Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells

Gaogan Jia , Huanyu Mao , Yanping Zhang , Yusu Ni , Yan Chen

Front. Med. ›› 2022, Vol. 16 ›› Issue (4) : 637 -650.

PDF (7572KB)
Front. Med. ›› 2022, Vol. 16 ›› Issue (4) : 637 -650. DOI: 10.1007/s11684-021-0864-3
RESEARCH ARTICLE
RESEARCH ARTICLE

Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells

Author information +
History +
PDF (7572KB)

Abstract

Oxidative stress plays an important role in the pathogenesis of aminoglycoside-induced hearing loss and represents a promising target for treatment. We tested the potential effect of apigenin, a natural flavonoid with anticancer, anti-inflammatory, and antioxidant activities, on neomycin-induced ototoxicity in cochlear hair cells in vitro. Results showed that apigenin significantly ameliorated the loss of hair cells and the accumulation of reactive oxygen species upon neomycin injury. Further evidence suggested that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was activated by apigenin treatment. Disruption of the Nrf2 axis abolished the effects of apigenin on the alleviation of oxidative stress and subsequent apoptosis of hair cells. This study provided evidence of the protective effect of apigenin on cochlear hair cells and its underlying mechanism.

Keywords

apigenin / aminoglycosides / ototoxicity / oxidative stress / Nrf2 signaling pathway

Cite this article

Download citation ▾
Gaogan Jia, Huanyu Mao, Yanping Zhang, Yusu Ni, Yan Chen. Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells. Front. Med., 2022, 16(4): 637-650 DOI:10.1007/s11684-021-0864-3

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Fink DJ. Hearing loss in adults. N Engl J Med 2018; 378(10): 969–970

[2]

Leis JA, Rutka JA, Gold WL. Aminoglycoside-induced ototoxicity. CMAJ 2015; 187(1): E52

[3]

Dai CF, Steyger PS. A systemic gentamicin pathway across the stria vascularis. Hear Res 2008; 235(1–2): 114–124

[4]

Marcotti W, Corns LF, Goodyear RJ, Rzadzinska AK, Avraham KB, Steel KP, Richardson GP, Kros CJ. The acquisition of mechano-electrical transducer current adaptation in auditory hair cells requires myosin VI. J Physiol 2016; 594(13): 3667–3681

[5]

Alharazneh A, Luk L, Huth M, Monfared A, Steyger PS, Cheng AG, Ricci AJ. Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PLoS One 2011; 6(7): e22347

[6]

Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clin Invest 2011; 121(12): 4796–4809

[7]

Ruhl D, Du TT, Wagner EL, Choi JH, Li S, Reed R, Kim K, Freeman M, Hashisaki G, Lukens JR, Shin JB. Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity. J Neurosci 2019; 39(15): 2951–2964

[8]

Prasad KN, Bondy SC. Increased oxidative stress, inflammation, and glutamate: potential preventive and therapeutic targets for hearing disorders. Mech Ageing Dev 2020; 185: 111191

[9]

Shulman E, Belakhov V, Wei G, Kendall A, Meyron-Holtz EG, Ben-Shachar D, Schacht J, Baasov T. Designer aminoglycosides that selectively inhibit cytoplasmic rather than mitochondrial ribosomes show decreased ototoxicity: a strategy for the treatment of genetic diseases. J Biol Chem 2014; 289(4): 2318–2330

[10]

Esterberg R, Linbo T, Pickett SB, Wu P, Ou HC, Rubel EW, Raible DW. Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death. J Clin Invest 2016; 126(9): 3556–3566

[11]

Liu L, Chen Y, Qi J, Zhang Y, He Y, Ni W, Li W, Zhang S, Sun S, Taketo MM, Wang L, Chai R, Li H. Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea. Cell Death Dis 2016; 7(3): e2136

[12]

Ojano-Dirain CP, Antonelli PJ, Le Prell CG. Mitochondria-targeted antioxidant MitoQ reduces gentamicin-induced ototoxicity. Otol Neurotol 2014; 35(3): 533–539

[13]

Tokgöz SA, Vuralkan E, Sonbay ND, Çalişkan M, Saka C, Beşalti Ö, Akin İ. Protective effects of vitamins E, B and C and L-carnitine in the prevention of cisplatin-induced ototoxicity in rats. J Laryngol Otol 2012; 126(5): 464–469

[14]

