The diagnosis and treatment of a variant type of auricular sinus: postauricular sinus.

OBJECTIVES: To make otolaryngologists aware of the variant types of auricular sinus, we have performed a systematic review of patient diagnoses and presented our operative experiences. METHODS: From 2009 to 2013 in Sun Yat-Sen Memorial Hospital, there was a total of 20 children with the variant type of auricular sinuses including the comprehensive group. Postauricular sinuses have pits located posterior to the imaginary vertical line that is tangent to the external auditory canal. Sinuses that penetrate the cartilage and cause postauricular swelling or skin defects characterize type 1 of the variant type, while sinuses that adhere to the cartilage and cause preauricular or auricular swelling or skin defects characterize type 2. Patients with pits both anterior to and posterior to the imaginary vertical line comprise the comprehensive group. The patients who had infected underwent auricular sinusectomy using a dual approach, with accurate fistula tracing and proper cartilage removal. RESULTS: Sixteen children who had infected sinus underwent surgery, while the other four were asymptomatic. Ten children (62.5%) of 16 patients were diagnosed as type 1 of the variant type, 2 (12.5%) as type 2. Four children (25%) were diagnosis as the comprehensive group. The asymptomatic could not be defined as the sinuses location were unknown. Sixteen children (100%) of 16 patients who underwent surgery had a history of misdiagnosis and treatment. These patients did not experience recurrence over a 5-year follow-up period. CONCLUSION: The locations of pits and sinuses help to categorize the different types of auricular sinus. The effective method that we have described should be considered a viable way to reduce recurrence.

Exercise Training at Maximal Fat Oxidation Intensity for Older Women with Type 2 Diabetes.

The purpose of this study was to investigate the pleiotropic effects of 12 weeks of supervised exercise training at maximal fat oxidation (FATmax) intensity on body composition, lipid profile, glycemic control, insulin sensitivity and serum adipokine levels in older women with type 2 diabetes. Thirty-one women with type 2 diabetes, aged 60 to 69 years, were randomly allocated into exercise and control groups. Body composition, lipid profile, blood glucose, insulin resistance and serum leptin and adiponectin concentrations were measured before and after the intervention. Exercise group (n=16) walked at individualized FATmax intensities for 1 h/day for 3 days/week over 12 weeks. No dietary intervention was introduced during the experimental period. Maximal fat oxidation rate was 0.37±0.10 g/min, and occurred at 37.3±7.3% of the estimated VO2max. Within the exercise group, significant improvements were observed for most of the measured variables compared to non-exercising controls; in particular, the FATmax program reduced body fat% (p<0.001), visceral fat% (p<0.001), and insulin resistance (p<0.001). There was no significant change in daily energy intake for all participants during the intervention period. These results suggest that individualized FATmax training is an effective exercise training intensity for managing type 2 diabetes in older women.

Resveratrol Promotes Recovery of Hearing following Intense Noise Exposure by Enhancing Cochlear SIRT1 Activity.

The sirtuin SIRT1 is a highly conserved nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase known to have protective effects against a wide range of neurological disorders. In the present study, we discovered that C57BL/6 mice fed a long-term diet supplemented with high-dose resveratrol exhibited increased cochlear SIRT1 activity and presented a better recovery of hearing and less loss of hair cells after intense noise exposure compared with those fed a standard chew. Moreover, resveratrol attenuated cochlear SIRT1 decrease and reduced oxidative stress in the cochlea after noise exposure. These results suggest a considerable therapeutic potential of resveratrol for the treatment of noise-induced hearing loss.

Effect of repetitive transcranial magnetic stimulation on auditory function following acoustic trauma.

