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OHCs and IHCs expressed the highest levels of Atg7 in the cochlea. A Representative immunoblot of Atg7 protein in the cochlea. B Expression of the Atg7 gene was analyzed by RT-PCR. C Atg7 was evident in OHCs and IHCs in the cochlear cryosections. D, E Atg7 puncta were distributed throughout the OHC cell bodies as indicated in the infracuticular, nuclear, and basal pool sections. N = 6 for each group (western blot: N = 3). Scale bar: A-C: 5 μm; D, E: 10 μm.
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Atg7 is an indispensable factor that plays a role in canonical nonselective autophagy. Here we show that genetic ablation of Atg7 in outer hair cells (OHCs) in mice caused stereocilium damage, somatic electromotility disturbances, and presynaptic ribbon degeneration over time, which led to the gradual wholesale loss of OHCs and subsequent early-ons...
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Context 1
... blot demonstrated that Atg7 was expressed in the cochlea and brain (Fig. 1A), and RT-PCR confirmed Atg7 mRNA expression in the cochlea (Fig. 1B). Immunostaining of cryosections showed that HCs had the highest expression level of Atg7 compared with supporting cells and other surrounding cells in the organ of Corti (Fig. 1C), and whole-mount immunostaining showed Atg7 puncta in the cell bodies of OHCs and IHCs ...
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... blot demonstrated that Atg7 was expressed in the cochlea and brain (Fig. 1A), and RT-PCR confirmed Atg7 mRNA expression in the cochlea (Fig. 1B). Immunostaining of cryosections showed that HCs had the highest expression level of Atg7 compared with supporting cells and other surrounding cells in the organ of Corti (Fig. 1C), and whole-mount immunostaining showed Atg7 puncta in the cell bodies of OHCs and IHCs (Fig. 1D, E, 2A). and P62 (SQSTM1) showed increased LC3-I, decreased ...
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... blot demonstrated that Atg7 was expressed in the cochlea and brain (Fig. 1A), and RT-PCR confirmed Atg7 mRNA expression in the cochlea (Fig. 1B). Immunostaining of cryosections showed that HCs had the highest expression level of Atg7 compared with supporting cells and other surrounding cells in the organ of Corti (Fig. 1C), and whole-mount immunostaining showed Atg7 puncta in the cell bodies of OHCs and IHCs (Fig. 1D, E, 2A). and P62 (SQSTM1) showed increased LC3-I, decreased LC3-II/LC3-I ratio, and elevated P62, supporting autophagy deficiency in our model (Fig. 2C). Furthermore, immunostaining of the cochlear whole mount revealed that P62 accumulated ...
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... (Fig. 1A), and RT-PCR confirmed Atg7 mRNA expression in the cochlea (Fig. 1B). Immunostaining of cryosections showed that HCs had the highest expression level of Atg7 compared with supporting cells and other surrounding cells in the organ of Corti (Fig. 1C), and whole-mount immunostaining showed Atg7 puncta in the cell bodies of OHCs and IHCs (Fig. 1D, E, 2A). and P62 (SQSTM1) showed increased LC3-I, decreased LC3-II/LC3-I ratio, and elevated P62, supporting autophagy deficiency in our model (Fig. 2C). Furthermore, immunostaining of the cochlear whole mount revealed that P62 accumulated in Atg7-deficient OHCs as early as P30 (Fig. 2D). In the cryosectioned samples at P30, we ...
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... The high vulnerability to degeneration makes OHC the crucial spot to understand the neurobiology of tinnitus. According to comprehensive manuscripts [11,12], the specific activity of OHC provides three kinds of signaling. ...
... the crucial spot to understand the neurobiology of tinnitus. According to comprehensive manuscripts [11,12], the specific activity of OHC provides three kinds of signaling. ...