He Z, Guo L, Shu Y, Fang Q, Zhou H, Liu Y, Liu D, Lu L, Zhang X, Ding X, Liu D, Tang M, Kong W, Sha S, Li H, Gao X, Chai R. Autophagy protects auditory hair cells against neomycin-induced damage. Autophagy 2017; 13(11): 1884–1904

[15]

Yang Q, Zhou Y, Yin H, Li H, Zhou M, Sun G, Cao Z, Man R, Wang H, Li J. PINK1 protects against gentamicin-induced sensory hair cell damage: possible relation to induction of autophagy and inhibition of p53 signal pathway. Front Mol Neurosci 2018; 11: 403

[16]

Noack V, Pak K, Jalota R, Kurabi A, Ryan AF. An antioxidant screen identifies candidates for protection of cochlear hair cells from gentamicin toxicity. Front Cell Neurosci 2017; 11: 242

[17]

Meresman G, Götte M, Laschke M. Plants as source of new therapies for endometriosis: a review of preclinical and clinical studies. Hum Reprod Update 2021; 27(2): 367–392

[18]

Lee YJ, Park KS, Nam HS, Cho MK, Lee SH. Apigenin causes necroptosis by inducing ROS accumulation, mitochondrial dysfunction, and ATP depletion in malignant mesothelioma cells. Korean J Physiol Pharmacol 2020; 24(6): 493–502

[19]

Ginwala R, Bhavsar R, Moore P, Bernui M, Singh N, Bearoff F, Nagarkatti M, Khan Z, Jain P. Apigenin modulates dendritic cell activities and curbs inflammation via RelB inhibition in the context of neuroinflammatory diseases. J Neuroimmune Pharmacol 2021; 16(2): 403–424 doi: 10.1007/s11481-020-09933-8

[20]

Ren K, Jiang T, Zhou HF, Liang Y, Zhao GJ. Apigenin retards atherogenesis by promoting ABCA1-mediated cholesterol efflux and suppressing inflammation. Cell Physiol Biochem 2018; 47(5): 2170–2184

[21]

Bougioukas I, Didilis V, Emmert A, Jebran AF, Waldmann-Beushausen R, Stojanovic T, Schoendube FA, Danner BC. Apigenin reduces NF-κB and subsequent cytokine production as protective effect in a rodent animal model of lung ischemia-reperfusion injury. J Invest Surg 2018; 31(2): 96–106 doi:10.1080/08941939.2017.1296512

[22]

Ogura Y, Kitada M, Xu J, Monno I, Koya D. CD38 inhibition by apigenin ameliorates mitochondrial oxidative stress through restoration of the intracellular NAD+/NADH ratio and Sirt3 activity in renal tubular cells in diabetic rats. Aging (Albany NY) 2020; 12(12): 11325–11336

[23]

Salehi B, Venditti A, Sharifi-Rad M, Kręgiel D, Sharifi-Rad J, Durazzo A, Lucarini M, Santini A, Souto EB, Novellino E, Antolak H, Azzini E, Setzer WN, Martins N. The therapeutic potential of apigenin. Int J Mol Sci 2019; 20(6): 1305

[24]

Tateya T, Sakamoto S, Ishidate F, Hirashima T, Imayoshi I, Kageyama R. Three-dimensional live imaging of Atoh1 reveals the dynamics of hair cell induction and organization in the developing cochlea. Development 2019; 146(21): dev177881

[25]

Qian X, He Z, Wang Y, Chen B, Hetrick A, Dai C, Chi F, Li H, Ren D. Hair cell uptake of gentamicin in the developing mouse utricle. J Cell Physiol 2021; 236(7): 5235–5252

[26]

Zallocchi M, Hati S, Xu Z, Hausman W, Liu H, He DZ, Zuo J. Characterization of quinoxaline derivatives for protection against iatrogenically induced hearing loss. JCI Insight 2021; 6(5): 141561

[27]

Cunningham LL, Cheng AG, Rubel EW. Caspase activation in hair cells of the mouse utricle exposed to neomycin. J Neurosci 2002; 22(19): 8532–8540

[28]

Zhong Z, Fu X, Li H, Chen J, Wang M, Gao S, Zhang L, Cheng C, Zhang Y, Li P, Zhang S, Qian X, Shu Y, Chai R, Gao X. Citicoline protects auditory hair cells against neomycin-induced damage. Front Cell Dev Biol 2020; 8: 712

