In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period

Sun, Shan; Sun, Mingzhi; Zhang, Yanping; Cheng, Cheng; Waqas, Muhammad; Yu, Huiqian; He, Yingzi; Xu, Bo; Wang, Lei; Wang, Jian; Yin, Shankai; Chai, Renjie; Li, Huawei

doi:10.3389/fncel.2014.00248

Cited by 52 publications

(46 citation statements)

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“…6a,c). Previous studies have reported that cleaved caspase-3 and TUNEL can be used as markers of apoptosis in aminoglycoside-induced HC death303233343536. To confirm our findings, we performed active caspase-3 and TUNEL staining to detect the apoptotic HEI-OC1 cells.…”

Section: Resultssupporting

confidence: 77%

“…To determine whether the c-Myb expression in cochlear HCs was affected by neomycin treatment, C57BL/6 mice were given daily subcutaneous injections of neomycin (200 mg/kg) from P7 to P14, which is the ototoxic-sensitive period in the cochlea32. Mice in the control group were given sterile saline.…”

Section: Resultsmentioning

confidence: 99%

“…Mice in the control group were given sterile saline. At P17, the cochlear sensory epithelium was dissected out, and as reported before, the HC loss after neomycin injection forms a gradient from the apex to the base with the basal turns having greater HC loss than the apical turns32. We chose the middle turn as the representative image (Fig.…”

Section: Resultsmentioning

confidence: 99%

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c-Myb knockdown increases the neomycin-induced damage to hair-cell-like HEI-OC1 cells in vitro

Liu

Fan

et al. 2017

Sci Rep

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c-Myb is a transcription factor that plays a key role in cell proliferation, differentiation, and apoptosis. It has been reported that c-Myb is expressed within the chicken otic placode, but whether c-Myb exists in the mammalian cochlea, and how it exerts its effects, has not been explored yet. Here, we investigated the expression of c-Myb in the postnatal mouse cochlea and HEI-OC1 cells and found that c-Myb was expressed in the hair cells (HCs) of mouse cochlea as well as in cultured HEI-OC1 cells. Next, we demonstrated that c-Myb expression was decreased in response to neomycin treatment in both cochlear HCs and HEI-OC1 cells, suggesting an otoprotective role for c-Myb. We then knocked down c-Myb expression with shRNA transfection in HEI-OC1 cells and found that c-Myb knockdown decreased cell viability, increased expression of pro-apoptotic factors, and enhanced cell apoptosis after neomycin insult. Mechanistic studies revealed that c-Myb knockdown increased cellular levels of reactive oxygen species and decreased Bcl-2 expression, both of which are likely to be responsible for the increased sensitivity of c-Myb knockdown cells to neomycin. This study provides evidence that c-Myb might serve as a new target for the prevention of aminoglycoside-induced HC loss.

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Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

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c-Myb knockdown increases the neomycin-induced damage to hair-cell-like HEI-OC1 cells in vitro

Liu

Fan

et al. 2017

Sci Rep

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“…Ototoxic drugs cause hearing loss by inducing HC apoptosis, primarily by altering the MMP of the mitochondria ( Huang et al, 2000 ; Wu et al, 2002 ; Sun et al, 2015 ; Guan et al, 2016 ; He et al, 2016 ; Yu et al, 2017 ). Mitochondria play an important role in cell metabolism, and aminoglycoside-induced apoptosis is closely related to mitochondrial dysfunction, which leads to decreased MMP and increased ROS ( Joza et al, 2001 ; Chipuk et al, 2004 ; Coffin et al, 2013 ; Sun et al, 2014 , 2015 ; Mei et al, 2015 ). The accumulation of ROS in the mitochondria is an important trigger of apoptosis, and it has been reported that ROS play an important role in noise-induced and ototoxic drug-induced HC damage and hearing loss ( Sun et al, 2014 , 2015 ; Chen et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is important to investigate the molecular mechanism behind aminoglycoside-induced auditory sensory cell damage and to seek effective drugs for preventing and treating aminoglycoside-induced deafness. Several studies have suggested that aminoglycosides induce intrinsic apoptosis of HCs through oxidative stress ( Mangiardi et al, 2004 ; Coffin et al, 2013 ; Sun et al, 2014 , 2015 ; Liu et al, 2016 ), while others have reported that the accumulation of reactive oxygen species (ROS) plays an important role in the death of HCs ( Clerici et al, 1996 ; Choung et al, 2009 ). ROS can be cleared by physiological cellular processes; however, they are harmful when their concentration exceeds the cell’s capacity to remove them ( He et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage

Zhong

et al. 2020

Front. Cell Dev. Biol.