... When observed at P60, OHCs are almost missing. The specific frailty of OHC compared with IHC to autophagy dysfunction was explored only recently in the manuscript by Zhou et al. [12]. In this work, the authors restricted the conditional knockout to OHC by suppressing the autophagy gene ATG7. ...
Tinnitus is the perception of noise in the absence of acoustic stimulation (phantom noise). In most patients suffering from chronic peripheral tinnitus, an alteration of outer hair cells (OHC) starting from the stereocilia (SC) occurs. This is common following ototoxic drugs, sound-induced ototoxicity, and acoustic degeneration. In all these conditions, altered coupling between the tectorial membrane (TM) and OHC SC is described. The present review analyzes the complex interactions involving OHC and TM. These need to be clarified to understand which mechanisms may underlie the onset of tinnitus and why the neuropathology of chronic degenerative tinnitus is similar, independent of early triggers. In fact, the fine neuropathology of tinnitus features altered mechanisms of mechanic-electrical transduction (MET) at the level of OHC SC. The appropriate coupling between OHC SC and TM strongly depends on autophagy. The involvement of autophagy may encompass degenerative and genetic tinnitus, as well as ototoxic drugs and acoustic trauma. Defective autophagy explains mitochondrial alterations and altered protein handling within OHC and TM. This is relevant for developing novel treatments that stimulate autophagy without carrying the burden of severe side effects. Specific phytochemicals, such as curcumin and berberin, acting as autophagy activators, may mitigate the neuropathology of tinnitus.
... Therefore, p62 protein expression is negatively correlated with autophagic activity. P62 is recognized as a classic marker of autophagy, which is not limited to mitophagy, and dramatic changes in p62 expression have been observed in studies of ototoxicity (He et al., 2017;Lin et al., 2019;Zhou et al., 2020). ...
Mitochondrial dysfunction is associated with ototoxicity, which is caused by external factors. Mitophagy plays a key role in maintaining mitochondrial homeostasis and function and is regulated by a series of key mitophagy regulatory proteins and signaling pathways. The results of ototoxicity models indicate the importance of this process in the etiology of ototoxicity. A number of recent investigations of the control of cell fate by mitophagy have enhanced our understanding of the mechanisms by which mitophagy regulates ototoxicity and other hearing-related diseases, providing opportunities for targeting mitochondria to treat ototoxicity.
... Several studies have reported the relationship between autophagy and hearing loss, and activation of autophagy can reduce noisiness (Guo et al., 2021), drug resistance Liu et al., 2021;Zhang et al., 2022), and the degree of inner ear damage and hearing loss in the elderly (He et al., 2020. It was found that autophagy is closely related to the occurrence and development of sensorineural deafness (Zhou et al., 2020) and that autophagy activators can effectively reduce the level of oxidative stress in hair cells and decrease hair cell death, thus attenuating high-intensity noise-induced damage to hair cells . In addition, autophagy also plays an important regulatory role during inner ear development and is essential for maintaining the morphology and function of auditory hair cells (Zhou et al., 2020). ...
... It was found that autophagy is closely related to the occurrence and development of sensorineural deafness (Zhou et al., 2020) and that autophagy activators can effectively reduce the level of oxidative stress in hair cells and decrease hair cell death, thus attenuating high-intensity noise-induced damage to hair cells . In addition, autophagy also plays an important regulatory role during inner ear development and is essential for maintaining the morphology and function of auditory hair cells (Zhou et al., 2020). ...
... These results suggest that autophagy plays an important early role in the pre-apoptotic transformation and degeneration of the Kölliker's organ during early postnatal development and that any disturbance in autophagy or apoptosis of Kölliker's organ-supporting cells during development will lead to impaired cochlear development and eventually cause hearing loss . Therefore, the dynamic balance between autophagy and apoptosis regulates the normal differentiation and orderly organization of developing cochlear supporting cells, but the regulatory mechanism of the dynamic balance between autophagy and apoptosis is currently unknown Zhou et al., 2020). Abnormal intracellular calcium signaling mediated by Gjb2 may be a key regulator of abnormal alterations in the autophagy-apoptosis signaling pathway and still requires in-depth study (Inoshita et al., 2014;Sun et al., 2022). ...
