This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury we...This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry,apoptosis assays,and auditory brainstem response.The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction(CUT&Tag-qPCR)analyses in the HEI-OC1 cell line.Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species.CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene,thus activating the expression of Pik3ca.These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatininduced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.展开更多
The waltzing guinea pig may be a good model to investigate if genetic factor can change the sensitivity in noise-induced hearing loss. A total of 34 waltzig guinea pigs were studied and we found that there is no any s...The waltzing guinea pig may be a good model to investigate if genetic factor can change the sensitivity in noise-induced hearing loss. A total of 34 waltzig guinea pigs were studied and we found that there is no any significant increased sensitivity to noise trauma if the age-induced hearing loss was considered in waltz-ing guinea pig.展开更多
miRNA-183 family, in normal biology, is expressed in a harmonious and stable manner in the neurosensory organs and cells. Studies have also shown that miRNA-183 family, in different pathways, affects the neurosensory ...miRNA-183 family, in normal biology, is expressed in a harmonious and stable manner in the neurosensory organs and cells. Studies have also shown that miRNA-183 family, in different pathways, affects the neurosensory development, maintenance, survival and function. In addition, it has potential neuroprotective effects in response to neurosensory destructive stimulations. miRNA-96 mutation causes hereditary deafness in humans and mice, and therefore affects the inner ear activity and its maintenance. Certain roles have been identified for mi R-96 in the maintenance and function of the inner ear. The comparison of the target genes of family-183 in transcriptomes of newborn and adult hair cells shows that hundreds of target genes in this family may affect development and maintenance of the ears. Identifying the genes that are regulated by miRNA-183 family provides researchers with important information about the complex development and environmental regulation of the inner ear, and can offer new approaches to the maintenance and regeneration of hair cells and auditory nerve.展开更多
Objectives:This study aimed to determine the prognostic value of otoacoustic emissions(OAEs)in idiopathic sudden sensorineural hearing loss patients.Methods:The study included 30 subjects with unilateral idiopathic su...Objectives:This study aimed to determine the prognostic value of otoacoustic emissions(OAEs)in idiopathic sudden sensorineural hearing loss patients.Methods:The study included 30 subjects with unilateral idiopathic sudden sensorineural hearing loss(ISSNHL).Each patient was evaluated four times:at baseline and after one week,one month,and three months of treatment.During each visit,each patient was subjected to full audiological history,otoscopic examination,basic audiological evaluations,and transiently evoked and distortion product otoacoustic emission(TEOAEs&DEOAEs).Results:The hearing thresholds(frequency range 250e8000 Hz)and word recognition scores of patients with detectable TEOAEs and DPOAEs improved significantly,whereas no significant improvements were observed in those with no response.Conclusion:Hearing improvement is better in patients with detectable TEOAEs and DPOAEs.As a result,TEOAEs and DPOAEs are recommended as routine tests in all SSNHL patients to predict outcomes and monitor treatment as TEOAEs and DPOAEs reflect the cochlear OHCs activity.展开更多
According to the World Health Organization’s world report on hearing,nearly 2.5 billion people worldwide will suffer from hearing loss by 2050,which may contribute to a severe impact on individual life quality and na...According to the World Health Organization’s world report on hearing,nearly 2.5 billion people worldwide will suffer from hearing loss by 2050,which may contribute to a severe impact on individual life quality and national economies.Sensorineural hearing loss(SNHL)occurs commonly as a result of noise exposure,aging,and ototoxic drugs,and is pathologically characterized by the impairment of mechanosensory hair cells of the inner ear,which is mainly triggered by reactive oxygen species accumulation,inflammation,and mitochondrial dysfunction.Though recent advances have been made in understanding the ability of cochlear repair and regeneration,there are still no effective therapeutic drugs for SNHL.Chinese herbal medicine which is widely distributed and easily accessible in China has demonstrated a unique curative effect against SNHL with higher safety and lower cost compared with Western medicine.Herein we present trends in research for Chinese herbal medicine for the treatment of SNHL,and elucidate their molecular mechanisms of action,to pave the way for further research and development of novel effective drugs in this field.展开更多
Deafness is the prevailing sensory impairment among humans,impacting every aspect of one's existence.Half of congenital deafness cases are attributed to genetic factors.Studies have shown that Luzp2 is expressed i...Deafness is the prevailing sensory impairment among humans,impacting every aspect of one's existence.Half of congenital deafness cases are attributed to genetic factors.Studies have shown that Luzp2 is expressed in hair cells(HCs)and supporting cells of the inner ear,but its specific role in hearing remains unclear.To determine the importance of Luzp2 in auditory function,we generated mice deficient in Luzp2.Our results revealed that Luzp2 has predominant expression within the HCs and pillar cells.However,the loss of Luzp2 did not result in any changes in auditory threshold.HCs or synapse number and HC stereocilia morphology in Luzp2 knockout mice did not show any notable distinctions.This was the first study of the role of Luzp2 in hearing in mice,and our results provide important guidance for the screening of deafness genes.展开更多
