals. J Neurochem. 2003;84(1):112–8. Batandier C, Leverve X, Fontaine E. Opening of the mitochondrial permeability transition pore induces reactive oxygen species production at the level of the respiratory chain complex I. J Biol Chem. 2004;279(17):17197–204. Fridberger A, Flock A, Ulfendahl M, Flock B. Acoustic overstimulation increases outer hair cell Ca2+ concentrations and causes dynamic contractions of the hearing organ. Proc Natl Acad Sci USA. 1998;95(12):7127–32. Heinrich UR, Maurer J, Mann W. Ultrastructural evidence for protection of the outer hair cells of the inner ear during intense noise exposure by application of the organic calcium channel blocker diltiazem. ORL; J Oto-rhino-laryngol Relat Spec. 1999;61(6):321–7. Shen H, Zhang B, Shin JH, Lei D, Du Y, Gao X, Wang Q, Ohlemiller KK, Piccirillo J, Bao J. Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss. Hear Res. 2007;226(1–2):52–60. Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol. 2003;4(7):552–65. Esterberg R, Hailey DW, Coffin AB, Raible DW, Rubel EW. Disruption of intracellular calcium regulation is integral to aminoglycoside-induced hair cell death. J Neurosci: Off J Soc Neurosci. 2013;33(17):7513–25. Esterberg R, Hailey DW, Rubel EW, Raible DW. ER-mitochondrial calcium flow underlies vulnerability of mechanosensory hair cells to damage. J Neurosci: Off J Soc Neurosci. 2014;34(29):9703–19. Tretter L, Adam-Vizi V. Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase. J Neurosci: Off J Soc Neurosci. 2004;24(36):7771–8. Sha SH, Taylor R, Forge A, Schacht J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear Res. 2001;155(1–2):1–8. Gentilin E, Cani A, Simoni E, Chicca M, Di Paolo ML, Martini A, Astolfi L. Hydrogen peroxide toxicity on auditory cells: an in vitro study. Chem Biol Interact. 2021;345:109575. Torres M. Mitogen-activated protein kinase pathways in redox signaling. Front Biosci. 2003;8:d369–91. Wortzel I, Seger R. The ERK cascade: distinct functions within various subcellular organelles. Genes Cancer. 2011;2(3):195–209. Dinh CT, Goncalves S, Bas E, Van De Water TR, Zine A. Molecular regulation of auditory hair cell death and approaches to protect sensory receptor cells and/or stimulate repair following acoustic trauma. Front Cell Neurosci. 2015;9:96. Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 2004;68(2):320–44. Keshet Y, Seger R. The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. Methods Mol Biol (Clifton, NJ). 2010;661:3–38. Murai N, Kirkegaard M, Järlebark L, Risling M, Suneson A, Ulfendahl M. Activation of JNK in the inner ear following impulse noise exposure. J Neurotrauma. 2008;25(1):72–7. Maeda Y, Fukushima K, Omichi R, Kariya S, Nishizaki K. Time courses of changes in phospho- and total- MAP kinases in the cochlea after intense noise exposure. PLoS ONE. 2013;8(3):e58775. Anttonen T, Herranen A, Virkkala J, Kirjavainen A, Elomaa P, Laos M, Liang X, Ylikoski J, Behrens A, Pirvola U. c-Jun N-terminal phosphorylation: biomarker for cellular stress rather than cell death in the injured cochlea. Eneuro. 2016;3(2). Zhang AR, Ma KF, She XJ, Liu HT, Cui B, Wang R. Preliminary observation on the differential expression of metformin in preventing noise-induced hearing loss in inner ear protein group of rats. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chin J Ind Hyg Occup Dis. 2022;40(4):248–54. Faris M, Kokot N, Latinis K, Kasibhatla S, Green DR, Koretzky GA, Nel A. The c-Jun N-terminal kinase cascade plays a role in stress-induced apoptosis in Jurkat cells by up-regulating Fas ligand expression. J Immunol (Baltimore, Md: 1950). 