The Kölliker’s organ is a transient cellular cluster structure in the development of the mammalian cochlea. It gradually degenerates from embryonic columnar cells to cuboidal cells in the internal sulcus at postnatal day 12 (P12)–P14, with the cochlea maturing when the degeneration of supporting cells in the Kölliker’s organ is complete, which is distinct from humans because it disappears at birth already. The supporting cells in the Kölliker’s organ play a key role during this critical period of auditory development. Spontaneous release of ATP induces an increase in intracellular Ca ²⁺ levels in inner hair cells in a paracrine form via intercellular gap junction protein hemichannels. The Ca ²⁺ further induces the release of the neurotransmitter glutamate from the synaptic vesicles of the inner hair cells, which subsequently excite afferent nerve fibers. In this way, the supporting cells in the Kölliker’s organ transmit temporal and spatial information relevant to cochlear development to the hair cells, promoting fine-tuned connections at the synapses in the auditory pathway, thus facilitating cochlear maturation and auditory acquisition. The Kölliker’s organ plays a crucial role in such a scenario. In this article, we review the morphological changes, biological functions, degeneration, possible trans-differentiation of cochlear hair cells, and potential molecular mechanisms of supporting cells in the Kölliker’s organ during the auditory development in mammals, as well as future research perspectives.
... In addition, it can trigger pathological-related changes in multiple organs. For example, it has been reported that prolonged fatigued working conditions can trigger pathological-related issues such as skeletal muscle damage (Constantin-Teodosiu and Constantin, 2021), hearing damage lesions such as sudden deafness (Zhou et al., 2020;Fu et al., 2021;Holman et al., 2021;Fu et al., 2022), gastrointestinal complications, and cardiovascular issues (Natelson et al., 2021). By establishing appropriate methods to closely monitor the fatigue status of personnel and relieve the fatigue on time, operation-related injuries can be reduced. ...
Fatigue results from a series of physiological and psychological changes due to continuous energy consumption. It can affect the physiological states of operators, thereby reducing their labor capacity. Fatigue can also reduce efficiency and, in serious cases, cause severe accidents. In addition, it can trigger pathological-related changes. By establishing appropriate methods to closely monitor the fatigue status of personnel and relieve the fatigue on time, operation-related injuries can be reduced. Existing fatigue detection methods mostly include subjective methods, such as fatigue scales, or those involving the use of professional instruments, which are more demanding for operators and cannot detect fatigue levels in real time. Speech contains information that can be used as acoustic biomarkers to monitor physiological and psychological statuses. In this study, we constructed a fatigue model based on the method of sleep deprivation by collecting various physiological indexes, such as P300 and glucocorticoid level in saliva, as well as fatigue questionnaires filled by 15 participants under different fatigue procedures and graded the fatigue levels accordingly. We then extracted the speech features at different instances and constructed a model to match the speech features and the degree of fatigue using a machine learning algorithm. Thus, we established a method to rapidly judge the degree of fatigue based on speech. The accuracy of the judgment based on unitary voice could reach 94%, whereas that based on long speech could reach 81%. Our fatigue detection method based on acoustic information can easily and rapidly determine the fatigue levels of the participants. This method can operate in real time and is non-invasive and efficient. Moreover, it can be combined with the advantages of information technology and big data to expand its applicability.
... Hearing loss is the most common sensory disorder affecting approximately 6.1% of the world population, which can be caused by ototoxic drugs [1][2][3][4], aging [5][6][7][8][9], excessive noise exposure [5], genetic factors [10][11][12][13][14], and infections [15][16][17]. The ototoxic drug cisplatin (CDP) is an effective and widely used chemotherapeutic drug for the treatment of human multi-site solid tumors. ...