Repetitive transcranial magnetic stimulation (rTMS) is one form of non-invasive brain stimulation and increasingly shows neuroprotection in multiple neurological disorders. However, the potential of rTMS for protective action on auditory function following acoustic trauma has not been investigated. Here, we examined effect of TMS on hearing conservation, neurons survival and brain-derived neurotrophin factor (BDNF) expression in the cochlea and auditory cortex following acoustic trauma in rats. Wistar rats were exposed to intense pure tone noise (10 kHz, 120 dB SPL for 2 h) followed by rTMS treatment or sham treatment (handling control) daily for 14 days. Auditory brainstem response revealed there was no significant difference in hearing threshold shifts between rTMS- and sham-treated rats, although rTMS-treated rats showed less neuron loss in the auditory cortex in comparison with sham rats. Additionally, acoustic trauma increased BDNF expression in the cochlea and auditory cortex, and this elevation could be attenuated by rTMS treatment. Our results suggest present regiment of rTMS does not protect hearing against acoustic trauma, but maybe have implications for tinnitus treatment.

Reactive Oxygen Species-Related Disruptions to Cochlear Hair Cell and Stria Vascularis Consequently Leading to Radiation-Induced Sensorineural Hearing Loss.

Aims: Radiation-induced sensorineural hearing loss (RISNHL) is one of the major side effects of radiotherapy for head and neck cancers. At present, no effective clinical treatment or prevention is available for RISNHL. This study thus aimed to investigate the cochlear pathology so that the underlying mechanisms of RISNHL may be elucidated, consequently paving the way for potential protective strategies to be developed. Results: Functional and morphological impairment in the stria vascularis (SV) was observed after irradiation (IR), as indicated by endocochlear potential (EP) reduction, hyperpermeability, and SV atrophy. The expression of zonulae occludins-1 was found to have decreased after IR. The loss of outer hair cells (OHCs) occurred later than SV damage. The disruption to the SV and OHCs could be attributed to reactive oxygen species (ROS)-related damage. In addition, EP shifts and the loss of OHCs were reduced when ROS was reduced by N-acetylcysteine (NAC) in C57BL/6 mice, attenuating auditory threshold shifts. Innovation: The damage to the SV was found to occur before OHC loss. ROS-related damage accounted for SV damage and OHC loss. The incidences of SV damage and OHC loss were decreased through ROS modulation by NAC, subsequently preventing RISNHL, suggesting the possible role of NAC as a possible protective agent against RISNHL. Conclusion: The findings from this study suggest oxidative stress-induced early SV injury and late OHC loss to be the key factors leading to RISNHL. NAC prevents IR-induced OHC loss, and attenuates auditory brainstem response and EP shifts by regulating the level of oxidative stress. Antioxid. Redox Signal. 40, 470-491.

Promoting TFEB nuclear localization with curcumin analog C1 attenuates sensory hair cell injury and delays age-related hearing loss in C57BL/6 mice.

Sensory hair cell (HC) injuries, especially outer hair cell (OHC) loss, are well-documented to be the primary pathology of age-related hearing loss (AHL). Recent studies have demonstrated that autophagy plays an important role in HC injury in the inner ear. In our previous works, a decline in autophagy levels and HC loss were found to occur simultaneously in the inner ears of aged C57BL/6 mice, and the administration of rapamycin promoted autophagy levels, which reduced OHC loss and delayed AHL, but the underlying mechanism of autophagy in AHL has not been well elucidated. Transcription factor EB (TFEB), an autophagy regulator and the downstream target of mammalian target of rapamycin (mTOR), is involved in the pathological development of neurodegenerative disease. This study would address the link between autophagy and TFEB in aged C57BL/6 mouse cochleae and clarify the effect of the TFEB activator curcumin analog C1 (C1) in aged cochleae. Decreased TFEB nuclear localization (p = 0.0371) and autophagy dysfunction (p = 0.0273) were observed in the cochleae of aged C57BL/6 mice that exhibited AHL, HCs loss and HCs senescence. Treatment with C1 promoted TFEB nuclear localization and restored autophagy, subsequently alleviating HC injury and delaying AHL. The protective effect of C1 on HEI-OC1 cells against autophagy disorder and aging induced by D-galactose was abolished by chloroquine, which is one of the commonly used autophagy inhibitors. Overall, our results demonstrated that the capacity to perform autophagy is mediated by the nuclear localization of TFEB in aged C57BL/6 mouse cochleae. C1 promotes the nuclear localization of TFEB, subsequently alleviating HC injury and delaying AHL by restoring the impaired autophagy function. TFEB may serve as a new therapeutic target for AHL treatment.

miR-34a/ATG9A/TFEB Signaling Modulates Autophagy in Cochlear Hair Cells and Correlates with Age-related Hearing Loss.