Rho GTPases are essential regulators of the actin cytoskeleton.They are involved in various physiological and biochemical processes such as the regulation of cytoskeleton dynamics,development,proliferation,survival,an...Rho GTPases are essential regulators of the actin cytoskeleton.They are involved in various physiological and biochemical processes such as the regulation of cytoskeleton dynamics,development,proliferation,survival,and regeneration.During the development of cochlear hair cells,Rho GTPases are activated by various extracellular signals through membrane receptors to further stimulate multiple downstream effectors.Specifically,RhoA,Cdc42,and Rac1,members of the classical subfamily of the Rho GTPase family,regulate the development and maintenance of cilia by inducing the polymerization of actin monomers and stabilizing actin filaments.In addition,they also regulate the normal morphology orientation of ciliary bundles in auditory hair cells,which is an important element of cell polarity regulation.Moreover,the actin-related pathways mediated by RhoA,Cdc42,and Rac1 also play a role in the motility of outer hair cells,indicating that the function of Rho GTPases is crucial in the highly polar auditory sensory system.In this review,we focus on the expression of RhoA,Cdc42,and Rac1 in cochlear hair cells and how these small molecules participate in ciliary bundle morphogenesis and cochlear hair cell movement.We also discuss the progress of current research investigating the use of these small molecules as drug targets for deafness treatment.展开更多
Oxidative stress is the key determinant in the pathogenesis of noise-induced hearing loss(NIHL). Given that cellular defense against oxidative stress is an energyconsuming process, the aim of the present study was to ...Oxidative stress is the key determinant in the pathogenesis of noise-induced hearing loss(NIHL). Given that cellular defense against oxidative stress is an energyconsuming process, the aim of the present study was to investigate whether increasing energy availability by glucose supplementation protects cochlear hair cells against oxidative stress and attenuates NIHL. Our results revealed that glucose supplementation reduced the noiseinduced formation of reactive oxygen species(ROS) and consequently attenuated noise-induced loss of outer hair cells, inner hair cell synaptic ribbons, and NIHL in CBA/J mice. In cochlear explants, glucose supplementation increased the levels of ATP and NADPH, as well as attenuating H_2O_2-induced ROS production and cytotoxicity. Moreover, pharmacological inhibition of glucose transporter type 1 activity abolished the protective effects of glucose against oxidative stress in HEI-OC1 cells. These findings suggest that energy availability is crucial for oxidative stress resistance and glucose supplementation offers a simple and effective approach for the protection of cochlear hair cells against oxidative stress and NIHL.展开更多
Hidden hearing loss(HHL),an auditory dysfunction that has gained much recent attention,has the hallmarks of speech discrimination and intelligibility deficits with normal or near-normal hearing thresholds.The patholog...Hidden hearing loss(HHL),an auditory dysfunction that has gained much recent attention,has the hallmarks of speech discrimination and intelligibility deficits with normal or near-normal hearing thresholds.The pathological mechanisms of HHL are complicated and are not yet fully understood.HHL can be resulted from disorders of the central nervous system such as auditory cortex,and/or pathological changes of inner ear.Thus far,2 pathological phenomena,synaptopathy and auditory nerve demyelination,have been reported as underlying causes of otogenic HHL.Here,we review the clinical and physiological characteristics of HHL as well as the molecular pathological mechanisms of otogenic HHL and aim to allude to potential therapy targets for clinical applications in the future.展开更多
This study examined the expression pattern of programmed cell death 5 (PDCD5) in co-chlear hair cells and spiral ganglion neurons (SGNs) and its association with age-related hearing loss in mice.Sixty C57BL/6J (C57) m...This study examined the expression pattern of programmed cell death 5 (PDCD5) in co-chlear hair cells and spiral ganglion neurons (SGNs) and its association with age-related hearing loss in mice.Sixty C57BL/6J (C57) mice at different ages were divided into four groups (3,6,9 or 12 months).PDCD5 expression was detected by using immunohistochemistry,real-time PCR and Western blot.Morphological change of the cochleae was also evaluated by using immunoassay.The results showed that the expression of PDCD5 had a gradual increase with ageing in both protein and RNA levels in C57 mice,as well as gradually increased apoptosis of cochlear hair cells and SGNs.In addition,we also found that caspase-3 activity was enhanced and its expression was enhanced with ageing.It is implied that overexpression of PDCD5 causes the increase in caspase-3 activity and the subsequent increase of apoptosis in cochlear hair cells and SGNs,and thereby plays a role in the pathogenesis of presbycusis.Thus,PDCD5 may be a new target site for the treatment and prevention of age-related hearing loss.展开更多