N6-methyladenosine (m6A) has been recognized as a common type of post-transcriptional epigenetic modification. m6A modification and YTHDF1, one of its reader proteins, have been documented to play a pivotal role in numerous human diseases via regulating mRNA splicing, translation, stability, and subcellular localization. The chemotherapeutic drug cisplatin (CDP) can damage sensory hair cells (HCs) and result in permanent sensorineural hearing loss. However, whether YTHDF1-mediated modification of mRNA is potentially involved in CDP-induced injury in sensory hair cells was not fully clarified. This study investigated the potential mechanisms for the modification of YTHDF1 in CDP-induced damage in HCs. Here, we discovered that YTHDF1's expression level statistically increased significantly after treating with CDP. Apoptosis and cell death of HCs induced by CDP were exacerbated after the knockdown of YTHDF1, while overexpression of YTHDF1 in HCs alleviated their injury induced by CDP. Moreover, YTHDF1 expression correlated with cisplatin-induced autophagy with statistical significance in HCs; namely, YTHDF1’s overexpression enhanced the activation of autophagy, while its deficiency suppressed autophagy and, at the same time, increased the loss of HCs after CDP damage. WB analysis and qRT-PCR results of autophagy-related genes indicated that YTHDF1 promoted the translation of autophagy-related genes ATG14, thus boosting autophagy. Therefore, CDP-induced YTHDF1 expression protected HCs against CDP-induced apoptosis by upregulating the translation of autophagy-related genes ATG14, along with enhancing autophagy. Based on these findings, it can be inferred that YTHDF1 is potentially a target for ameliorating drug-induced HCs damage through m6A modification.
... Hearing loss is the most common sensorineural disorder affecting approximately 6.1% of the world population Zhang et al., 2021a;Fu et al., 2021;Lv et al., 2021). It is estimated that more than half of the hearing loss cases are attributable to genetic factors (He et al., 2017;Wang et al., 2022), while the other half of hearing loss cases could be caused by ototoxic drugs, such as aminoglycosides and anti-tumor drugs, aging, excessive noise exposure, and infections (Li et al., 2018a;Li et al., 2018b;Liu et al., 2019a;Cheng et al., 2019;Han et al., 2020;He et al., 2020;Zhong et al., 2020;Zhou et al., 2020;Liu et al., 2021a;Zhang et al., 2021b;Guo et al., 2021;He et al., 2021;Bu et al., 2022;Fu et al., 2022;Jiang et al., 2022). The functions of these hearing loss genes play an essential role in the development and function of hair cells and synaptic transmission of spiral ganglion neurons (Wang et al., 2017;Zhu et al., 2018;Cheng et al., 2021). ...
... In addition, PTPRQ protein forms a complex with myosin VI to tether the membrane of the stereocilia to stereocilia, causing reorganization of the actin cytoskeleton, and plays an important role in the mechanical transduction and adaptation of hair cells (Takenawa and Itoh, 2001;Hirono et al., 2004;Sakaguchi et al., 2008). Studies in families with PTPRQ mutations show that mutants of the PTPRQ gene could cause autosomal recessive or autosomal dominant congenital sensorineural hearing loss, damage all frequency or high frequency, with or without vestibular dysfunction in infancy or early childhood (Li et al., 2018a;Li et al., 2018b;Liu et al., 2019a;Cheng et al., 2019;Zhou et al., 2020;Liu et al., 2021a;Guo et al., 2021;He et al., 2021;Bu et al., 2022;Fu et al., 2022;Jiang et al., 2022). The hearing loss was progressive in some cases. ...
