{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T16:40:53Z","timestamp":1776789653639,"version":"3.51.2"},"reference-count":87,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Heinsius Houbolt Foundation and the Royal National Institute for Deaf People","award":["No number"],"award-info":[{"award-number":["No number"]}]},{"name":"MD\/PhD scholarship from the Junior Scientific Masterclass (Graduate School of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands)","award":["16-59"],"award-info":[{"award-number":["16-59"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Age-related hearing loss (ARHL) or presbycusis is a prevalent condition associated with social isolation, cognitive impairment, and dementia. Age-related changes in the cochlea, the auditory portion of the inner ear, are the primary cause of ARHL. Unfortunately, there are currently no pharmaceutical approaches to treat ARHL. To examine the biological processes underlying age-related changes in the cochlea and identify candidate drugs for rapid repurposing to treat ARHL, we utilized bulk RNA sequencing to obtain transcriptomes from the functional substructures of the cochlea\u2014the sensorineural structures, including the organ of Corti and spiral ganglion neurons (OC\/SGN) and the stria vascularis and spiral ligament (SV\/SL)\u2014in young (6-week-old) and old (2-year-old) C57BL\/6 mice. Transcriptomic analyses revealed both overlapping and unique patterns of gene expression and gene enrichment between substructures and with ageing. Based on these age-related transcriptional changes, we queried the protein products of genes differentially expressed with ageing in DrugBank and identified 27 FDA\/EMA-approved drugs that are suitable to be repurposed to treat ARHL. These drugs target the protein products of genes that are differentially expressed with ageing uniquely in either the OC\/SGN or SV\/SL and that interrelate diverse biological processes. Further transcriptomic analyses revealed that most genes differentially expressed with ageing in both substructures encode protein products that are promising drug target candidates but are, nevertheless, not yet linked to approved drugs. Thus, with this study, we apply a novel approach to characterize the druggable genetic landscape for ARHL and propose a list of drugs to test in pre-clinical studies as potential treatment options for ARHL.<\/jats:p>","DOI":"10.3390\/biom12040498","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T15:31:21Z","timestamp":1648222281000},"page":"498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3611-2939","authenticated-orcid":false,"given":"Nick M. A.","family":"Schubert","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"},{"name":"Graduate School of Medical Sciences Research School of Behavioural and Cognitive Neurosciences, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"van Tuinen","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1873-2707","authenticated-orcid":false,"given":"Sonja J.","family":"Pyott","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"},{"name":"Graduate School of Medical Sciences Research School of Behavioural and Cognitive Neurosciences, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1016\/S0140-6736(16)31678-6","article-title":"Global, Regional, and National Incidence, Prevalence, and Years Lived with Disability for 310 Diseases and Injuries, 1990\u20132015: A Systematic Analysis for the Global Burden of Disease Study 2015","volume":"388","author":"Vos","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/S0140-6736(21)00516-X","article-title":"Hearing Loss Prevalence and Years Lived with Disability, 1990\u20132019: Findings from the Global Burden of Disease Study 2019","volume":"397","author":"Haile","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/path.2102","article-title":"Ageing and Hearing Loss","volume":"211","author":"Liu","year":"2007","journal-title":"J. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1093\/geront\/43.5.661","article-title":"The Impact of Hearing Loss on Quality of Life in Older Adults","volume":"43","author":"Dalton","year":"2003","journal-title":"Gerontologist"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1001\/jamaoto.2020.0674","article-title":"Health-Related Quality of Life Changes Associated With Hearing Loss","volume":"146","author":"Dixon","year":"2020","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1001\/jamaoto.2017.2513","article-title":"Association of Age-Related Hearing Loss With Cognitive Function, Cognitive Impairment, and Dementia: A Systematic Review and Meta-Analysis","volume":"144","author":"Loughrey","year":"2018","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/nrd4533","article-title":"New Treatment Options for Hearing