1998;160(1):134–44. Budhram-Mahadeo V, Morris PJ, Smith MD, Midgley CA, Boxer LM, Latchman DS. p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. J Biol Chem. 1999;274(21):15237–44. Eichhorst ST, Müller M, Li-Weber M, Schulze-Bergkamen H, Angel P, Krammer PH. A novel AP-1 element in the CD95 ligand promoter is required for induction of apoptosis in hepatocellular carcinoma cells upon treatment with anticancer drugs. Mol Cell Biol. 2000;20(20):7826–37. Whitfield J, Neame SJ, Paquet L, Bernard O, Ham J. Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron. 2001;29(3):629–43. Liu J, Lin A. Role of JNK activation in apoptosis: a double-edged sword. Cell Res. 2005;15(1):36–42. Oleinik NV, Krupenko NI, Krupenko SA. Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene. 2007;26(51):7222–30. Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene. 2008;27(48):6245–51. Amaral JD, Xavier JM, Steer CJ, Rodrigues CM. The role of p53 in apoptosis. Discov Med. 2010;9(45):145–52. Jia H, Yu Z, Ge X, Chen Z, Huang X, Wei Y. Glucocorticoid-induced leucine zipper protects noise-induced apoptosis in cochlear cells by inhibiting endoplasmic reticulum stress in rats. Med Mol Morphol. 2020;53(2):73–81. Ottilie S, Diaz JL, Horne W, Chang J, Wang Y, Wilson G, Chang S, Weeks S, Fritz LC, Oltersdorf T. Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins. J Biol Chem. 1997;272(49):30866–72. Puthalakath H, Huang DC, O’Reilly LA, King SM, Strasser A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell. 1999;3(3):287–96. Donovan N, Becker EB, Konishi Y, Bonni A. JNK phosphorylation and activation of BAD couples the stress-activated signaling pathway to the cell death machinery. J Biol Chem. 2002;277(43):40944–9. Lei K, Nimnual A, Zong WX, Kennedy NJ, Flavell RA, Thompson CB, Bar-Sagi D, Davis RJ. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol. 2002;22(13):4929–42. Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA. 2003;100(5):2432–7. Wang XT, Pei DS, Xu J, Guan QH, Sun YF, Liu XM, Zhang GY. Opposing effects of Bad phosphorylation at two distinct sites by Akt1 and JNK1/2 on ischemic brain injury. Cell Signal. 2007;19(9):1844–56. Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y, Piao JH, Yagita H, Okumura K, Doi T, Nakano H. NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J. 2003;22(15):3898–909. Pirvola U, Xing-Qun L, Virkkala J, Saarma M, Murakata C, Camoratto AM, Walton KM, Ylikoski J. Rescue of hearing, auditory hair cells, and neurons by CEP-1347/KT7515, an inhibitor of c-Jun N-terminal kinase activation. J Neurosci: Off J Soc Neurosci. 2000;20(1):43–50. Wang X, Truong T, Billings PB, Harris JP, Keithley EM. Blockage of immune-mediated inner ear damage by etanercept. Otol Neurotol: Off Publ Am Otol Soc Am Neurotol Soc Eur Acad Otol Neurotol. 2003;24(1):52–7. Wang J, Ruel J, Ladrech S, Bonny C, van de Water TR, Puel JL. Inhibition of the c-Jun N-terminal kinase-mediated mitochondrial cell death pathway restores auditory function in sound-exposed animals. Mol Pharmacol. 2007;71(3):654–66. Godic A, Poljšak B, Adamic M, Dahmane R. The role of antioxidants in skin cancer prevention and treatment. Oxid Med Cell Longev. 2014;2014:860479. Pisoschi AM, Pop A. The role of antioxidants in the chemistry of oxidative stress: a review. Eur J Med Chem. 2015;97:55–74. Yin H, Xu L, Porter NA. Free radical lipid peroxidation: mechanisms and analysis. Chem Rev. 2011;111(10):5944–72. Martysiak-Żurowska D, Wenta W. A comparison of ABTS and DPPH methods for assessing the total antioxidant capacity of human milk. Acta Sci Pol Technol Aliment. 2012;11(1):83–9. Poljsak B, Šuput D, Milisav I. Achieving the balance between ROS and antioxidants: when to use the synthetic antioxidants. Oxid Med Cell Longev. 