Hearing loss is among the most common congenital sensory impairments. Genetic causes account for more than 50% of the cases of congenital hearing loss. The PTPRQ gene, encoding protein tyrosine phosphatase receptor Q, plays an important role in maintaining the stereocilia structure and function of hair cells. Mutations in the PTPRQ gene have been reported to cause hereditary sensorineural hearing loss. By using next-generation sequencing and Sanger sequencing, we identified a novel compound heterozygous mutation (c.997 G > A and c.6603-3 T > G) of the PTPRQ gene in a Chinese consanguineous family. This is the first report linking these two mutations to recessive hereditary sensorineural hearing loss. These findings contribute to the understanding of the relationship between genotype and hearing phenotype of PTPRQ-related hearing loss, which may be helpful to clinical management and genetic counseling.
... Inner and outer hair cells in the cochlea are called as mechanical transduction cells, which are fragile and almost has no regeneration capacity, thus formation and progression of inflammation in the inner part of the ear can greatly impact the endurance of hair cell. [79][80][81][82] Prevention of hair cells damage from ototoxic drug and noise is the crucial part to the treatment of hearing loss. 79,81,83 Nanoparticle based therapeutic molecule delivery procedures have been found to enrich high loading capacity and drug availability in the inner ear, targeting specific site by surface modification, magnetically and cell penetrating peptides, drugs release in sustained manner into cochlear region and capable of transport across RWM. ...
... [79][80][81][82] Prevention of hair cells damage from ototoxic drug and noise is the crucial part to the treatment of hearing loss. 79,81,83 Nanoparticle based therapeutic molecule delivery procedures have been found to enrich high loading capacity and drug availability in the inner ear, targeting specific site by surface modification, magnetically and cell penetrating peptides, drugs release in sustained manner into cochlear region and capable of transport across RWM. Advantages of NPs have made them emerging and effective candidates for non-invasive and targeted otoprotective material delivery to the complicated structure of the otic region. ...
Efficient delivery of therapeutic material to target site of the inner ear is considered as the most challenging process due to their poor blood flow and inaccessibility sensitivity towards chemical stimuli, inability of drug to be delivered as well. Novel nanoparticlebased drug transport approaches have emerged for overcoming the restriction associated with inner ear therapeutic material delivery. The main focus of this article is to highlight the potential benefits, pre-clinical level otoprotective effect of different types of NPs based payload delivery strategies in mitigating sensorineural hearing impairment resulting from medication (cisplatin and antibiotic treatment) and noise exposure. This review converses about advantage of nanocarrier assisted targeted cell specific inner ear drug delivery approach and demonstrates that targeted NPs delivery systems have the capability to be utilized as vehicle to transport therapeutic materials into the OHCs within the cochlea in controlled and sustained way and maximize following therapeutic effects. Efficacy of systemic and minimally invasive intratympanic and RWM approach for delivering steroids/ genetic material to the inner ear has also been compared in this article. Understanding the importance (design, formulation, cochlear biocompatibility and cell specific binding efficiency of NPs, mechanistic pathways, route of delivery, positive therapeutic outcomes) and hitches (adverse effects after treatment, negative therapeutic outcome) of currently available NPs based drug delivery systems offer new opportunity to develop best treatment methods for sensorineural hearing dysfunction.
... Inner ear sensory hair cells (HCs) mainly function for transduction of mechanical stimuli into electrical signals and are mechanoreceptors for sound recognition (Li et al., 2018;Liu et al., 2019;Zhang et al., 2019). Aging, ototoxic drugs, trauma, inflammation, and other factors can all contribute to hair cell damage, resulting in sensorineural hearing loss (Liu et al., 2016;Zhou et al., 2020). Sensorineural hearing loss is a common sensory disease caused by damage or loss of HCs, affecting millions of people worldwide. ...
