{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T19:54:45Z","timestamp":1788983685086,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T00:00:00Z","timestamp":1617580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taiwan.","award":["MOST109-2314-B-016-005 to C.P.S. and MOST107-2314-B-663-001-MY3 to C.H.W."],"award-info":[{"award-number":["MOST109-2314-B-016-005 to C.P.S. and MOST107-2314-B-663-001-MY3 to C.H.W."]}]},{"name":"Tri-Service General Hospital grants","award":["TSGH-A-109001 to C.P.S."],"award-info":[{"award-number":["TSGH-A-109001 to C.P.S."]}]},{"name":"Taichung Armed Forces General Hospital grant","award":["CAFGH-D-109025 to C.H.W., TCAFGH-E-109044 to H.C.C. and C.H.W."],"award-info":[{"award-number":["CAFGH-D-109025 to C.H.W., TCAFGH-E-109044 to H.C.C. and C.H.W."]}]},{"name":"Teh-Tzer Study Group for Human Medical Research Foundation","award":["A1071025 to H.C.C. and A1061019 to C.H.W."],"award-info":[{"award-number":["A1071025 to H.C.C. and A1061019 to C.H.W."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Noise-induced hearing loss (NIHL) is a common inner ear disease but has complex pathological mechanisms, one of which is increased oxidative stress in the cochlea. The high-mobility group box 1 (HMGB1) protein acts as an inflammatory mediator and shows different activities with redox modifications linked to the generation of reactive oxygen species (ROS). We aimed to investigate whether manipulation of cochlear HMGB1 during noise exposure could prevent noise-induced oxidative stress and hearing loss. Sixty CBA\/CaJ mice were divided into two groups. An intraperitoneal injection of anti-HMGB1 antibodies was administered to the experimental group; the control group was injected with saline. Thirty minutes later, all mice were subjected to white noise exposure. Subsequent cochlear damage, including auditory threshold shifts, hair cell loss, expression of cochlear HMGB1, and free radical activity, was then evaluated. The levels of HMGB1 and 4-hydroxynonenal (4-HNE), as respective markers of reactive nitrogen species (RNS) and ROS formation, showed slight increases on post-exposure day 1 and achieved their highest levels on post-exposure day 4. After noise exposure, the antibody-treated mice showed markedly less ROS formation and lower expression of NADPH oxidase 4 (NOX4), nitrotyrosine, inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1) than the saline-treated control mice. A significant amelioration was also observed in the threshold shifts of the auditory brainstem response and the loss of outer hair cells in the antibody-treated versus the saline-treated mice. Our results suggest that inhibition of HMGB1 by neutralization with anti-HMGB1 antibodies prior to noise exposure effectively attenuated oxidative stress and subsequent inflammation. This procedure could therefore have potential as a therapy for NIHL.<\/jats:p>","DOI":"10.3390\/cells10040810","type":"journal-article","created":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T11:48:29Z","timestamp":1617623309000},"page":"810","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Inhibition of Cochlear HMGB1 Expression Attenuates Oxidative Stress and Inflammation in an Experimental Murine Model of Noise-Induced Hearing Loss"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5515-2509","authenticated-orcid":false,"given":"Cheng-Ping","family":"Shih","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Tri-Service General Hospital, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8201-5799","authenticated-orcid":false,"given":"Chao-Yin","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Tri-Service General Hospital, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Yung","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Tri-Service General Hospital, Taipei 11490, Taiwan"},{"name":"Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chun","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-2019","authenticated-orcid":false,"given":"Hang-Kang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Tri-Service General Hospital, Taipei 11490, Taiwan"},{"name":"Taichung Armed Forces General Hospital, Taichung 41168, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Tri-Service General Hospital, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5498-5621","authenticated-orcid":false,"given":"Hsin-Chien","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Tri-Service General Hospital, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5058-4356","authenticated-orcid":false,"given":"Chih-Hung","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Tri-Service General Hospital, Taipei 11490, Taiwan"},{"name":"Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan"},{"name":"Taichung Armed Forces General Hospital, Taichung 41168, Taiwan"},{"name":"Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1002\/ajim.20223","article-title":"The global burden of occupational noise\u2014Induced hearing loss","volume":"48","author":"Nelson","year":"2005","journal-title":"Am. J. Ind. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1017\/S0022215118001275","article-title":"Global burden of hearing impairment and ear disease","volume":"133","author":"Graydon","year":"2019","journal-title":"J. Laryngol. Otol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/01.aud.0000191942.36672.f3","article-title":"The role of oxidative stress in noise\u2014Induced hearing loss","volume":"27","author":"Henderson","year":"2006","journal-title":"Ear Hear."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4020","DOI":"10.1121\/1.5132545","article-title":"Inflammation associated with noise\u2014Induced hearing loss","volume":"146","author":"Frye","year":"2019","journal-title":"J. Acoust. Soc. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.heares.2016.11.013","article-title":"Cellular mechanisms of noise\u2014Induced hearing loss","volume":"349","author":"Kurabi","year":"2017","journal-title":"Hear. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.brainres.2004.05.104","article-title":"Delayed production of free radicals following noise exposure","volume":"1019","author":"Yamashita","year":"2004","journal-title":"Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"162","DOI":"10.4161\/viru.2.2.15480","article-title":"HMGB1 release by inflammasomes","volume":"2","author":"Kanneganti","year":"2011","journal-title":"Virulence"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gozlan, J., Borde, C., and Marechal, V. (2010). Extracellular HMGB1: An ambiguous messenger during HIV-1 infection. Soluble Factors Mediat. Innate Immune Responses HIV Infect., 64\u201380.","DOI":"10.2174\/978160805006211001010064"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1189\/jlb.1104648","article-title":"The cytokine activity of HMGB1","volume":"78","author":"Yang","year":"2005","journal-title":"J. Leukoc. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1073\/pnas.2434651100","article-title":"Reversing established sepsis with antagonists of endogenous high-mobility group box 1","volume":"101","author":"Yang","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.jjcc.2012.01.007","article-title":"High-mobility group box 1 protein blockade suppresses development of abdominal aortic aneurysm","volume":"59","author":"Kohno","year":"2012","journal-title":"J. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1164\/rccm.200402-188OC","article-title":"Contributions of high mobility group box protein in experimental and clinical acute lung injury","volume":"170","author":"Ueno","year":"2004","journal-title":"Am. j. Respir. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1084\/jem.20042614","article-title":"The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion","volume":"201","author":"Tsung","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1681\/ASN.2009101048","article-title":"HMGB1 contributes to kidney ischemia reperfusion injury","volume":"21","author":"Wu","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.neuro.2005.05.010","article-title":"Cisplatin ototoxicity to the rat inner ear: A role for HMG1 and iNOS","volume":"27","author":"Li","year":"2006","journal-title":"Neurotoxicology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19891","DOI":"10.3390\/ijms141019891","article-title":"Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond","volume":"14","author":"Daffu","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/srep00896","article-title":"Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia","volume":"2","author":"Suzuki","year":"2012","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1084\/jem.20070247","article-title":"HMGB1 release induced by liver ischemia involves Toll-like receptor 4\u2014Dependent reactive oxygen species production and calcium-mediated signaling","volume":"204","author":"Tsung","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1002\/lary.27713","article-title":"Middle-ear dexamethasone delivery via ultrasound microbubbles attenuates noise\u2014Induced hearing loss","volume":"129","author":"Shih","year":"2019","journal-title":"Laryngoscope"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1172\/JCI22782","article-title":"The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism","volume":"115","author":"Abeyama","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0378-5955(02)00796-7","article-title":"Altered expression of inducible nitric oxide synthase (iNOS) in the cochlea","volume":"177","author":"Shi","year":"2003","journal-title":"Hear. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"809","DOI":"10.3109\/00016489.2011.568524","article-title":"Astragaloside IV attenuates impulse noise-induced trauma in guinea pig","volume":"131","author":"Xiong","year":"2011","journal-title":"Acta Oto-Laryngol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1254\/jphs.10113FP","article-title":"Mechanism underlying the protective effect of tempol and N\u03c9-nitro-L-arginine methyl ester on acoustic injury: Possible involvement of c-Jun N-terminal kinase pathway and connexin26 in the cochlear spiral ligament","volume":"114","author":"Nagashima","year":"2010","journal-title":"J. Pharmacol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.heares.2006.09.004","article-title":"Immune cell recruitment following acoustic trauma","volume":"222","author":"Tornabene","year":"2006","journal-title":"Hear. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1111\/jnc.14451","article-title":"Hearing vulnerability after noise exposure in a mouse model of reactive oxygen species overproduction","volume":"146","author":"Morioka","year":"2018","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1159\/000490818","article-title":"Emerging role of high mobility group box-1 in thrombosis-related diseases","volume":"47","author":"Wu","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.4049\/jimmunol.173.6.3589","article-title":"Cutting edge: Direct interaction of TLR4 with NAD (P) H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-\u03baB","volume":"173","author":"Park","year":"2004","journal-title":"J. Immunol."