2013;2013:956792. Willett WC. The Mediterranean diet: science and practice. Public Health Nutr. 2006;9(1a):105–10. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA. 2002;99(18):11908–13. Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA. 2005;102(12):4584–9. Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul. 2006;46:113–40. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014;39(4):199–218. Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med. 2015;88(Pt B):179–88. Nguyen T, Yang CS, Pickett CB. The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med. 2004;37(4):433–41. Itoh K, Mimura J, Yamamoto M. Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal. 2010;13(11):1665–78. Tu W, Wang H, Li S, Liu Q, Sha H. The anti-inflammatory and anti-oxidant mechanisms of the keap1/Nrf2/ARE signaling pathway in chronic diseases. Aging Dis. 2019;10(3):637–51. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12(3):213–23. Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress, Biochimica et biophysica acta. Mol Cell Res. 2018;1865(5):721–33. Fetoni AR, Paciello F, Rolesi R, Eramo SL, Mancuso C, Troiani D, Paludetti G. Rosmarinic acid up-regulates the noise-activated Nrf2/HO-1 pathway and protects against noise-induced injury in rat cochlea. Free Radic Biol Med. 2015;85:269–81. Maines MD. The heme oxygenase system: past, present, and future. Antioxid Redox Signal. 2004;6(5):797–801. Clark JE, Foresti R, Green CJ, Motterlini R. Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress. Biochem J. 2000;348(Pt 3):615–9. Motterlini R, Foresti R. Heme oxygenase-1 as a target for drug discovery. Antioxid Redox Signal. 2014;20(11):1810–26. Balla J, Vercellotti GM, Jeney V, Yachie A, Varga Z, Jacob HS, Eaton JW, Balla G. Heme, heme oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment. Antioxid Redox Signal. 2007;9(12):2119–37. Stefanson AL, Bakovic M. Dietary regulation of Keap1/Nrf2/ARE pathway: focus on plant-derived compounds and trace minerals. Nutrients. 2014;6(9):3777–801. Lu SC. Regulation of glutathione synthesis. Mol Asp Med. 2009;30(1–2):42–59. Calabrese G, Morgan B, Riemer J. Mitochondrial glutathione: regulation and functions. Antioxid Redox Signal. 2017;27(15):1162–77. Cosentino C, Grieco D, Costanzo V. ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair. EMBO J. 2011;30(3):546–55. Finkel T. Signal transduction by reactive oxygen species. J Cell Biol. 2011;194(1):7–15. Lenaz G, Genova ML. Supramolecular organisation of the mitochondrial respiratory chain: a new challenge for the mechanism and control of oxidative phosphorylation. Adv Exp Med Biol. 2012;748:107–44. Holmström KM, Baird L, Zhang Y, Hargreaves I, Chalasani A, Land JM, Stanyer L, Yamamoto M, Dinkova-Kostova AT, Abramov AY. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol Open. 2013;2(8):761–70. Chen GD, Zhao HB. Effects of intense noise exposure on the outer hair cell plasma membrane fluidity. Hear Res. 2007;226(1–2):14–21. Tiede L, Steyger PS, Nichols MG, Hallworth R. Metabolic imaging of the organ of corti—a window on cochlea bioenergetics. Brain Res. 2009;1277:37–41. Tekpli X, Landvik NE, Anmarkud KH, Skaug V, Haugen A, Zienolddiny S. DNA methylation at promoter regions of interleukin 1B, interleukin 6, and interleukin 8 in non-small cell lung cancer. Cancer Immunol Immunother: CII. 2013;62(2):337–45. Alvarado JC, Fuentes-Santamaría V, Juiz JM. Antioxidants and vasodilators for the treatment of noise-induced hearing loss: are they really effective? Front Cell Neurosci. 2020;14:226. Kopke RD, Weisskopf PA, Boone JL, Jackson RL, Wester DC, Hoffer ME, Lambert DC, Charon CC, Ding DL, McBride D. Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla. Hear Res. 2000;149(1–2):138–46. Kopke RD, Jackson RL, Coleman JK, Liu J, Bielefeld EC, Balough BJ. NAC for noise: from the bench top to the clinic. Hear Res. 2007;226(1–2):114–25. Schmitt B, Vicenzi M, Garrel C, Denis FM. Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: a comparative crossover study. Redox Biol. 2015;6:198–205. Kopke R, Slade MD, Jackson R, Hammill T, Fausti S, Lonsbury-Martin B, Sanderson A, Dreisbach L, Rabinowitz P, Torre P 3rd, Balough B. Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial. Hear Res. 2015;323:40–50. De Rosa SC, Zaretsky MD, Dubs JG, Roederer M, Anderson M, Green A, Mitra D, Watanabe N, Nakamura H, Tjioe I, Deresinski SC, Moore WA, Ela SW, Parks D, Herzenberg LA, Herzenberg LA. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest. 2000;30(10):915–29. Lu J, Li W, Du X, Ewert DL, West MB, Stewart C, Floyd RA, Kopke RD. Antioxidants reduce cellular and functional changes induced by intense noise in the inner ear and cochlear nucleus. J Assoc Res Otolaryngol: JARO. 2014;15(3):353–72. Hong SY, Gil HW, Yang JO, Lee EY, Kim HK, Kim SH, Chung YH, Lee EM, Hwang SK. Effect of high-dose intravenous N-acetylcysteine on the concentration of plasma sulfur-containing amino acids. Korean J Intern Med. 2005;20(3):217–23. Baker DH. Comparative species utilization and toxicity of sulfur amino acids. J Nutr. 2006;136(6 Suppl):1670s–5s. De Flora S, Izzotti A, D’Agostini F, Balansky RM. Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. Carcinogenesis. 2001;22(7):999–1013. Hashimoto S, Gon Y, Matsumoto K, Takeshita I, Horie T. N-acetylcysteine attenuates TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells. Br J Pharmacol. 2001;132(1):270–6. Cocco T, Sgobbo P, Clemente M, Lopriore B, Grattagliano I, Di Paola M, Villani G. Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine. Free Radic Biol Med. 2005;38(6):796–805. Grattagliano I, Portincasa P, Cocco T, Moschetta A, Di Paola M, Palmieri VO, Palasciano G. Effect of dietary restriction and N-acetylcysteine supplementation on intestinal mucosa and liver mitochondrial redox status and function in aged rats. Exp Gerontol. 2004;39(9):1323–32. Kil J, Pierce C, Tran H, Gu R, Lynch ED. Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase. Hear Res. 2007;226(1–2):44–51. Kim SJ, Park C, Han AL, Youn MJ, Lee JH, Kim Y, Kim ES, Kim HJ, Kim JK, Lee HK, Chung SY, So H, Park R. Ebselen attenuates cisplatin-induced ROS generation through Nrf2 activation in auditory cells. Hear Res. 2009;251(1–2):70–82. Kil J, Lobarinas E, Spankovich C, Griffiths SK, Antonelli PJ, Lynch ED, Le Prell CG. Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet (London, England). 2017;390(10098):969–79. Sies H, Stahl W. Vitamins E and C, beta-carotene, and other carotenoids as antioxidants. Am J Clin Nutr. 1995;62(6 Suppl):1315s–21s. Schafer FQ, Wang HP, Kelley EE, Cueno KL, Martin SM, Buettner GR. Comparing beta-carotene, vitamin E and nitric oxide as membrane antioxidants. Biol Chem. 2002;383(3–4):671–81. Le Prell CG, Hughes LF, Miller JM. Free radical scavengers vitamins A C, and E plus magnesium reduce noise trauma. Free Radic Biol Med. 2007;42(9):1454–63. Alvarado JC, Fuentes-Santamaría V, Melgar-Rojas P, Valero ML, Gabaldón-Ull MC, Miller JM, Juiz JM. Synergistic effects of free radical scavengers and cochlear vasodilators: a new otoprotective strategy for age-related hearing loss. Front Aging Neurosci. 2015;7:86. Alvarado JC, Fuentes-Santamaría V, Gabaldón-Ull MC, Juiz JM. An oral combination of vitamins A, C, E, and Mg(++) improves auditory thresholds in age-related hearing loss. Front Neurosci. 