Zebrafish have the potential to regrow injured organs and tissues,but their use as a model for hearing regeneration following blast injury has never been reported.In this study,zebrafish were exposed to a blast wave p...Zebrafish have the potential to regrow injured organs and tissues,but their use as a model for hearing regeneration following blast injury has never been reported.In this study,zebrafish were exposed to a blast wave produced by an underwater blast wave generator.The first peak sound pressures produced by this generator were up to 224dB and 160kPa,measured at 25cm away from the machine.Zebrafish hearing sensitivity was examined by analyzing auditory evoked potentials from 1 to 35 days post blast wave exposure.Cell death and cell proliferation in inner ear organs,including the saccule,lagena,and utricle,were investigated using a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay,and cell proliferation assay using 5-ethynyl-20-deoxyuridine,respectively.Significant differences in auditory evoked potential thresholds were observed between exposed and control groups,demonstrating both blast wave-induced hearing loss and recovery of hearing sensitivity.An apoptosis assay revealed significantly increased numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labelingpositive cells in the inner ear sensory epithelia of exposed groups compared with the control group.However,numbers of 5-ethynyl-20-deoxyuridine-positive cells in the inner ear of exposed groups recovered to a normal level within 10 post blast wave exposure.Furthermore,blast wave exposure caused brain injury with increased cell apoptosis and decreased neurogenesis.Compared with drug or noise-induced zebrafish models,our blast wave-induced model elicited more serious hearing loss phenotypes,which required more time to return to a normal level.Overall,this zebrafish model can provide a reliable animal model for both hearing loss and regeneration research.The study was approved by the Shanghai 6th Hospital Animal Care and Use Committee,China(approval No.2017-0196)on February 28,2017.展开更多
Diabetes mellitus (DM) is a chronic systemic disease characterized by hyperglycemia, with various patho-genic mechanisms. From absolute or relative insulin deficiency, patients with DM often demonstrate vari-ous level...Diabetes mellitus (DM) is a chronic systemic disease characterized by hyperglycemia, with various patho-genic mechanisms. From absolute or relative insulin deficiency, patients with DM often demonstrate vari-ous levels of metabolic disorders. Major clinical manifestations of DM include metabolic disorders, vascu-lar lesions, circulatory disturbances and neurologic complications. Along with advances in DM research, re-ports of DM related tinnitus and hearing impairment have increased continuously. Research on DM related auditory system dysfunction has focused on cochlear microcirculation, cellular homeostasis, genetics and ag-ing. Cochlear microcirculation plays an important role in cochlear physiology and its disorders are associat-ed with many inner ear diseases. Ischemia and subsequent reperfusion seen in cochlear microcirculation dis-orders are important factors in hearing damage. Understanding cochlear microcirculation and structural as well as functional changes in DM patients with hearing loss and their causal factors will help reveal patho-genic mechanisms in diabetic hearing loss and provide new ideas in developing interventions and preventing damages caused by diabetes.展开更多
Auditory hair cells(HCs)are the mechanosensory receptors of the cochlea,and HC loss or malfunction can result from genetic defects.Dock4,a member of the Dock180-related protein superfamily,is a guanine nucleotide exch...Auditory hair cells(HCs)are the mechanosensory receptors of the cochlea,and HC loss or malfunction can result from genetic defects.Dock4,a member of the Dock180-related protein superfamily,is a guanine nucleotide exchange factor for Rac1,and previous reports have shown that Dock4 mutations are associated with autism spectrum disorder,myelodysplastic syndromes,and tumorigenesis.Here,we found that Dock4 is highly expressed in the cochlear HCs of mice.However,the role of Dock4 in the inner ear has not yet been investigated.Taking advantage of the piggyBac transposon system,Dock4 knockdown(KD)mice were established to explore the role of Dock4 in the cochlea.Compared to wild-type controls,Dock4 KD mice showed significant hearing impairment from postnatal day 60.Dock4 KD mice showed hair bundle deficits and increased oxidative stress,which eventually led to HC apoptosis,late-onset HC loss,and progressive hearing loss.Furthermore,molecular mechanism studies showed that Rac1/β-catenin signaling was significantly downregulated in Dock4 KD cochleae and that this was the cause for the disorganized stereocilia and increased oxidative stress in HCs.Overall,our work demonstrates that the Dock4/Rac1/β-catenin signaling pathway plays a critical role in the maintenance of auditory HCs and hearing function.展开更多