Our previous studies revealed that miR-34a suppresses autophagy in the ageing cochlea, which correlates with cochlear hair cell loss and age-related hearing loss (AHL). However, the mechanisms underlying miR-34a regulation of autophagy in the cochlea remain unclear. Here, we show that nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy, was regulated by miR-34a in HEI-OC1 cells. Moreover, ATG9A, one of the main targets of miR-34a, was shown to interact with TFEB and thus promote its nuclear translocation in HEI-OC1 cells. Rapamycin rescued the inhibition of TFEB nuclear translocation induced by miR-34a/ATG9A activation, restored autophagic flux and consequently prevented HEI-OC1 cell death. Long-term supplementation with rapamycin attenuated outer hair cells (OHCs) and inner hair cell synaptic ribbons, and delayed AHL in C57BL/6 mice. Most importantly, rapamycin partially restored TFEB's nuclear localization and autophagic flux in OHCs of the ageing cochlea. These findings open new avenues for protection against AHL through miR-34a/ATG9a/TFEB modulation of autophagy.

Autophagy-dependent ferroptosis contributes to cisplatin-induced hearing loss.

Cisplatin-induced hearing loss is a common side effect of cisplatin chemotherapy, for which clinical therapy remains unavailable. Apoptosis of hair cells is considered the primary cause of cisplatin-induced ototoxicity; however, inhibiting apoptosis can only partially restore cisplatin-induced hearing loss. Therefore, auditory cell death caused by cisplatin damage requires further study. Ferroptosis, a novel form of regulated cell death, has been shown to play a role in the mechanism of cisplatin toxicity. In this study, we observed proferroptotic alterations (lipid peroxidation and impaired antioxidant capacity) in the cochleae of C57BL/6 mice after cisplatin damage, verifying the induction of ferroptosis. Using the HEI-OC1 cell line, we observed that cisplatin induced proferroptotic alterations and activated ferritinophagy (specific autophagy pathway). Employing chloroquine, we confirmed that the blockage of autophagy remarkably alleviated cisplatin-induced ferroptosis in HEI-OC1 cells; therefore, the induction of ferroptosis in cisplatin-treated auditory cells was dependent on the activation of autophagy. In addition, the ferroptosis inhibitor ferrostatin-1 and iron chelator deferoxamine significantly attenuated cisplatin-induced cytotoxicity in HEI-OC1 cells and cochlear explants. Moreover, pharmacologically inhibiting ferroptosis using ferrostatin-1 significantly decreased the auditory cell loss and, notably, attenuated hearing loss in C57BL/6 mice after cisplatin damage. Collectively, these findings indicate that autophagy-dependent ferroptosis plays an integrated role in the mechanism of cisplatin-induced hearing loss.

Mitochondrial dysfunction resulting from the down-regulation of bone morphogenetic protein 5 may cause microtia.

BACKGROUND: Bone morphogenetic protein 5 (BMP5) has been identified as one of the important risk factors for microtia; however, the link between them has yet to be clarified. In this study, we aimed to demonstrate the relationship of BMP5 with mitochondrial function and investigate the specific role of mitochondria in regulating microtia development. METHODS: BMP5 expression was measured in auricular cartilage tissues from patients with and without microtia. The effects of BMP5 knockdown on cellular function and mitochondrial function were also analyzed in vitro. Changes in genome-wide expression profiles were measured in BMP5-knockdown cells. Finally, the specific impact of BMP5 down-regulation on mitochondrial fat oxidation was analyzed in vitro. RESULTS: BMP5 expression was down-regulated in the auricular cartilage tissues of microtia patients. BMP5 down-regulation inhibited various cellular functions in vitro, including cell proliferation, mobility, and cytoactivity. The functional integrity of mitochondria was also damaged, accompanied by a decrease in mitochondrial membrane potential, reactive oxygen species (ROS) neutralization, and reduced adenosine triphosphate (ATP) production. Carnitine O-palmitoyltransferase 2 and diacylglycerol acyltransferase 2, two of the key regulators of mitochondrial lipid oxidation, were also found to be decreased by BMP5 down-regulation. CONCLUSIONS: Down-regulation of BMP5 affects glycerolipid metabolism and fatty acid degradation, leading to mitochondrial dysfunction, reduced ATP production, and changes in cell function, and ultimately resulting in microtia. This research provides supporting evidence for an important role of BMP5 down-regulation in affecting mitochondrial metabolism in cells, and sheds new light on the mechanisms underlying the pathogenesis of microtia.

Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity.

Cisplatin, the most widely used platinum-based anticancer drug, often causes progressive and irreversible sensorineural hearing loss in cancer patients. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. Nicotinamide adenine dinucleotide (NAD+), a co-substrate for the sirtuin family and PARPs, has emerged as a potent therapeutic molecular target in various diseases. In our investigates, we observed that NAD+ level was changed in the cochlear explants of mice treated with cisplatin. Supplementation of a specific inhibitor (TES-1025) of α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), a rate-limiting enzyme of NAD+de novo synthesis pathway, promoted SIRT1 activity, increased mtDNA contents and enhanced AMPK expression, thus significantly reducing hair cells loss and deformation. The protection was blocked by EX527, a specific SIRT1 inhibitor. Meanwhile, the use of NMN, a precursor of NAD+ salvage synthesis pathway, had shown beneficial effect on hair cell under cisplatin administration, effectively suppressing PARP1. In vivo experiments confirmed the hair cell protection of NAD+ modulators in cisplatin treated mice and zebrafish. In conclusion, we demonstrated that modulation of NAD+ biosynthesis via the de novo synthesis pathway and the salvage synthesis pathway could both prevent ototoxicity of cisplatin. These results suggested that direct modulation of cellular NAD+ levels could be a promising therapeutic approach for protection of hearing from cisplatin-induced ototoxicity.

Clinical significance of COL1A1 and COL1A2 expression levels in hypopharyngeal squamous cell carcinoma.

Alterations in collagen type I α1 (COL1A1) and collagen type I α 2 (COL1A2) expression levels have been reported to predict prognosis in various types of cancer. However, the effect of these biomarkers on hypopharyngeal squamous cell carcinoma (HPSCC) is yet to be fully elucidated. The present study aimed to explore the prognostic significance of COL1A1 and COL1A2 expression levels in HPSCC. The expression levels of COL1A1 and COL1A2 in 67 patients with HPSCC were examined using an immunohistochemical assay in a tissue microarray. The associations between COL1A1/COL1A2 expression levels and patient clinicopathological features were analyzed using ANOVA, Pearson's χ2 or Fisher's exact test. The Cox proportional hazard models and Kaplan-Meier survival analysis with log-rank tests were used to analyze the significance of COL1A1/COL1A2 as prognostic markers for patients with HPSCC. As a result, immunohistochemical staining revealed that COL1A1 was positively expressed in all cases, among which 40.3% were strong positive, while COL1A2 was positively expressed in 76.1% of the HPSCC cases with 6.0% of the samples exhibiting strong staining. Further analysis revealed no significant association between the expression levels of COL1A1/COL1A2 and other clinicopathological features. Cox regression analysis revealed that a high COL1A2 expression level predicted a high locoregional recurrence and a less favorable disease-free survival rate (P=0.042 and 0.020, respectively). Overall, the present study indicated that COL1A2 expression levels may have value as a prognostic indicator in HPSCC.

Transcriptomic analysis highlights cochlear inflammation associated with age-related hearing loss in C57BL/6 mice using next generation sequencing.