Loss","volume":"14","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_8","first-page":"CD012023","article-title":"Hearing Aids for Mild to Moderate Hearing Loss in Adults","volume":"9","author":"Ferguson","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nrn3744","article-title":"Is the Din Really Harmless? Long-Term Effects of Non-Traumatic Noise on the Adult Auditory System","volume":"15","author":"Edeline","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6357","DOI":"10.1523\/JNEUROSCI.0937-20.2020","article-title":"Age-Related Hearing Loss Is Dominated by Damage to Inner Ear Sensory Cells, Not the Cellular Battery That Powers Them","volume":"40","author":"Wu","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4439","DOI":"10.1523\/JNEUROSCI.3238-20.2021","article-title":"Primary Neural Degeneration in Noise-Exposed Human Cochleas: Correlations with Outer Hair Cell Loss and Word-Discrimination Scores","volume":"41","author":"Wu","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1097\/01.mlg.0000234940.33569.39","article-title":"Age-Dependent Degeneration of the Stria Vascularis in Human Cochleae","volume":"116","author":"Suzuki","year":"2006","journal-title":"Laryngoscope"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.3389\/fnins.2021.680856","article-title":"Age-Related Changes in the Cochlea and Vestibule: Shared Patterns and Processes","volume":"15","author":"Paplou","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.ajhg.2019.09.008","article-title":"GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank","volume":"105","author":"Wells","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.heares.2018.05.002","article-title":"Animal Model Studies Yield Translational Solutions for Cochlear Drug Delivery","volume":"368","author":"Frisina","year":"2018","journal-title":"Hear. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1097\/MAO.0000000000001427","article-title":"Emerging Therapies for Sensorineural Hearing Loss","volume":"38","author":"Crowson","year":"2017","journal-title":"Otol. Neurotol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chester, J., Johnston, E., Walker, D., Jones, M., Ionescu, C.M., Wagle, S.R., Kovacevic, B., Brown, D., Mikov, M., and Mooranian, A. (2021). A Review on Recent Advancement on Age-Related Hearing Loss: The Applications of Nanotechnology, Drug Pharmacology, and Biotechnology. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13071041"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug Repurposing: Progress, Challenges and Recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug Repositioning: Identifying and Developing New Uses for Existing Drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"44450","DOI":"10.1038\/srep44450","article-title":"Effects of Cdh23 Single Nucleotide Substitutions on Age-Related Hearing Loss in C57BL\/6 and 129S1\/Sv Mice and Comparisons with Congenic Strains","volume":"7","author":"Johnson","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s10162-007-0098-3","article-title":"Age-Related Hearing Loss in C57BL\/6J Mice Has Both Frequency-Specific and Non-Frequency-Specific Components That Produce a Hyperacusis-Like Exaggeration of the Acoustic Startle Reflex","volume":"8","author":"Ison","year":"2007","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"a033217","DOI":"10.1101\/cshperspect.a033217","article-title":"Age-Related Hearing Loss","volume":"9","author":"Bowl","year":"2019","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1038\/s41598-019-39119-z","article-title":"Sodium-Activated Potassium Channels Shape Peripheral Auditory Function and Activity of the Primary Auditory Neurons in Mice","volume":"9","author":"Reijntjes","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8975","DOI":"10.1523\/JNEUROSCI.1554-17.2017","article-title":"Wnt9a Can Influence Cell Fates and Neural Connectivity across the Radial Axis of the Developing Cochlea","volume":"37","author":"Munnamalai","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the Tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2016). Ggplot2: Elegant Graphics for Data Analysis, Springer International Publishing. [2nd ed.]. Use R!.","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"ref_28","unstructured":"Kolde, R. (2022, March 21). Pheatmap: Pretty Heatmaps, Version 1.0.12. Available online: https:\/\/CRAN.R-project.org\/package=pheatmap."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"W191","DOI":"10.1093\/nar\/gkz369","article-title":"G:Profiler: A Web Server for Functional Enrichment Analysis and Conversions of Gene Lists (2019 Update)","volume":"47","author":"Raudvere","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"D1334","DOI":"10.1093\/nar\/gkaa993","article-title":"TCRD and Pharos 2021: Mining the Human Proteome for Disease Biology","volume":"49","author":"Sheils","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A Major Update to the DrugBank Database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"ref_32","unstructured":"Ali, M., Ezzat, A., Zhu, H., and Mendelsohn, E. (2021, January 19). Dbparser: \u201cDrugBank\u201d Database XML Parser, Version 1.2.0. Available online: https:\/\/cran.r-project.org\/web\/packages\/dbparser\/index.html."