{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T17:56:50Z","timestamp":1785175010499,"version":"3.55.0"},"reference-count":37,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T00:00:00Z","timestamp":1589500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF- 2016M3A9E8941669 and 2020R1A2C4002594"],"award-info":[{"award-number":["NRF- 2016M3A9E8941669 and 2020R1A2C4002594"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Previous studies have described the effects of zingerone (ZO) on cisplatin (CXP)-induced injury to the kidneys, liver, and other organs but not to the cochlea. This study aimed to investigate the effects of ZO on CXP-induced ototoxicity. Eight-week-old Sprague\u2013Dawley rats were used and divided into a control group, a CXP group, and a CXP + ZO group. Rats in the CXP group received 5 mg\/kg\/day CXP intraperitoneally for five days. Rats in the CXP + ZO group received 5 mg\/kg\/day CXP intraperitoneally for five days and 50 mg\/kg\/day ZO intraperitoneally for seven days. Auditory brainstem response thresholds (ABRTs) were measured before (day 0) and after (day 10) drug administration. Cochlear histology was examined using hematoxylin and eosin (H&amp;E) staining and cochlear whole mounts. The expression levels of cytochrome P450 (CYP)1A1, CYP1B1, inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF\u03baB), tumor necrosis factor alpha (TNF\u03b1), and interleukin 6 (IL6) were estimated using quantitative reverse transcription-polymerase chain reaction. The expression levels of heme oxygenase 1 (HO1) and caspase 3 were analyzed via Western blotting. The auditory thresholds at 4, 8, and 16 kHz were attenuated in the CXP + ZO group compared with the CXP group. The mRNA expression levels of CYP1A1, CYP1B1, iNOS, NF\u03baB, TNF\u03b1, and IL6 were lower in the CXP + ZO group than in the CXP group. The protein expression levels of HO1 and caspase 3 were lower in the CXP + ZO group than in the CXP group. Cotreatment with ZO exerted otoprotective effects against CXP-induced cochlear injury via antioxidative and anti-inflammatory activities involving CYPs, iNOS, NF\u03baB, and TNF\u03b1.<\/jats:p>","DOI":"10.3390\/ijms21103503","type":"journal-article","created":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T10:53:59Z","timestamp":1589540039000},"page":"3503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Otoprotective Effects of Zingerone on Cisplatin-Induced Ototoxicity"],"prefix":"10.3390","volume":"21","author":[{"given":"Chang Ho","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, CHA University College of Medicine, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-hye","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, CHA University College of Medicine, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, CHA University College of Medicine, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7361-4930","authenticated-orcid":false,"given":"So Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, CHA University College of Medicine, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.tips.2013.05.006","article-title":"Understanding platinum-induced ototoxicity","volume":"34","author":"Langer","year":"2013","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.heares.2017.12.004","article-title":"The expression of oxidative stress response genes is modulated by a combination of resveratrol and N-acetylcysteine to ameliorate ototoxicity in the rat cochlea","volume":"358","author":"Pulido","year":"2018","journal-title":"Hear. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4011","DOI":"10.1523\/JNEUROSCI.2282-12.2013","article-title":"Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: Cochlear and cortical responses after an increase in antioxidant defense","volume":"33","author":"Fetoni","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_4","first-page":"4081","article-title":"Nuclear-factor kappa B (NF-kappa B)-inducible nitric oxide synthase (iNOS\/NOS II) pathway damages the stria vascularis in cisplatin-treated mice","volume":"22","author":"Watanabe","year":"2002","journal-title":"Anticancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"338","DOI":"10.3389\/fncel.2017.00338","article-title":"Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection","volume":"11","author":"Sheth","year":"2017","journal-title":"Front. Cell. Neurosci"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"268","DOI":"10.3390\/toxics3030268","article-title":"Cisplatin-Induced Ototoxicity: Effects, Mechanisms and Protection Strategies","volume":"3","author":"Callejo","year":"2015","journal-title":"Toxics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1007\/s10162-007-0084-9","article-title":"Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-kappaB","volume":"8","author":"So","year":"2007","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.freeradbiomed.2018.02.025","article-title":"PINK1 Protects Auditory Hair Cells and Spiral Ganglion Neurons from Cisplatin-induced Ototoxicity via Inducing Autophagy and Inhibiting JNK Signaling Pathway","volume":"120","author":"Yang","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/S0196-0709(86)80050-3","article-title":"Cisplatin: Evaluation of its ototoxic potential","volume":"7","author":"Anniko","year":"1986","journal-title":"Am. J. Otolaryngol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.heares.2005.03.023","article-title":"The cochlear targets of cisplatin: An electrophysiological and morphological time-sequence study","volume":"205","author":"Klis","year":"2005","journal-title":"Hear. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1517\/14656566.4.6.889","article-title":"Toxicity of platinum compounds","volume":"4","author":"Hartmann","year":"2003","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.taap.2018.06.010","article-title":"Protective roles of fenofibrate against cisplatin-induced ototoxicity by the rescue of peroxisomal and mitochondrial dysfunction","volume":"353","author":"Kim","year":"2018","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Youn, C.K., Kim, J., Jo, E.R., Oh, J., Do, N.Y., and Cho, S.I. (2016). Protective Effect of Tempol against Cisplatin-Induced Ototoxicity. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17111931"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"66","DOI":"10.21053\/ceo.2017.01704","article-title":"Is Hyperbaric Oxygen Therapy Effective in Cisplatin-Induced Ototoxicity in Rats?","volume":"12","author":"Cobanoglu","year":"2019","journal-title":"Clin. Exp. Otorhinolaryngol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22562","DOI":"10.1007\/s11356-019-05505-3","article-title":"Protective effects of zingerone on cisplatin-induced nephrotoxicity in female rats","volume":"26","author":"Kandemir","year":"2019","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1093\/jrr\/rrz065","article-title":"Protective effects of zingerone derivate on ionizing radiation-induced intestinal injury","volume":"60","author":"Wu","year":"2019","journal-title":"J. Radiat. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.cbi.2017.12.031","article-title":"Protective effects of zingerone on lipopolysaccharide-induced hepatic failure through the modulation of inflammatory pathways","volume":"281","author":"Lee","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"271","DOI":"10.5483\/BMBRep.2019.52.4.175","article-title":"Renal protective effects of zingerone in a mouse model of sepsis","volume":"52","author":"Lee","year":"2019","journal-title":"BMB Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.biopha.2018.05.085","article-title":"Protective effects of zingerone on oxidative stress and inflammation in cisplatin-induced rat nephrotoxicity","volume":"105","author":"Alibakhshi","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"108891","DOI":"10.1016\/j.apradiso.2019.108891","article-title":"Modulatory effect of zingerone against cisplatin or gamma-irradiation induced hepatotoxicity by molecular targeting regulation","volume":"154","author":"Mohamed","year":"2019","journal-title":"Appl. Radiat. Isot."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s00210-018-1506-4","article-title":"Cardioprotective effect of zingerone against oxidative stress, inflammation, and apoptosis induced by cisplatin or gamma radiation in rats","volume":"391","author":"Soliman","year":"2018","journal-title":"Naunyn Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.biopha.2018.03.119","article-title":"Zingerone ameliorates cisplatin-induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats","volume":"102","author":"Kaygusuzoglu","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.toxlet.2015.06.012","article-title":"An integrated view of cisplatin-induced nephrotoxicity and ototoxicity","volume":"237","author":"Karasawa","year":"2015","journal-title":"Toxicol. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ejps.2019.02.016","article-title":"CYP enzymes, expressed within live human suspension cells, are superior to widely-used microsomal enzymes in identifying potent CYP1A1\/CYP1B1 inhibitors: Identification of quinazolinones as CYP1A1\/CYP1B1 inhibitors that efficiently reverse B[a]P toxicity and cisplatin resistance","volume":"131","author":"Sonawane","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.mrfmmm.2005.03.023","article-title":"Phenolics as potential antioxidant therapeutic agents: Mechanism and actions","volume":"579","author":"Soobrattee","year":"2005","journal-title":"Mutat. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.lfs.2003.10.042","article-title":"iNOS-mediated nitric oxide production and its regulation","volume":"75","author":"Aktan","year":"2004","journal-title":"Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1146\/annurev.immunol.16.1.225","article-title":"NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses","volume":"16","author":"Ghosh","year":"1998","journal-title":"Annu. Rev. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4845","DOI":"10.4049\/jimmunol.174.8.4845","article-title":"Microbial antigen triggers rapid mobilization of TNF-alpha to the surface of mouse neutrophils transforming them into inducers of high-level dendritic cell TNF-alpha production","volume":"174","author":"Bennouna","year":"2005","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1034\/j.1600-0625.2001.100503.x","article-title":"Human skin mast cells rapidly release preformed and newly generated TNF-alpha and IL-8 following stimulation with anti-IgE and other secretagogues","volume":"10","author":"Gibbs","year":"2001","journal-title":"Exp. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S1359-6101(03)00021-2","article-title":"The signaling adaptors and pathways activated by TNF superfamily","volume":"14","author":"Dempsey","year":"2003","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"F777","DOI":"10.1152\/ajprenal.00590.2007","article-title":"Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells","volume":"294","author":"Yang","year":"2008","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13056","DOI":"10.1523\/JNEUROSCI.1307-08.2008","article-title":"Short interfering RNA against transient receptor potential vanilloid 1 attenuates cisplatin-induced hearing loss in the rat","volume":"28","author":"Mukherjea","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e731","DOI":"10.1097\/MAO.0000000000001911","article-title":"The Novel Peptide Vaccine GV1001 Protects Hearing in a Kanamycin-induced Ototoxicity Mouse Model","volume":"39","author":"Kim","year":"2018","journal-title":"Otol. Neurotol."},{"key":"ref_34","first-page":"e56678","article-title":"Auditory Brainstem Response and Outer Hair Cell Whole-cell Patch Clamp Recording in Postnatal Rats","volume":"135","author":"Chang","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1016\/j.ajpath.2011.12.034","article-title":"Identification of three novel hearing loss mouse strains with mutations in the Tmc1 gene","volume":"180","author":"Manji","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"134838","DOI":"10.1016\/j.neulet.2020.134838","article-title":"Tauroursodeoxycholic acid attenuates cisplatin-induced hearing loss in rats","volume":"722","author":"Lee","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.neuro.2018.06.001","article-title":"Effects of inhaled particulate matter on the central nervous system in mice","volume":"67","author":"Kim","year":"2018","journal-title":"Neurotoxicology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3503\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:29:05Z","timestamp":1760174945000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,15]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ijms21103503"],"URL":"https:\/\/doi.org\/10.3390\/ijms21103503","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,15]]}}}