BACKGROUND: In our aging society, age-related hearing loss (AHL) is the most common sensory disorder in old people. Much progress has been made in understanding the pathological process of AHL over the past few decades. However, the mechanism of cochlear degeneration during aging is still not fully understood. METHODS: Next generation sequencing technique was used to sequence the whole transcriptome of the cochlea of C57BL/6 mice, a mouse model of AHL. Differentially expressed genes (DEGs) were identified using the Cuffdiff software. GO and KEGG pathway enrichment analyses of the DEGs were implemented by using the GOseq R package and KOBAS software, respectively. RESULTS: A total of 731 genes (379 up- and 352 down-regulated) were revealed to be differentially expressed in the cochlea of aged mice compared to the young. Many genes associated with aging, apoptosis, necroptosis and particularly, inflammation were identified as being significantly modulated in the aged cochlea. GO and KEGG analyses of the upregulated DEGs revealed that the most enriched terms were associated with immune responses and inflammatory pathways, whereas many of the downregulated genes are involved in ion channel function and neuronal signaling. Real-time qPCR showed that H2O2 treatment significantly induced the expression of multiple inflammation and necroptosis-related genes in HEI-OC1 cells. CONCLUSION: Using next generation sequencing, our transcriptomic analysis revealed the differences of gene expression pattern with age in the cochlea of C57BL/6 mice. Our study also revealed multiple immune and inflammatory transcriptomic changes during cochlear aging and provides new insights into the molecular mechanisms underlying cochlear inflammation in AHL.

Nrf2 activation protects auditory hair cells from cisplatin-induced ototoxicity independent on mitochondrial ROS production.

Cisplatin is a well-known and commonly used chemotherapeutic agent. However, cisplatin-induced ototoxicity limits its clinical use. Previous studies have shown an important role of reactive oxygen species (ROS) accumulation in the pathogenesis of cisplatin-induced ototoxicity. In many cell types, the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE) protect against oxidative stress by suppressing ROS. Here our results showed that cisplatin injury reduced Nrf2 expression and inhibited Nrf2 translocation in HEI-OC1 cells and Nrf2 activator tert-butylhydroquinone (TBHQ) rescued hair cells from cisplatin induced apoptosis by suppressing the total cellular ROS accumulation. Moreover, we found that decreased ROS accumulation induced by TBHQ didn't depend on mitochondrial derived ROS production, indicating that Nrf2 activation alleviated cisplatin induced oxidative stress and apoptosis through mitochondrial-independent ROS production. Therefore, we provide a potential strategy of prevention and treatment for cisplatin-induced ototoxicity by Nrf2 activation. In conclusion, Nrf2 activation protects auditory hair cells from cisplatin-induced ototoxicity through suppressing the total cellular ROS levels which arise from sources other than mitochondria.

Inhibition of DRP-1-Dependent Mitophagy Promotes Cochlea Hair Cell Senescence and Exacerbates Age-Related Hearing Loss.

Background: Mitochondrial dysfunction is considered to contribute to the development of age-related hearing loss (AHL). The regulation of mitochondrial function requires mitochondrial quality control, which includes mitophagy and dynamics. Dynamin-related Protein 1 (DRP-1) is believed to play a central role in this regulation. However, the underlying mechanism of DRP-1 in AHL remains unclear. Here, we examined whether the decline of DRP-1-dependent mitophagy contributes to the development of AHL. Methods: We induced cellular and cochlear senescence using hydrogen peroxide (H2O2) and evaluated the level of senescence through senescence-associated ß-galactosidase staining. We evaluated mitophagy levels via fluorescence imaging and Western Blotting of LC3II and P62. Mitochondrial function was assessed by ATP assay, mtDNA assay, and JC-1. Results: We found that both the expression of DRP-1 and the mitophagy level decreased in senescent cells and aged mice. DRP-1 overexpression in HEI-OC1 cells initiated mitophagy and preserved mitochondrial function when exposed to H2O2, while cells with DRP-1 silencing displayed otherwise. Moreover, inhibition of DRP-1 by Mdivi-1 blocked mitophagy and exacerbated hearing loss in aged C57BL/6 mice. Conclusion: These results indicated that DRP-1 initiated mitophagy, eliminated mitochondrial dysfunction, and may protect against oxidative stress-induced senescence. These results provide a potential therapeutic target for AHL.