},{"key":"ref_28","first-page":"4628962","article-title":"Glycine suppresses AGE\/RAGE signaling pathway and subsequent oxidative stress by restoring Glo1 function in the aorta of diabetic rats and in HUVECs","volume":"2019","author":"Wang","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4407","DOI":"10.1038\/s41598-018-36344-w","article-title":"AKF-PD alleviates diabetic nephropathy via blocking the RAGE\/AGEs\/NOX and PKC\/NOX pathways","volume":"9","author":"Qin","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2962","DOI":"10.1111\/ejn.12290","article-title":"Supporting cells regulate the remodelling of aminoglycoside\u2014Injured organ of C orti, through the release of high mobility group box 1","volume":"38","author":"Ladrech","year":"2013","journal-title":"Eur. J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1080\/00016489.2017.1328743","article-title":"Molecular mechanisms underlying the protective effects of hydrogen-saturated saline on noise-induced hearing loss","volume":"137","author":"Chen","year":"2017","journal-title":"Acta Oto-Laryngol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1089\/dna.2013.2198","article-title":"Genomic analysis and differential expression of HMG and S100A family in human arthritis: Upregulated expression of chemokines, IL-8 and nitric oxide by HMGB1","volume":"33","author":"Amin","year":"2014","journal-title":"DNA cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.4049\/jimmunol.1002183","article-title":"Activation of lipopolysaccharide-TLR4 signaling accelerates the ototoxic potential of cisplatin in mice","volume":"186","author":"Oh","year":"2011","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.molimm.2012.10.042","article-title":"High mobility group box 1 protein synergizes with lipopolysaccharide and peptidoglycan for nitric oxide production in mouse peritoneal macrophages in vitro","volume":"54","author":"Chakraborty","year":"2013","journal-title":"Mol. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.heares.2013.07.012","article-title":"Noise-induced changes in expression levels of NADPH oxidases in the cochlea","volume":"304","author":"Vlajkovic","year":"2013","journal-title":"Hear. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3766\/jaaa.24.6.3","article-title":"Reduction in impulse noise-induced permanent threshold shift with intracochlear application of an NADPH oxidase inhibitor","volume":"24","author":"Bielefeld","year":"2013","journal-title":"J. Am. Acad. Audiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5977","DOI":"10.2174\/1381612821666151029112421","article-title":"Nox3-targeted therapies for inner ear pathologies","volume":"21","author":"Rousset","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s11010-013-1773-9","article-title":"Advanced glycation end products delay corneal epithelial wound healing through reactive oxygen species generation","volume":"383","author":"Shi","year":"2013","journal-title":"Mol. Cell. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/lary.20940","article-title":"Expression of advanced glycation end\u2014product receptors in the cochlea","volume":"120","author":"Hanusek","year":"2010","journal-title":"Laryngoscope"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"484","DOI":"10.3389\/fimmu.2020.00484","article-title":"Targeting inflammation driven by HMGB1","volume":"11","author":"Yang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1089\/ars.2010.3356","article-title":"High-mobility group box 1, oxidative stress, and disease","volume":"14","author":"Tang","year":"2011","journal-title":"Antioxid. redox Signal."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"105779","DOI":"10.1016\/j.intimp.2019.105779","article-title":"SIRT1-regulated HMGB1 release is partially involved in TLR4 signal transduction: A possible anti-neuroinflammatory mechanism of resveratrol in neonatal hypoxic-ischemic brain injury","volume":"75","author":"Le","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_43","first-page":"459","article-title":"Resveratrol protects against asthma\u2014Induced airway inflammation and remodeling by inhibiting the HMGB1\/TLR4\/NF-\u03baB pathway","volume":"18","author":"Jiang","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.chembiol.2007.03.007","article-title":"Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities","volume":"14","author":"Mollica","year":"2007","journal-title":"Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S0196-0709(82)80016-1","article-title":"Transport characteristics of the blood\u2014Perilymph barrier","volume":"3","author":"Juhn","year":"1982","journal-title":"Am. J. Otolaryngol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1001\/archotol.1982.00790530006003","article-title":"Immunologic study on the inner ear. Immunoglobulins in perilymph","volume":"108","author":"Mogi","year":"1982","journal-title":"Arch. Otolaryngol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/S0196-0709(85)80076-4","article-title":"Inner ear immunology","volume":"6","author":"Mogi","year":"1985","journal-title":"Am. J. Otolaryngol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/0014-4886(90)90144-H","article-title":"A saturable mechanism for transport of immunoglobulin G across the blood-brain barrier of the guinea pig","volume":"107","author":"Zlokovic","year":"1990","journal-title":"Exp. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.neuroscience.2018.05.010","article-title":"HMGB1 neutralization attenuates hippocampal neuronal death and cognitive impairment in rats with chronic cerebral hypoperfusion via suppressing inflammatory responses and oxidative stress","volume":"383","author":"Hei","year":"2018","journal-title":"Neuroscience"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.jphs.2019.04.006","article-title":"Anti-HMGB1 monoclonal antibody therapy for a wide range of CNS and PNS diseases","volume":"140","author":"Nishibori","year":"2019","journal-title":"J. Pharmacol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1016\/j.jid.2019.03.1148","article-title":"Oxidative stress-induced hmgb1 release from melanocytes: A paracrine mechanism underlying the cutaneous inflammation in vitiligo","volume":"139","author":"Cui","year":"2019","journal-title":"J. Investig. Dermatol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/4\/810\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:11:19Z","timestamp":1760364679000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/4\/810"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,5]]},"references-count":51,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["cells10040810"],"URL":"https:\/\/doi.org\/10.3390\/cells10040810","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,5]]}}}