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Aminoglycoside-induced hair cell (HC) loss is one of the most important causes of hearing loss. After entering the inner ear, aminoglycosides induce the production of high levels of reactive oxygen species (ROS) that subsequently activate apoptosis in HCs. Citicoline, a nucleoside derivative, plays a therapeutic role in central nervous system injury and in neurodegenerative disease models, including addictive disorders, stroke, head trauma, and cognitive impairment in the elderly, and has been widely used in the clinic as an FDA approved drug. However, its effect on auditory HCs remains unknown. Here, we used HC-like HEI-OC-1 cells and whole organ explant cultured mouse cochleae to explore the effect of citicoline on aminoglycoside-induced HC damage. Consistent with previous reports, both ROS levels and apoptosis were significantly increased in neomycin-induced cochlear HCs and HEI-OC-1 cells compared to undamaged controls. Interestingly, we found that co-treatment with citicoline significantly protected against neomycin-induced HC loss in both HEI-OC-1 cells and whole organ explant cultured cochleae. Furthermore, we demonstrated that citicoline could significantly reduce neomycin-induced mitochondrial dysfunction and inhibit neomycin-induced ROS accumulation and subsequent apoptosis. Thus, we conclude that citicoline can protect against neomycin-induced HC loss by inhibiting ROS aggregation and thus preventing apoptosis in HCs, and this suggests that citicoline might serve as a potential therapeutic drug in the clinic to protect HCs.

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Hippo/YAP signaling pathway protects against neomycin-induced hair cell damage in the mouse cochlea

Wang

Dong

Gao

et al. 2022

Cell. Mol. Life Sci.

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The Hippo/Yes-associated protein (YAP) signaling pathway has been shown to be able to maintain organ size and homeostasis by regulating cell proliferation, differentiation, and apoptosis. The abuse of aminoglycosides is one of the main causes of sensorineural hearing loss (SSNHL). However, the role of the Hippo/YAP signaling pathway in cochlear hair cell (HC) damage protection in the auditory field is still unclear. In this study, we used the YAP agonist XMU-MP-1 (XMU) and the inhibitor Verteporfin (VP) to regulate the Hippo/YAP signaling pathway in vitro. We showed that YAP overexpression reduced neomycin-induced HC loss, while downregulated YAP expression increased HC vulnerability after neomycin exposure in vitro. We next found that activation of YAP expression inhibited C-Abl-mediated cell apoptosis, which led to reduced HC loss. Many previous studies have reported that the level of reactive oxygen species (ROS) is significantly increased in cochlear HCs after neomycin exposure. In our study, we also found that YAP overexpression significantly decreased ROS accumulation, while downregulation of YAP expression increased ROS accumulation. In summary, our results demonstrate that the Hippo/YAP signaling pathway plays an important role in reducing HC injury and maintaining auditory function after aminoglycoside exposure. YAP overexpression could protect against neomycin-induced HC loss by inhibiting C-Abl-mediated cell apoptosis and decreasing ROS accumulation, suggesting that YAP could be a novel therapeutic target for aminoglycosides-induced sensorineural hearing loss in the clinic.

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In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period

Cited by 52 publications

References 46 publications

c-Myb knockdown increases the neomycin-induced damage to hair-cell-like HEI-OC1 cells in vitro

c-Myb knockdown increases the neomycin-induced damage to hair-cell-like HEI-OC1 cells in vitro

Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage

Hippo/YAP signaling pathway protects against neomycin-induced hair cell damage in the mouse cochlea

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