Modulation of miR-34a/SIRT1 signaling protects cochlear hair cells against oxidative stress and delays age-related hearing loss through coordinated regulation of mitophagy and mitochondrial biogenesis.

Mitophagy and mitochondrial biogenesis are 2 pathways that regulate mitochondrial content and metabolism maintaining cellular homeostasis. The imbalance between these opposing processes impairs mitochondrial function and is suggested to be the pathophysiological basis of a variety of neurodegenerative diseases and aging. Here we investigated the role of mitophagy and mitochondrial biogenesis in oxidative damage to the cochlear hair cells and age-related hearing loss. In cultured mouse House Ear Institute-Organ of Corti 1 hair cells, oxidative stress activated mitophagy but inhibited mitochondrial biogenesis and impaired mitochondrial function. Pharmacological inhibition of miR-34a/SIRT1 signaling enhanced mitophagy, mitochondrial biogenesis, and attenuated House Ear Institute-Organ of Corti 1 cell death induced by oxidative stress. In the cochlea of C57BL/6 mice, mitophagy and mitochondrial biogenesis were both upregulated during aging. Long-term supplementation with resveratrol, a SIRT1 activator, not only improved the balance between mitophagy and mitochondrial biogenesis but also significantly reduced age-related cochlear hair cell loss, spiral ganglion neuron loss, stria vascularis atrophy, and hearing threshold shifts in C57BL/6 mice. Moreover, SIRT1 overexpression or miR-34a deficiency both attenuated age-related cochlear hair cell loss and hearing loss in C57BL/6 mice. Our findings reveal that imbalance between mitophagy and mitochondrial biogenesis contributes to cochlea hair cell damage caused by oxidative stress and during aging. Coordinated regulation of these 2 processes by miR-34a/SIRT1 signaling might serve as a promising approach for the treatment of age-related cochlear degeneration and hearing loss.

LncRNA AW112010 Promotes Mitochondrial Biogenesis and Hair Cell Survival: Implications for Age-Related Hearing Loss.

Long noncoding RNA (lncRNA) disorder has been found in many kinds of age-associated diseases. However, the role of lncRNA in the development of age-related hearing loss (AHL) is still largely unknown. This study sought to uncover AHL-associated lncRNAs and the function. RNA-sequencing was conducted to profile lncRNA expression in the cochlea of an early-onset AHL mouse model. RT-qPCR assay was used to validate the expression pattern of lncRNAs. ATP assay, JC-1 assay, mitochondrial probe staining, CCK-8 assay, Western blot, and immunocytochemistry were performed to detect the effects of lncRNA AW112010 in HEI-OC1 cells and the mouse cochlea. We identified 88 significantly upregulated lncRNAs and 46 significantly downregulated lncRNAs in the cochlea of aged C57BL/6 mice. We focused on the significantly upregulated AW112010. Silencing of AW112010 decreased the ATP level, mitochondrial membrane potential, and cell viability and increased mitochondrial ROS generation under oxidative stress in HEI-OC1 cells. AW112010 overexpression promoted cell survival in HEI-OC1 cells. AW112010 knockdown reduced mitochondrial mass and impaired mitochondrial biogenesis in HEI-OC1 cells. Activation of mitochondrial biogenesis by resveratrol and STR1720 promoted cell survival. The mitochondrial biogenesis process was activated in the cochlea of aged mice. Moreover, AW112010 regulated AMPK signaling in HEI-OC1 cells. Transcription factor Arid5b elevated in the aged cochlea and induced AW112010 expression and mitochondrial biogenesis in HEI-OC1 cells. Taken together, lncRNAs are dysregulated with aging in the cochlea of C57BL/6 mice. The Arid5b/AW112010 signaling was induced in the aged mouse cochlea and positively modulated the mitochondrial biogenesis to maintain mitochondrial function.

SIRT1 protects cochlear hair cell and delays age-related hearing loss via autophagy.

