title: Adjudin protects rodent cochlear hair cells against gentamicin ototoxicity via the SIRT3-ROS pathway.
abstract: Hearing loss resulting from hair cell degeneration is a common disease that affects millions of people worldwide. Strategies to overcome the apparent irreversible hair cell loss in mammals become paramount for hearing protection. Here we reported that, by using a well-established gentamicin-induced hair cell loss model in vitro, adjudin, a multi-functional small molecule drug, protected cochlear hair cells from gentamicin damage. Immunohistochemistry, Western blotting and quantitative RT-PCR analyses revealed that adjudin exerted its otoprotective effects by up-regulating the level of Sirt3, a member of Sirtuin family protein located in mitochondria, which regulates reactive oxygen species (ROS) production in cochlear cells and inhibits the production of ROS and apoptotic cells induced by gentamicin. Sirt3 silencing experiments confirmed that Sirt3-ROS signaling axis mediated hair cell protection against gentamicin by adjudin, at least in part. Furthermore, adjudin's otoprotection effects were also observed in an in vivo gentamicin-injured animal model. Taken together, these findings identify adjudin as a novel otoprotective small molecule via elevating Sirt3 levels and Sirt3 may be of therapeutic value in hair cell protection from ototoxic insults.
authors: 1] State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China [2] School of Biomedical Engineering &Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
authors: Yizhou
authors: Y
authors: Quan
authors: Department of Otolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China.
authors: Li
authors: L
authors: Xia
authors: 1] State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China [2] School of Biomedical Engineering &Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
authors: Jiaxiang
authors: J
authors: Shao
authors: Department of Otolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China.
authors: Shankai
authors: S
authors: Yin
authors: The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, New York, New York, USA.
authors: C Yan
authors: CY
authors: Cheng
authors: 1] State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China [2] School of Biomedical Engineering &Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
authors: Weiliang
authors: W
authors: Xia
authors: 1] State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China [2] School of Biomedical Engineering &Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
authors: Wei-Qiang
authors: WQ
authors: Gao
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D002478:Cells, Cultured; D003051:Cochlea / Q000166:cytology; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism; D005839:Gentamicins / Q000633:toxicity; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D034381:Hearing Loss / Q000188:drug therapy; D006834:Hydrazines / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009925:Organ of Corti / Q000166:cytology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C432482:1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D006834:Hydrazines; D007191:Indazoles; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D056566:Sirtuin 3
references: Auris Nasus Larynx. 2007 Mar;34(1):1-4
references: 16934423
references: Trends Amplif. 2012 Mar;16(1):4-18
references: 22514095
references: Cancer Cell. 2010 Jan 19;17(1):41-52
references: 20129246
references: J Biotechnol. 2007 Jul 15;130(4):455-62
references: 17610977
references: Neuroscience. 2007 Oct 12;149(1):213-22
references: 17869439
references: Biol Pharm Bull. 2009 Feb;32(2):213-9
references: 19182378
references: Neuroscience. 2009 Jun 16;161(1):214-26
references: 19318119
references: Anat Rec (Hoboken). 2012 Nov;295(11):1837-50
references: 23045231
references: J Neuroimmunol. 2013 Jan 15;254(1-2):83-90
references: 23084372
references: Neuron. 2013 Jan 9;77(1):58-69
references: 23312516
references: Hear Res. 2013 Mar;297:42-51
references: 23321648
references: Exp Mol Med. 2013;45:e12
references: 23470714
references: Nat Neurosci. 2000 Jun;3(6):580-6
references: 10816314
references: Biol Reprod. 2001 Aug;65(2):449-61
references: 11466213
references: Hear Res. 2002 Apr;166(1-2):33-43
references: 12062756
references: J Biol Chem. 2003 Jan 31;278(5):3170-5
references: 12419811
references: Hear Res. 2003 Aug;182(1-2):24-33
references: 12948598
references: J Neurosci. 2003 Sep 17;23(24):8596-607
references: 13679429
references: Brain Res. 2004 Jan 30;997(1):40-51
references: 14715148
references: Cancer Res. 1981 Nov;41(11 Pt 1):4661-6
references: 7306982
references: N Engl J Med. 1993 Oct 7;329(15):1092-102
references: 8371732
references: Eur J Neurosci. 1996 Sep;8(9):1897-905
references: 8921280
references: Neuron. 1997 Nov;19(5):947-50
references: 9390507
references: J Neurobiol. 1999 Apr;39(1):29-40
references: 10213451
references: Neuroscience. 2005;131(2):513-21
references: 15708492
references: Free Radic Biol Med. 2006 May 15;40(10):1810-9
references: 16678019
references: Hear Res. 2010 Mar;261(1-2):67-74
references: 20074632
references: Nature. 2010 Mar 4;464(7285):121-5
references: 20203611
references: Cell. 2010 Nov 24;143(5):802-12
references: 21094524
references: J Nutr Biochem. 2011 Sep;22(9):886-94
references: 21190826
references: Neurotox Res. 2011 Nov;20(4):307-19
references: 21455790
references: Nat Rev Mol Cell Biol. 2012 Apr;13(4):225-38
references: 22395773
references: J Biomed Sci. 2009;16:79
references: 19723345