[29]

Xu X, Li M, Chen W, Yu H, Yang Y, Hang L. Apigenin attenuates oxidative injury in ARPE-19 cells thorough activation of Nrf2 pathway. Oxid Med Cell Longev 2016; 2016: 4378461

[30]

Zhang Y, Yang Y, Yu H, Li M, Hang L, Xu X. Apigenin protects mouse retina against oxidative damage by regulating the Nrf2 pathway and autophagy. Oxid Med Cell Longev 2020; 2020: 9420704

[31]

Xu W, Zhao T, Xiao H. The implication of oxidative stress and AMPK-Nrf2 antioxidative signaling in pneumonia pathogenesis. Front Endocrinol (Lausanne) 2020; 11: 400

[32]

Müller U, Barr-Gillespie PG. New treatment options for hearing loss. Nat Rev Drug Discov 2015; 14(5): 346–365

[33]

Rizk HG, Lee JA, Liu YF, Endriukaitis L, Isaac JL, Bullington WM. Drug-induced ototoxicity: a comprehensive review and reference guide. Pharmacotherapy 2020; 40(12): 1265–1275

[34]

Cobley JN. Mechanisms of mitochondrial ROS production in assisted reproduction: the known, the unknown, and the intriguing. Antioxidants 2020; 9(10): 933

[35]

Wang L, Ai Z, Khoyratty T, Zec K, Eames HL, van Grinsven E, Hudak A, Morris S, Ahern D, Monaco C, Eruslanov EB, Luqmani R, Udalova IA. ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies. JCI Insight 2020; 5(20): e139163

[36]

Madreiter-Sokolowski CT, Thomas C, Ristow M. Interrelation between ROS and Ca2+ in aging and age-related diseases. Redox Biol 2020; 36: 101678

[37]

Chen W, Li D. Reactive oxygen species (ROS)-responsive nanomedicine for solving ischemia-reperfusion injury. Front Chem 2020; 8: 732

[38]

Banerjee S, Ghosh S, Mandal A, Ghosh N, Sil PC. ROS-associated immune response and metabolism: a mechanistic approach with implication of various diseases. Arch Toxicol 2020; 94(7): 2293–2317

[39]

Tsubata T. Involvement of reactive oxygen species (ROS) in BCR signaling as a second messenger. Adv Exp Med Biol 2020; 1254: 37–46

[40]

Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 2020; 21(7): 363–383

[41]

Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997; 275(5303): 1132–1136

[42]

Chong SJ, Low IC, Pervaiz S. Mitochondrial ROS and involvement of Bcl-2 as a mitochondrial ROS regulator. Mitochondrion 2014; 19(Pt A): 39–48

[43]

Wang L, Duan Q, Wang T, Ahmed M, Zhang N, Li Y, Li L, Yao X. Mitochondrial respiratory chain inhibitors involved in ROS production induced by acute high concentrations of iodide and the effects of SOD as a protective factor. Oxid Med Cell Longev 2015; 2015: 217670

[44]

Zhang P, Li T, Wu X, Nice EC, Huang C, Zhang Y. Oxidative stress and diabetes: antioxidative strategies. Front Med 2020; 14(5): 583–600

[45]

Yang M, Jiang ZH, Li CG, Zhu YJ, Li Z, Tang YZ, Ni CL. Apigenin prevents metabolic syndrome in high-fructose diet-fed mice by Keap1-Nrf2 pathway. Biomed Pharmacother 2018; 105: 1283–1290

[46]

Galicia-Moreno M, Lucano-Landeros S, Monroy-Ramirez HC, Silva-Gomez J, Gutierrez-Cuevas J, Santos A, Armendariz-Borunda J. Roles of Nrf2 in liver diseases: molecular, pharmacological, and epigenetic aspects. Antioxidants 2020; 9(10): 980

[47]

Owusu-Ansah A, Choi SH, Petrosiute A, Letterio JJ, Huang AY. Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review. Front Med 2015; 9(1): 46–56

[48]

Moretti D, Tambone S, Cerretani M, Fezzardi P, Missineo A, Sherman L, Munoz-Sajuan I, Harper S, Dominquez C, Pacifici R, Tomei L, Park L, Bresciani A. NRF2 activation by reversible KEAP1 binding induces the antioxidant response in primary neurons and astrocytes of a Huntington’s disease mouse model. Free Radic Biol Med 2021; 162: 243–254