Disabling hearing loss is the most common sensorineural disability worldwide.It affects around 466 million people and its incidence is expected to rise to around 900 million people by 2050,according to World Health Or...Disabling hearing loss is the most common sensorineural disability worldwide.It affects around 466 million people and its incidence is expected to rise to around 900 million people by 2050,according to World Health Organization estimates.Most cases of hearing impairment are due to the degeneration of hair cells(HCs)in the cochlea,mechano-receptors that transduce incoming sound information into electrical signals that are sent to the brain.Damage to these cells is mainly caused by exposure to aminoglycoside antibiotics and to some anti-cancer drugs such as cisplatin,loud sounds,age,infections and genetic mutations.Hearing deficits may also result from damage to the spiral ganglion neurons that innervate cochlear HCs.Differently from what is observed in avian and nonmammalian species,there is no regeneration of missing sensory cell types in the adult mammalian cochlea,what makes hearing loss an irreversible process.This review summarizes the research that has been conducted with the aim of developing cell-based strategies that lead to sensory cell replacement in the adult cochlea and,ultimately,to hearing restoration.Two main lines of research are discussed,one directed toward the transplantation of exogenous replacement cells into the damaged tissue,and another that aims at reactivating the regenerative potential of putative progenitor cells in the adult inner ear.Results from some of the studies that have been conducted are presented and the advantages and drawbacks of the various approaches discussed.展开更多
Most recent studies on regeneration of inner ear hair cells focus on use of stem cells, gene therapy and neurotrophic factors. Cochlear gene therapy has been successfully used in the treatment of neu- rosensory hearin...Most recent studies on regeneration of inner ear hair cells focus on use of stem cells, gene therapy and neurotrophic factors. Cochlear gene therapy has been successfully used in the treatment of neu- rosensory hearing loss. This suggests that cochlear hair cell regeneration is possible. The objective of this paper is to review research and clinical application of inner near hair cell regeneration.展开更多
Hearing loss has become increasingly prevalent and causes considerable disability,thus gravely burdening the global economy.Irreversible loss of hair cells is a main cause of sensorineural hearing loss,and currently,t...Hearing loss has become increasingly prevalent and causes considerable disability,thus gravely burdening the global economy.Irreversible loss of hair cells is a main cause of sensorineural hearing loss,and currently,the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids,but these are of limited benefit in patients.It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies.At present,how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research.Multi-ple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells,and in this article,we first review the principal mechanisms underlying hair cell reproduction.We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration,and we summarize current achievements in hair cell regeneration.Lastly,we discuss potential future approaches,such as small molecule drugs and gene therapy,which might be applied for regenerating functional hair cells in the clinic.展开更多
Gene expression changes contribute greatly to phenotypic variations in nature.Studying patterns of regulators of gene expression is important to fully understand the molecular mechanism underlying phenotypic variation...Gene expression changes contribute greatly to phenotypic variations in nature.Studying patterns of regulators of gene expression is important to fully understand the molecular mechanism underlying phenotypic variations.In horseshoe bats,the cochleae are fnely tuned to echoes of call frequency.Here,using 2 recently diverged subspecies of the intermediate horseshoe bat(Rhinolophus affnis hainanus and R.a.himalayanus)with great acoustic variations as the system,we aim to explore relative roles of different regulators of gene expression(differential gene expression,alternative splicing(AS)and long non-coding RNAs(lncRNAs))in phenotypic variation with a combination of Illumina short-read and Nanopore long-read RNA-seq data from the cochlea.Compared to R.a.hainanus,R.a.himalayanus exhibited much more upregulated differentially expressed genes(DEGs)and multiple of them may play important roles in the maintenance and damage repair of auditory hair cells.We identifed 411 differentially expressed lncRNAs and their target DEGs upregulated in R.a.himalayanus were also mainly involved in a protective mechanism for auditory hair cells.Using 3 different methods of AS analysis,we identifed several candidate alternatively spliced genes(ASGs)that expressed different isoforms which may be associated with acoustic divergence of the 2 subspecies.We observed signifcantly less overlap than expected between DEGs and ASGs,supporting complementary roles of differential gene expression and AS in generating phenotypic variations.Overall,our study highlights the importance of a combination of short-read and long-read RNA-seq data in examining the regulation of gene expression changes responsible for phenotypic variations.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.:82271158,82192865,and 82071045)Wenzhou Municipal Science and Technology Research Program(Grant No.:2021Y0681).
文摘This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry,apoptosis assays,and auditory brainstem response.The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction(CUT&Tag-qPCR)analyses in the HEI-OC1 cell line.Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species.CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene,thus activating the expression of Pik3ca.These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatininduced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.