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pomaznoy, M., Ha, B., and Peters, B. (2018). GOnet: A Tool for Interactive Gene Ontology Analysis. BMC Bioinform., 19.","DOI":"10.1186\/s12859-018-2533-3"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D1083","DOI":"10.1093\/nar\/gkx1042","article-title":"Human Ageing Genomic Resources: New and Updated Databases","volume":"46","author":"Tacutu","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_35","unstructured":"Van Camp, G., and Smith, R. (2021, October 13). Hereditary Hearing Loss. Available online: https:\/\/hereditaryhearingloss.org."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s10162-016-0589-1","article-title":"Application of Mouse Models to Research in Hearing and Balance","volume":"17","author":"Ohlemiller","year":"2016","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1038\/nature04844","article-title":"Increased Cell-to-Cell Variation in Gene Expression in Ageing Mouse Heart","volume":"441","author":"Bahar","year":"2006","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1126\/science.aah4115","article-title":"Aging Increases Cell-to-Cell Transcriptional Variability upon Immune Stimulation","volume":"355","author":"Eling","year":"2017","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.mod.2005.03.002","article-title":"Otolith Matrix Proteins OMP-1 and Otolin-1 Are Necessary for Normal Otolith Growth and Their Correct Anchoring onto the Sensory Maculae","volume":"122","author":"Murayama","year":"2005","journal-title":"Mech. Dev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.cell.2018.07.007","article-title":"Sensory Neuron Diversity in the Inner Ear Is Shaped by Activity","volume":"174","author":"Shrestha","year":"2018","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1016\/j.cell.2018.07.008","article-title":"Hair Cell Mechanotransduction Regulates Spontaneous Activity and Spiral Ganglion Subtype Specification in the Auditory System","volume":"174","author":"Sun","year":"2018","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e9737","DOI":"10.7717\/peerj.9737","article-title":"Transcriptomic Analysis Highlights Cochlear Inflammation Associated with Age-Related Hearing Loss in C57BL\/6 Mice Using next Generation Sequencing","volume":"8","author":"Su","year":"2020","journal-title":"PeerJ"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8605","DOI":"10.1128\/MCB.21.24.8605-8614.2001","article-title":"Normal Light Response, Photoreceptor Integrity, and Rhodopsin Dephosphorylation in Mice Lacking Both Protein Phosphatases with EF Hands (PPEF-1 and PPEF-2)","volume":"21","author":"Ramulu","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wang, J., and Puel, J.-L. (2020). Presbycusis: An Update on Cochlear Mechanisms and Therapies. J. Clin. Med., 9.","DOI":"10.3390\/jcm9010218"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lewis, M.A., Nolan, L.S., Cadge, B.A., Matthews, L.J., Schulte, B.A., Dubno, J.R., Steel, K.P., and Dawson, S.J. (2018). Whole Exome Sequencing in Adult-Onset Hearing Loss Reveals a High Load of Predicted Pathogenic Variants in Known Deafness-Associated Genes and Identifies New Candidate Genes. BMC Med. Genom., 11.","DOI":"10.1186\/s12920-018-0395-1"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"31278","DOI":"10.1073\/pnas.2010782117","article-title":"Ultrarare Heterozygous Pathogenic Variants of Genes Causing Dominant Forms of Early-Onset Deafness Underlie Severe Presbycusis","volume":"117","author":"Boucher","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nrd.2018.14","article-title":"Unexplored Therapeutic Opportunities in the Human Genome","volume":"17","author":"Oprea","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/MAO.0000000000002194","article-title":"Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders","volume":"40","author":"Schilder","year":"2019","journal-title":"Otol. Neurotol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/s10162-014-0479-3","article-title":"Distribution of Na,K-ATPase \u03b1 Subunits in Rat Vestibular Sensory Epithelia","volume":"15","author":"Schuth","year":"2014","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3389\/fcell.2015.00066","article-title":"Transcriptional Regulators of Na,K-ATPase Subunits","volume":"3","author":"Li","year":"2015","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1080\/02713680902829624","article-title":"The Effects of Dexamethasone on the Na,K-ATPase Activity and Pump Function of Corneal Endothelial Cells","volume":"34","author":"Hatou","year":"2009","journal-title":"Curr. Eye Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s004050000304","article-title":"Occurrence of NaK-ATPase Isoforms during Rat Inner Ear Development and Functional Implications","volume":"258","author":"Peters","year":"2001","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0378-5955(92)90034-K","article-title":"Lateral Wall Na, K-ATPase and Endocochlear Potentials Decline with Age in Quiet-Reared Gerbils","volume":"61","author":"Schulte","year":"1992","journal-title":"Hear. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.joto.2016.10.001","article-title":"Ototoxic Effects and Mechanisms of Loop Diuretics","volume":"11","author":"Ding","year":"2016","journal-title":"J. Otol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.heares.2016.03.011","article-title":"The Afferent Signaling Complex: Regulation of Type I Spiral Ganglion Neuron Responses in the Auditory Periphery","volume":"336","author":"Reijntjes","year":"2016","journal-title":"Hear. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.arr.2017.10.002","article-title":"Chronic Inflammation\u2014Inflammaging\u2014in the Ageing Cochlea: A Novel Target for Future Presbycusis Therapy","volume":"40","author":"Watson","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.heares.2011.08.006","article-title":"Physiopathology of the Cochlear Microcirculation","volume":"282","author":"Shi","year":"2011","journal-title":"Hear. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"9911","DOI":"10.1073\/pnas.1402261111","article-title":"Role of Cysteinyl Leukotriene Signaling in a Mouse Model of Noise-Induced Cochlear Injury","volume":"111","author":"Park","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.nbd.2011.10.018","article-title":"Transcriptional Changes in Adhesion-Related Genes Are Site-Specific during Noise-Induced Cochlear Pathogenesis","volume":"45","author":"Cai","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1159\/000341989","article-title":"Idiopathic Sudden Sensorineural Hearing Loss: Classic Cardiovascular and New Genetic Risk Factors","volume":"17","author":"Ballesteros","year":"2012","journal-title":"Audiol. Neurootol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1111\/j.0906-6705.2004.00145.x","article-title":"Human Leukocyte Elastase and Cathepsin G Are Specific Inhibitors of C5a-Dependent Neutrophil Enzyme Release and Chemotaxis","volume":"13","author":"Tralau","year":"2004","journal-title":"Exp. Dermatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"15167","DOI":"10.1038\/s41598-020-72181-6","article-title":"The Immune Response after Noise Damage in the Cochlea Is Characterized by a Heterogeneous Mix of Adaptive and Innate Immune Cells","volume":"10","author":"Rai","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.joto.2016.06.001","article-title":"A Novel PIK3CD C896T Mutation Detected in Bilateral Sudden Sensorineural Hearing Loss Using next Generation Sequencing: An Indication of Primary Immunodeficiency","volume":"11","author":"Zou","year":"2016","journal-title":"J. Otol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"390601","DOI":"10.1155\/2014\/390601","article-title":"Progress and Prospects in Human Genetic Research into Age-Related Hearing Impairment","volume":"2014","author":"Uchida","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.plefa.2008.11.001","article-title":"A Polymorphism in the Cyclooxygenase 1 Gene Is Associated with Decreased Inflammatory Prostaglandin F2alpha Formation and Lower Risk of Cardiovascular Disease","volume":"80","author":"Helmersson","year":"2009","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/09537100500441101","article-title":"Aspirin Resistance in Coronary Artery Disease Is Correlated to Elevated Markers for Oxidative Stress but Not to the Expression of Cyclooxygenase (COX) 1\/2, a Novel COX-1 Polymorphism or the PlA(1\/2) Polymorphism","volume":"17","author":"Kranzhofer","year":"2006","journal-title":"Platelets"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1016\/j.neurobiolaging.2006.06.025","article-title":"Oxidative Imbalance in the Aging Inner Ear","volume":"28","author":"Jiang","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e022854","DOI":"10.1136\/bmjopen-2018-022854","article-title":"Gout and Hearing Impairment in the Elderly: A Retrospective Cohort Study Using the US Medicare Claims Data","volume":"8","author":"Singh","year":"2018","journal-title":"BMJ Open"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.heares.2004.08.002","article-title":"Reduction of Acute Cisplatin Ototoxicity and Nephrotoxicity in Rats by Oral Administration of Allopurinol and Ebselen","volume":"201","author":"Lynch","year":"2005","journal-title":"Hear. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"227","DOI":"10.3109\/14992020309101318","article-title":"Effect over Time of Allopurinol on Noise-Induced Hearing Loss in Guinea Pigs","volume":"42","author":"Sequino","year":"2003","journal-title":"Int. J. Audiol."},{"key":"ref_71","unstructured":"Nakao, K., Minato, N., and Uemoto, S. (2015). Diverting glycolysis to combat oxidative stress. Innovative Medicine: Basic Research and Development, Springer."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e13275","DOI":"10.1111\/acel.13275","article-title":"G6PD Overexpression Protects from Oxidative Stress and Age-Related Hearing Loss","volume":"19","author":"Celaya","year":"2020","journal-title":"Aging Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"476","DOI":"10.3109\/14756360903257900","article-title":"Effects of Some Drugs on Human Erythrocyte 6-Phosphogluconate Dehydrogenase: An in Vitro Study","volume":"25","author":"Akkemik","year":"2010","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0092-8674(00)00112-4","article-title":"Signaling Networks: The Origins of Cellular Multitasking","volume":"103","author":"Jordan","year":"2000","journal-title":"Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.bjorl.2018.12.009","article-title":"Osteoporosis and Hearing Loss: Findings from the Korea National Health and Nutrition Examination Survey 2009\u20132011","volume":"86","author":"Yoo","year":"2020","journal-title":"Braz. J. Otorhinolaryngol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"109758","DOI":"10.1016\/j.celrep.2021.109758","article-title":"A Cell-Type-Specific Atlas of the Inner Ear Transcriptional Response to Acoustic Trauma","volume":"36","author":"Milon","year":"2021","journal-title":"Cell Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1038\/nm.2064","article-title":"Role of NMDA Receptor-Dependent Activation of SREBP1 in Excitotoxic and Ischemic Neuronal Injuries","volume":"15","author":"Taghibiglou","year":"2009","journal-title":"Nat. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6366","DOI":"10.1523\/JNEUROSCI.5126-14.2015","article-title":"Gene Expression by Mouse Inner Ear Hair Cells during Development","volume":"35","author":"Scheffer","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e007322","DOI":"10.1161\/CIRCEP.119.007322","article-title":"Genetic Discovery of ATP-Sensitive K+ Channels in Cardiovascular Diseases","volume":"12","author":"Huang","year":"2019","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4457","DOI":"10.1038\/s41467-019-12428-7","article-title":"ABCC9-Related Intellectual Disability Myopathy Syndrome Is a KATP Channelopathy with Loss-of-Function Mutations in ABCC9","volume":"10","author":"Smeland","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2147\/TACG.S155022","article-title":"Novel Mutation in ABBC9 Gene Associated with Congenital Hypertrichosis and Acromegaloid Facial Features, without Cardiac or Skeletal Anomalies: A New Phenotype","volume":"11","author":"Pachajoa","year":"2018","journal-title":"Appl. Clin. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/ng1226","article-title":"Association of Cadherin 23 with Polygenic Inheritance and Genetic Modification of Sensorineural Hearing Loss","volume":"35","author":"Zheng","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature10098","article-title":"Global Quantification of Mammalian Gene Expression Control","volume":"473","author":"Busse","year":"2011","journal-title":"Nature"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nbt.2151","article-title":"Use of Genome-Wide Association Studies for Drug Repositioning","volume":"30","author":"Sanseau","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"58","DOI":"10.3389\/fnagi.2015.00058","article-title":"Mechanisms of Sensorineural Cell Damage, Death and Survival in the Cochlea","volume":"7","author":"Wong","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"276","DOI":"10.3389\/fncel.2015.00276","article-title":"Age-Related Hearing Impairment and the Triad of Acquired Hearing Loss","volume":"9","author":"Yang","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/s41592-021-01200-9","article-title":"GEAR: Gene Expression Analysis Resource Portal for Community-Driven, Multi-Omic Data Exploration","volume":"18","author":"Orvis","year":"2021","journal-title":"Nat. Methods"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/4\/498\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:42:56Z","timestamp":1760136176000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/4\/498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,25]]},"references-count":87,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["biom12040498"],"URL":"https:\/\/doi.org\/10.3390\/biom12040498","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,25]]}}}