[49]

Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, Attucks OC, Franklin S, Levonen AL, Kensler TW, Dinkova-Kostova AT. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov 2019; 18(4): 295–317

[50]

Drummond GS, Baum J, Greenberg M, Lewis D, Abraham NG. HO-1 overexpression and underexpression: clinical implications. Arch Biochem Biophys 2019; 673: 108073

[51]

Honkura Y, Matsuo H, Murakami S, Sakiyama M, Mizutari K, Shiotani A, Yamamoto M, Morita I, Shinomiya N, Kawase T, Katori Y, Motohashi H. NRF2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea. Sci Rep 2016; 6(1): 19329

[52]

Zhang W, Xiong H, Pang J, Su Z, Lai L, Lin H, Jian B, He W, Yang H, Zheng Y. Nrf2 activation protects auditory hair cells from cisplatin-induced ototoxicity independent on mitochondrial ROS production. Toxicol Lett 2020; 331: 1–10

[53]

Zhang Y, Chen D, Zhao L, Li W, Ni Y, Chen Y, Li H. Nfatc4 deficiency attenuates ototoxicity by suppressing Tnf-mediated hair cell apoptosis in the mouse cochlea. Front Immunol 2019; 10: 1660

[54]

Huang CH, Kuo PL, Hsu YL, Chang TT, Tseng HI, Chu YT, Kuo CH, Chen HN, Hung CH. The natural flavonoid apigenin suppresses Th1- and Th2-related chemokine production by human monocyte THP-1 cells through mitogen-activated protein kinase pathways. J Med Food 2010; 13(2): 391–398

[55]

Nicholas C, Batra S, Vargo MA, Voss OH, Gavrilin MA, Wewers MD, Guttridge DC, Grotewold E, Doseff AI. Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-κB through the suppression of p65 phosphorylation. J Immunol 2007; 179(10): 7121–7127

[56]

Li F, Lang F, Zhang H, Xu L, Wang Y, Zhai C, Hao E. Apigenin alleviates endotoxin-induced myocardial toxicity by modulating inflammation, oxidative stress, and autophagy. Oxid Med Cell Longev 2017; 2017: 2302896

[57]

de Font-Réaulx Rojas E, Dorazco-Barragan G. Clinical stabilisation in neurodegenerative diseases: clinical study in phase II. Rev Neurol 2010; 50(9): 520–528 (in Spanish)

[58]

Shoara R, Hashempur MH, Ashraf A, Salehi A, Dehshahri S, Habibagahi Z. Efficacy and safety of topical Matricaria chamomilla L. (chamomile) oil for knee osteoarthritis: a randomized controlled clinical trial. Complement Ther Clin Pract 2015; 21(3): 181–187

[59]

Qiu JG, Wang L, Liu WJ, Wang JF, Zhao EJ, Zhou FM, Ji XB, Wang LH, Xia ZK, Wang W, Lin MC, Liu LZ, Huang YX, Jiang BH. Apigenin inhibits IL-6 transcription and suppresses esophageal carcinogenesis. Front Pharmacol 2019; 10: 1002

[60]

Granato M, Gilardini Montani MS, Santarelli R, D’Orazi G, Faggioni A, Cirone M. Apigenin, by activating p53 and inhibiting STAT3, modulates the balance between pro-apoptotic and pro-survival pathways to induce PEL cell death. J Exp Clin Cancer Res 2017; 36(1): 167

[61]

Tang D, Chen K, Huang L, Li J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opin Drug Metab Toxicol 2017; 13(3): 323–330

[62]

Sang Z, Wang K, Shi J, Cheng X, Zhu G, Wei R, Ma Q, Yu L, Zhao Y, Tan Z, Liu W. Apigenin-rivastigmine hybrids as multi-target-directed liagnds for the treatment of Alzheimer’s disease. Eur J Med Chem 2020; 187: 111958

[63]

Huang Y, Zhao X, Zu Y, Wang L, Deng Y, Wu M, Wang H. Enhanced solubility and bioavailability of apigenin via preparation of solid dispersions of mesoporous silica nanoparticles. Iran J Pharm Res 2019; 18(1): 168–182

RIGHTS & PERMISSIONS

Higher Education Press

AI Summary AI Mindmap
PDF (7572KB)

2408

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/