基金supported by Tysta Skolan and Karolinska Institutet,Stockholm,Sweden
文摘The waltzing guinea pig may be a good model to investigate if genetic factor can change the sensitivity in noise-induced hearing loss. A total of 34 waltzig guinea pigs were studied and we found that there is no any significant increased sensitivity to noise trauma if the age-induced hearing loss was considered in waltz-ing guinea pig.
文摘miRNA-183 family, in normal biology, is expressed in a harmonious and stable manner in the neurosensory organs and cells. Studies have also shown that miRNA-183 family, in different pathways, affects the neurosensory development, maintenance, survival and function. In addition, it has potential neuroprotective effects in response to neurosensory destructive stimulations. miRNA-96 mutation causes hereditary deafness in humans and mice, and therefore affects the inner ear activity and its maintenance. Certain roles have been identified for mi R-96 in the maintenance and function of the inner ear. The comparison of the target genes of family-183 in transcriptomes of newborn and adult hair cells shows that hundreds of target genes in this family may affect development and maintenance of the ears. Identifying the genes that are regulated by miRNA-183 family provides researchers with important information about the complex development and environmental regulation of the inner ear, and can offer new approaches to the maintenance and regeneration of hair cells and auditory nerve.
文摘Objectives:This study aimed to determine the prognostic value of otoacoustic emissions(OAEs)in idiopathic sudden sensorineural hearing loss patients.Methods:The study included 30 subjects with unilateral idiopathic sudden sensorineural hearing loss(ISSNHL).Each patient was evaluated four times:at baseline and after one week,one month,and three months of treatment.During each visit,each patient was subjected to full audiological history,otoscopic examination,basic audiological evaluations,and transiently evoked and distortion product otoacoustic emission(TEOAEs&DEOAEs).Results:The hearing thresholds(frequency range 250e8000 Hz)and word recognition scores of patients with detectable TEOAEs and DPOAEs improved significantly,whereas no significant improvements were observed in those with no response.Conclusion:Hearing improvement is better in patients with detectable TEOAEs and DPOAEs.As a result,TEOAEs and DPOAEs are recommended as routine tests in all SSNHL patients to predict outcomes and monitor treatment as TEOAEs and DPOAEs reflect the cochlear OHCs activity.
基金supported by grants from the National Key R&D Program of China(Nos.2021YFA1101300,2021YFA1101800,and 2020YFA0112503)Strategic Priority Research Program of the Chinese Academy of Science(XDA16010303,China)+3 种基金National Natural Science Foundation of China(Nos.82101228,82030029,81970882,and 92149304)Science and Technology Department of Sichuan Province(No.2021YFS0371,China)Shenzhen Science and Technology Program(JCYJ20190814093401920 and JCYJ20210324125608022,China)Open Research Fund of State Key Laboratory of Genetic Engineering,Fudan University(No.SKLGE-2104,China).
文摘According to the World Health Organization’s world report on hearing,nearly 2.5 billion people worldwide will suffer from hearing loss by 2050,which may contribute to a severe impact on individual life quality and national economies.Sensorineural hearing loss(SNHL)occurs commonly as a result of noise exposure,aging,and ototoxic drugs,and is pathologically characterized by the impairment of mechanosensory hair cells of the inner ear,which is mainly triggered by reactive oxygen species accumulation,inflammation,and mitochondrial dysfunction.Though recent advances have been made in understanding the ability of cochlear repair and regeneration,there are still no effective therapeutic drugs for SNHL.Chinese herbal medicine which is widely distributed and easily accessible in China has demonstrated a unique curative effect against SNHL with higher safety and lower cost compared with Western medicine.Herein we present trends in research for Chinese herbal medicine for the treatment of SNHL,and elucidate their molecular mechanisms of action,to pave the way for further research and development of novel effective drugs in this field.
基金supported by grants from the National Natural Science Foundation of China (81970884,81900941,81970885,82371157,82171145,82271173,and 81771019)the Natural Science Foundation of Jiangsu Province (BK20190121 and BK20200133)+1 种基金the China Postdoctoral Science Foundation (2020M681555)a Distinguished Young Scholarship supported by the Medical Science and Technology Development Foundation,Nanjing Department of Health (JQX20003).