2018;12:527. Ahn JH, Kang HH, Kim YJ, Chung JW. Anti-apoptotic role of retinoic acid in the inner ear of noise-exposed mice. Biochem Biophys Res Commun. 2005;335(2):485–90. Ahn JH, Shin JE, Chung BY, Lee HM, Kang HH, Chung JW, Pak JH. Involvement of retinoic acid-induced peroxiredoxin 6 expression in recovery of noise-induced temporary hearing threshold shifts. Environ Toxicol Pharmacol. 2013;36(2):463–71. Prasad KN, Bondy SC. Increased oxidative stress, inflammation, and glutamate: potential preventive and therapeutic targets for hearing disorders. Mech Ageing Dev. 2020;185:111191. Evans P, Halliwell B. Free radicals and hearing. Cause, consequence, and criteria. Ann N Y Acad Sci. 1999;884:19–40. McFadden SL, Woo JM, Michalak N, Ding D. Dietary vitamin C supplementation reduces noise-induced hearing loss in guinea pigs. Hear Res. 2005;202(1–2):200–8. Loukzadeh Z, Hakimi A, Esmailidehaj M, Mehrparvar AH. Effect of ascorbic acid on noise induced hearing loss in rats. Iran J Otorhinolaryngol. 2015;27(81):267–72. Shemesh Z, Attias J, Ornan M, Shapira N, Shahar A. Vitamin B12 deficiency in patients with chronic-tinnitus and noise-induced hearing loss. Am J Otolaryngol. 1993;14(2):94–9. Gok U, Halifeoglu I, Canatan H, Yildiz M, Gursu MF, Gur B. Comparative analysis of serum homocysteine, folic acid and Vitamin B12 levels in patients with noise-induced hearing loss. Auris Nasus Larynx. 2004;31(1):19–22. Martínez-Vega R, Garrido F, Partearroyo T, Cediel R, Zeisel SH, Martínez-Álvarez C, Varela-Moreiras G, Varela-Nieto I, Pajares MA. Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism. FASEB J: Off Publ Fed Am Soc Exp Biol. 2015;29(2):418–32. Abbasi M, Pourrajab B, Tokhi MO. Protective effects of vitamins/antioxidants on occupational noise-induced hearing loss: a systematic review. J Occup Health. 2021;63(1):e12217. Kawada H, Blessing K, Kiyota T, Woolman T, Winchester L, Kador PF. Effects of multifunctional antioxidants on mitochondrial dysfunction and amyloid-β metal dyshomeostasis. J Alzheimer’s Dis: JAD. 2015;44(1):297–307. Kawada H, Kador PF. Orally bioavailable metal chelators and radical scavengers: multifunctional antioxidants for the coadjutant treatment of neurodegenerative diseases. J Med Chem. 2015;58(22):8796–805. Chen GD, Daszynski DM, Ding D, Jiang H, Woolman T, Blessing K, Kador PF, Salvi R. Novel oral multifunctional antioxidant prevents noise-induced hearing loss and hair cell loss. Hear Res. 2020;388:107880. Bielefeld EC, Hu BH, Harris KC, Henderson D. Damage and threshold shift resulting from cochlear exposure to paraquat-generated superoxide. Hear Res. 2005;207(1–2):35–42. Möhrle D, Reimann K, Wolter S, Wolters M, Varakina K, Mergia E, Eichert N, Geisler HS, Sandner P, Ruth P, Friebe A, Feil R, Zimmermann U, Koesling D, Knipper M, Rüttiger L. NO-sensitive guanylate cyclase isoforms NO-GC1 and NO-GC2 contribute to noise-induced inner hair cell synaptopathy. Mol Pharmacol. 2017;92(4):375–88. Bielefeld EC, Kopke RD, Jackson RL, Coleman JK, Liu J, Henderson D. Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration. Acta oto-laryngolog. 2007;127(9):914–9. Fetoni AR, Mancuso C, Eramo SL, Ralli M, Piacentini R, Barone E, Paludetti G, Troiani D. In vivo protective effect of ferulic acid against noise-induced hearing loss in the guinea-pig. Neuroscience. 2010;169(4):1575–88. Fetoni AR, Eramo S, Troiani D, Paludetti G. Therapeutic window for ferulic acid protection against noise-induced hearing loss in the guinea pig. Acta Otolaryngol. 2011;131(4):419–27. Le Prell CG, Gagnon PM, Bennett DC, Ohlemiller KK. Nutrient-enhanced diet reduces noise-induced damage to the inner ear and hearing loss. Transl Res: J Lab Clin Med. 2011;158(1):38–53.