The ideal treatment for sensory hearing loss is to regenerate inner ear hair cells (HCs) through stem cell therapy, thereby restoring the function and structure of the cochlea. Previous studies have found that Lgr5+ supporting cells (SCs) in the inner ear can regenerate HCs, thus being considered inner ear progenitor cells. In addition to traditional biochemical factors, physical factors such as electrical conductivity also play a crucial role in the regulation of stem cell proliferation and differentiation. In this study, the graphene substrates were used to culture Lgr5+ progenitor cells and investigated their regulatory effects on cells. It was demonstrated that the graphene substrates displayed great cytocompatibility for Lgr5+ progenitors and promoted their sphere-forming ability. Moreover, more Myosin7a+ cells were found on the graphene substrates compared with tissue culture polystyrene (TCPS). These results suggest that graphene is an efficient interface that can promote the differentiation of Lgr5+ progenitors into HCs, which is great significance for its future application in combination with Lgr5+ cells to regenerate HCs in the inner ear.
... Hearing loss is the most common sensory disorder affecting approximately 6.1% of the world population, which can be caused by ototoxic drugs (1)(2)(3)(4)(5), excessive noise exposure (6), aging6 (6)(7)(8)(9)(10), genetic factors (11)(12)(13)(14)(15), and infections (16)(17)(18). The ototoxic drug cisplatin is the pioneer of anticancer drugs and mainstay of cancer treatment and has been widely used in the treatment of solid tumors, including ovarian, testicular, and lung cancer (19). ...
Better understanding the mechanism of cisplatin-induced ototoxicity is of great significance for clinical prevention and treatment of cisplatin-related hearing loss. However, the mechanism of cisplatin-induced inflammatory response in cochlear stria vascularis and the mechanism of marginal cell (MC) damage have not been fully clarified. In this study, a stable model of cisplatin-induced MC damage was established in vitro, and the results of PCR and Western blotting showed increased expressions of NLRP3, Caspase-1, IL-1β, and GSDMD in MCs. Incomplete cell membranes including many small pores appearing on the membrane were also observed under transmission electron microscopy and scanning electron microscopy. In addition, downregulation of NLRP3 by small interfering RNA can alleviate cisplatin-induced MC pyroptosis, and reducing the expression level of TXNIP possesses the inhibition effect on NLRP3 inflammasome activation and its mediated pyroptosis. Taken together, our results suggest that NLRP3 inflammasome activation may mediate cisplatin-induced MC pyroptosis in cochlear stria vascularis, and TXNIP is a possible upstream regulator, which may be a promising therapeutic target for alleviating cisplatin-induced hearing loss.
... autophagy via Sesn2/AMPK/mTOR signaling may cause hair cell loss and influence auditory function (10,11). However, excessive activation of autophagy might also promote cell death via the apoptosis pathway and pathological changes (12). ...
Gentamicin is an important aminoglycoside antibiotic used in the treatment of gram‑negative bacterial infections, but nephrotoxicity and ototoxicity reduce its utility. The autophagy pathway is involved in damage of auditory hair cells. With the aim of developing new strategies for attenuating gentamicin ototoxicity, the present study investigated the otoprotective mechanism of 2,3,4',5‑tetrahydroxystilbene‑2‑O‑β‑D-glucoside (THSG) in vitro using the mouse cochlear cell line UB/OC‑2. MTT assay demonstrated that gentamicin reduced UB/OC‑2 cell viability and western blotting showed that gentamicin upregulated autophagy‑related proteins, such as Beclin, autophagy related 5 and LC3‑II. THSG significantly attenuated gentamicin‑induced cytotoxicity, clearly reduced LDH release observed by LDH assay and decreased the expression of autophagy‑related proteins. Reverse‑transcription‑quantitative (RT‑q) PCR and western blotting showed that THSG against gentamicin‑induced autophagy via suppressing the expression of Sesn2, at both the mRNA and protein level and a possible involvement of AMP‑activated protein kinase (AMPK)/mTOR signaling response. Collectively, the present study demonstrated that THSG decreased gentamicin‑induced ototoxicity in UB/OC‑2 cochlear cells via the autophagic signaling in regulating Sesn2/AMPK/mTOR pathway. These results suggested that THSG might be a new therapeutic agent with the potential to attenuate gentamicin ototoxicity.