文摘Deafness is the prevailing sensory impairment among humans,impacting every aspect of one's existence.Half of congenital deafness cases are attributed to genetic factors.Studies have shown that Luzp2 is expressed in hair cells(HCs)and supporting cells of the inner ear,but its specific role in hearing remains unclear.To determine the importance of Luzp2 in auditory function,we generated mice deficient in Luzp2.Our results revealed that Luzp2 has predominant expression within the HCs and pillar cells.However,the loss of Luzp2 did not result in any changes in auditory threshold.HCs or synapse number and HC stereocilia morphology in Luzp2 knockout mice did not show any notable distinctions.This was the first study of the role of Luzp2 in hearing in mice,and our results provide important guidance for the screening of deafness genes.
基金supported by the Natural Science Foundation of Jiangsu Province,No.BK20221377(to JG)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China,No.22KJB180023(to JG)。
文摘Rho GTPases are essential regulators of the actin cytoskeleton.They are involved in various physiological and biochemical processes such as the regulation of cytoskeleton dynamics,development,proliferation,survival,and regeneration.During the development of cochlear hair cells,Rho GTPases are activated by various extracellular signals through membrane receptors to further stimulate multiple downstream effectors.Specifically,RhoA,Cdc42,and Rac1,members of the classical subfamily of the Rho GTPase family,regulate the development and maintenance of cilia by inducing the polymerization of actin monomers and stabilizing actin filaments.In addition,they also regulate the normal morphology orientation of ciliary bundles in auditory hair cells,which is an important element of cell polarity regulation.Moreover,the actin-related pathways mediated by RhoA,Cdc42,and Rac1 also play a role in the motility of outer hair cells,indicating that the function of Rho GTPases is crucial in the highly polar auditory sensory system.In this review,we focus on the expression of RhoA,Cdc42,and Rac1 in cochlear hair cells and how these small molecules participate in ciliary bundle morphogenesis and cochlear hair cell movement.We also discuss the progress of current research investigating the use of these small molecules as drug targets for deafness treatment.
基金supported by the National Natural Science Foundation of China (81570916, 81771018, and 81873699)。
文摘Oxidative stress is the key determinant in the pathogenesis of noise-induced hearing loss(NIHL). Given that cellular defense against oxidative stress is an energyconsuming process, the aim of the present study was to investigate whether increasing energy availability by glucose supplementation protects cochlear hair cells against oxidative stress and attenuates NIHL. Our results revealed that glucose supplementation reduced the noiseinduced formation of reactive oxygen species(ROS) and consequently attenuated noise-induced loss of outer hair cells, inner hair cell synaptic ribbons, and NIHL in CBA/J mice. In cochlear explants, glucose supplementation increased the levels of ATP and NADPH, as well as attenuating H_2O_2-induced ROS production and cytotoxicity. Moreover, pharmacological inhibition of glucose transporter type 1 activity abolished the protective effects of glucose against oxidative stress in HEI-OC1 cells. These findings suggest that energy availability is crucial for oxidative stress resistance and glucose supplementation offers a simple and effective approach for the protection of cochlear hair cells against oxidative stress and NIHL.
基金the National Natural Science Foundation of China(No.81771010,81570911)the Nature Science Foundation(No.17ZR1404600)from Shanghai Science and Technology Committee,China.
文摘Hidden hearing loss(HHL),an auditory dysfunction that has gained much recent attention,has the hallmarks of speech discrimination and intelligibility deficits with normal or near-normal hearing thresholds.The pathological mechanisms of HHL are complicated and are not yet fully understood.HHL can be resulted from disorders of the central nervous system such as auditory cortex,and/or pathological changes of inner ear.Thus far,2 pathological phenomena,synaptopathy and auditory nerve demyelination,have been reported as underlying causes of otogenic HHL.Here,we review the clinical and physiological characteristics of HHL as well as the molecular pathological mechanisms of otogenic HHL and aim to allude to potential therapy targets for clinical applications in the future.
基金supported by a grant from the National Natural Science Foundation of China (No. 30672307)
文摘This study examined the expression pattern of programmed cell death 5 (PDCD5) in co-chlear hair cells and spiral ganglion neurons (SGNs) and its association with age-related hearing loss in mice.Sixty C57BL/6J (C57) mice at different ages were divided into four groups (3,6,9 or 12 months).PDCD5 expression was detected by using immunohistochemistry,real-time PCR and Western blot.Morphological change of the cochleae was also evaluated by using immunoassay.The results showed that the expression of PDCD5 had a gradual increase with ageing in both protein and RNA levels in C57 mice,as well as gradually increased apoptosis of cochlear hair cells and SGNs.In addition,we also found that caspase-3 activity was enhanced and its expression was enhanced with ageing.It is implied that overexpression of PDCD5 causes the increase in caspase-3 activity and the subsequent increase of apoptosis in cochlear hair cells and SGNs,and thereby plays a role in the pathogenesis of presbycusis.Thus,PDCD5 may be a new target site for the treatment and prevention of age-related hearing loss.