Age-related hearing loss (AHL) is typically caused by the irreversible death of hair cells (HCs). Autophagy is a constitutive pathway to strengthen cell survival under normal or stress condition. Our previous work suggested that impaired autophagy played an important role in the development of AHL in C57BL/6 mice, although the underlying mechanism of autophagy in AHL still needs to be investigated. SIRT1 as an important regulator involves in AHL and is also a regulator of autophagy. Thus, we hypothesized that the modulation between SIRT1 and autophagy contribute to HC death and the progressive hearing dysfunction in aging. In the auditory cell line HEI-OC1, SIRT1 modulated autophagosome induction because of SIRT1 deacetylating a core autophagy protein ATG9A. The deacetylation of ATG9A not only affects the autophagosome membrane formation but also acts as a sensor of endoplasmic reticulum (ER) stress inducing autophagy. Moreover, the silencing of SIRT1 facilitated cell death via autophagy inhibition, whereas SIRT1 and autophagy activation reversed the SIRT1 inhibition media cell death. Notably, resveratrol, the first natural agonist of SIRT1, altered the organ of Corti autophagy impairment of the 12-month-old C57BL/6 mice and delayed AHL. The activation of SIRT1 modulates the deacetylation status of ATG9A, which acts as a sensor of ER stress, providing a novel perspective in elucidating the link between ER stress and autophagy in aging. Because SIRT1 activation restores autophagy with reduced HC death and hearing loss, it could be used as a strategy to delay AHL.

Sirtuin 1 and Autophagy Attenuate Cisplatin-Induced Hair Cell Death in the Mouse Cochlea and Zebrafish Lateral Line.

Cisplatin-induced ototoxicity is one of the major adverse effects in cisplatin chemotherapy, and hearing protective approaches are unavailable in clinical practice. Recent work unveiled a critical role of autophagy in cell survival in various types of hearing loss. Since the excessive activation of autophagy can contribute to apoptotic cell death, whether the activation of autophagy increases or decreases the rate of cell death in CDDP ototoxicity is still being debated. In this study, we showed that CDDP induced activation of autophagy in the auditory cell HEI-OC1 at the early stage. We then used rapamycin, an autophagy activator, to increase the autophagy activity, and found that the cell death significantly decreased after CDDP injury. In contrast, treatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly increased cell death. In accordance with in vitro results, rapamycin alleviated CDDP-induced death of hair cells in zebrafish lateral line and cochlear hair cells in mice. Notably, we found that CDDP-induced increase of Sirtuin 1 (SIRT1) in the HEI-OC1 cells modulated the autophagy function. The specific SIRT1 activator SRT1720 could successfully protect against CDDP-induced cell loss in HEI-OC1 cells, zebrafish lateral line, and mice cochlea. These findings suggest that SIRT1 and autophagy activation can be suggested as potential therapeutic strategies for the treatment of CDDP-induced ototoxicity.

The protective effect of autophagy on ischemia/reperfusion-induced hearing loss: implications for sudden hearing loss.

The present study aimed to determine the effects of ischemia/reperfusion (IR) injury for the carotid system on hearing, particularly, the role of autophagy in this process. Sixty-three Sprague-Dawley rats were divided randomly into three groups: sham surgery animals (S), temporary carotid artery occlusion (ischemia) for 30 min (I30), and temporary carotid artery occlusion for 60 min (I60). Auditory brainstem response measurements were performed on mice. After 72 h of reperfusion, the microcirculation was measured in mice after ischemia injury. Immunofluorescence was used to examine the expression of caspase-3 and light chain 3B in the cochlear sections. Temporary carotid artery occlusion lasting for 30 (I30) or 60 min (I60) caused significant hearing loss in the ischemia phase. Following a recovery during the postreperfusion phase, the temporal threshold shift occurred in the I30 group, whereas a permanent threshold shift occurred in the I60 group. Moreover, both microcirculation and autophagy affected hearing 24 h after reperfusion, whereas at 72 h, autophagy works as an intrinsic cellular process that protects against death from the IR effect. These results suggest that the sooner the reperfusion, the better the hearing recovery. In conclusion, autophagy promotes cell survival in the cochlea; however, excessive IR damage counteracts the beneficial potential of autophagy protection and leads to a permanent threshold shift.