基金the State Key Program of National Natural Science Foundation of China(No.81530029 to SY)International Cooperation and Exchange of the National Natural Science Foundation of China(No.8171001156 to SY)+1 种基金National Natural Science Foundation of China(No.81771007 to JW)the Major Program of Shanghai Committee of Science and Technology of China(No.14DJ1400202 to SY).
文摘Zebrafish have the potential to regrow injured organs and tissues,but their use as a model for hearing regeneration following blast injury has never been reported.In this study,zebrafish were exposed to a blast wave produced by an underwater blast wave generator.The first peak sound pressures produced by this generator were up to 224dB and 160kPa,measured at 25cm away from the machine.Zebrafish hearing sensitivity was examined by analyzing auditory evoked potentials from 1 to 35 days post blast wave exposure.Cell death and cell proliferation in inner ear organs,including the saccule,lagena,and utricle,were investigated using a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay,and cell proliferation assay using 5-ethynyl-20-deoxyuridine,respectively.Significant differences in auditory evoked potential thresholds were observed between exposed and control groups,demonstrating both blast wave-induced hearing loss and recovery of hearing sensitivity.An apoptosis assay revealed significantly increased numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labelingpositive cells in the inner ear sensory epithelia of exposed groups compared with the control group.However,numbers of 5-ethynyl-20-deoxyuridine-positive cells in the inner ear of exposed groups recovered to a normal level within 10 post blast wave exposure.Furthermore,blast wave exposure caused brain injury with increased cell apoptosis and decreased neurogenesis.Compared with drug or noise-induced zebrafish models,our blast wave-induced model elicited more serious hearing loss phenotypes,which required more time to return to a normal level.Overall,this zebrafish model can provide a reliable animal model for both hearing loss and regeneration research.The study was approved by the Shanghai 6th Hospital Animal Care and Use Committee,China(approval No.2017-0196)on February 28,2017.
基金Projects of Hebei Provincial Administration of Traditional Chinese Medicine,No.2012068
文摘Diabetes mellitus (DM) is a chronic systemic disease characterized by hyperglycemia, with various patho-genic mechanisms. From absolute or relative insulin deficiency, patients with DM often demonstrate vari-ous levels of metabolic disorders. Major clinical manifestations of DM include metabolic disorders, vascu-lar lesions, circulatory disturbances and neurologic complications. Along with advances in DM research, re-ports of DM related tinnitus and hearing impairment have increased continuously. Research on DM related auditory system dysfunction has focused on cochlear microcirculation, cellular homeostasis, genetics and ag-ing. Cochlear microcirculation plays an important role in cochlear physiology and its disorders are associat-ed with many inner ear diseases. Ischemia and subsequent reperfusion seen in cochlear microcirculation dis-orders are important factors in hearing damage. Understanding cochlear microcirculation and structural as well as functional changes in DM patients with hearing loss and their causal factors will help reveal patho-genic mechanisms in diabetic hearing loss and provide new ideas in developing interventions and preventing damages caused by diabetes.
基金This work was supported by grants from National Key R&D Program of China(2021YFA1101300,2020YFA0112503,2020YFA0113600)the Strategic Priority Research Program of the Chinese Academy of Science(XDA16010303)+5 种基金the National Natural Science Foundation of China(82030029,81970882,82071013,81870721,92149304,82000984)the Natural Science Foundation of Jiangsu Province(BE2019711)the Science and Technology Department of Sichuan Province(2021YFS0371)the Shenzhen Fundamental Research Program(JCYJ20190814093401920,JCYJ20210324125608022)the China National Postdoctoral Program for Innovative Talents(BX20200082)the Open Research Fund of State Key Laboratory of Genetic Engineering,Fudan University(SKLGE-2109).
文摘Auditory hair cells(HCs)are the mechanosensory receptors of the cochlea,and HC loss or malfunction can result from genetic defects.Dock4,a member of the Dock180-related protein superfamily,is a guanine nucleotide exchange factor for Rac1,and previous reports have shown that Dock4 mutations are associated with autism spectrum disorder,myelodysplastic syndromes,and tumorigenesis.Here,we found that Dock4 is highly expressed in the cochlear HCs of mice.However,the role of Dock4 in the inner ear has not yet been investigated.Taking advantage of the piggyBac transposon system,Dock4 knockdown(KD)mice were established to explore the role of Dock4 in the cochlea.Compared to wild-type controls,Dock4 KD mice showed significant hearing impairment from postnatal day 60.Dock4 KD mice showed hair bundle deficits and increased oxidative stress,which eventually led to HC apoptosis,late-onset HC loss,and progressive hearing loss.Furthermore,molecular mechanism studies showed that Rac1/β-catenin signaling was significantly downregulated in Dock4 KD cochleae and that this was the cause for the disorganized stereocilia and increased oxidative stress in HCs.Overall,our work demonstrates that the Dock4/Rac1/β-catenin signaling pathway plays a critical role in the maintenance of auditory HCs and hearing function.
文摘Disabling hearing loss is the most common sensorineural disability worldwide.It affects around 466 million people and its incidence is expected to rise to around 900 million people by 2050,according to World Health Organization estimates.Most cases of hearing impairment are due to the degeneration of hair cells(HCs)in the cochlea,mechano-receptors that transduce incoming sound information into electrical signals that are sent to the brain.Damage to these cells is mainly caused by exposure to aminoglycoside antibiotics and to some anti-cancer drugs such as cisplatin,loud sounds,age,infections and genetic mutations.Hearing deficits may also result from damage to the spiral ganglion neurons that innervate cochlear HCs.Differently from what is observed in avian and nonmammalian species,there is no regeneration of missing sensory cell types in the adult mammalian cochlea,what makes hearing loss an irreversible process.This review summarizes the research that has been conducted with the aim of developing cell-based strategies that lead to sensory cell replacement in the adult cochlea and,ultimately,to hearing restoration.Two main lines of research are discussed,one directed toward the transplantation of exogenous replacement cells into the damaged tissue,and another that aims at reactivating the regenerative potential of putative progenitor cells in the adult inner ear.Results from some of the studies that have been conducted are presented and the advantages and drawbacks of the various approaches discussed.
文摘Most recent studies on regeneration of inner ear hair cells focus on use of stem cells, gene therapy and neurotrophic factors. Cochlear gene therapy has been successfully used in the treatment of neu- rosensory hearing loss. This suggests that cochlear hair cell regeneration is possible. The objective of this paper is to review research and clinical application of inner near hair cell regeneration.
基金supported by grants from the National Key R&D Program of China(2021YFA1101300,2021YFA1101800,2020YFA0112503)the National Natural Science Foundation of China(82030029,81970882,82000984,92149304)+4 种基金the Science and Technology Department of Sichuan Province(2021YFS0371)the Shenzhen Fundamental Research Program(JCYJ20190814093401920,JCYJ20210324125608022)the China National Postdoctoral Program for Innovative Talents(BX20200082)the China Postdoctoral Science Foundation(2020M681468)the Open Research Fund of State Key Laboratory of Genetic Engineering,Fudan University(SKLGE-2104).
文摘Hearing loss has become increasingly prevalent and causes considerable disability,thus gravely burdening the global economy.Irreversible loss of hair cells is a main cause of sensorineural hearing loss,and currently,the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids,but these are of limited benefit in patients.It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies.At present,how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research.Multi-ple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells,and in this article,we first review the principal mechanisms underlying hair cell reproduction.We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration,and we summarize current achievements in hair cell regeneration.Lastly,we discuss potential future approaches,such as small molecule drugs and gene therapy,which might be applied for regenerating functional hair cells in the clinic.
基金supported by the Scientifc and Technological Innovation Plan of the Shanghai Science and Technology Committee(20ZR1417000).
文摘Gene expression changes contribute greatly to phenotypic variations in nature.Studying patterns of regulators of gene expression is important to fully understand the molecular mechanism underlying phenotypic variations.In horseshoe bats,the cochleae are fnely tuned to echoes of call frequency.Here,using 2 recently diverged subspecies of the intermediate horseshoe bat(Rhinolophus affnis hainanus and R.a.himalayanus)with great acoustic variations as the system,we aim to explore relative roles of different regulators of gene expression(differential gene expression,alternative splicing(AS)and long non-coding RNAs(lncRNAs))in phenotypic variation with a combination of Illumina short-read and Nanopore long-read RNA-seq data from the cochlea.Compared to R.a.hainanus,R.a.himalayanus exhibited much more upregulated differentially expressed genes(DEGs)and multiple of them may play important roles in the maintenance and damage repair of auditory hair cells.We identifed 411 differentially expressed lncRNAs and their target DEGs upregulated in R.a.himalayanus were also mainly involved in a protective mechanism for auditory hair cells.Using 3 different methods of AS analysis,we identifed several candidate alternatively spliced genes(ASGs)that expressed different isoforms which may be associated with acoustic divergence of the 2 subspecies.We observed signifcantly less overlap than expected between DEGs and ASGs,supporting complementary roles of differential gene expression and AS in generating phenotypic variations.Overall,our study highlights the importance of a combination of short-read and long-read RNA-seq data in examining the regulation of gene expression changes responsible for phenotypic variations.