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Mitochondrial DNA Mutations Associated with Aminoglycoside Ototoxicity

Journal of Otology 2006年第2期1卷 65-75页

作者： GUAN Min-Xin Division of Human Genetics and center for hearing and Deafness Research, Cincinnati Children’s Hospital Medical center, Cincinnati, Ohio 45229, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA Division of Human Genetics and center for hearing and Deafness Research Cincinnati Children’s Hospital Medical Center Cincinnati Ohio 45229 USA Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio 45229 USA

The mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and non-syndromic hearing loss. Of all the mutations, the homoplasmic A1555G and C1494T mutations at a highly conserved decoding region in the 12S rRNA have been associated with aminoglycoside-induced and non-syndromic hearing loss in many families worldwide. The A1555G or C1494T mutation is expected to form novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the secondary structure of this RNA more closely resemble the corresponding region of bacterial 16S rRNA. Thus, the new U-A or G-C pair in 12S rRNA created by the C1494T or A1555G transition facilitates the binding of aminoglycosides, thereby accounting for the fact that the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying these mutations. Furthermore, the growth defect and impairment of mitochondrial translation were observed in cell lines carrying the A1555G or C1494T mutation in the presence of high concentration of aminoglycosides. In addition, nuclear modifier genes and mitochondrial haplotypes modulate the phenotypic manifestation of the A1555G and C1494T mutations. These observations provide the direct genetic and biochemical evidences that the A1555G or C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and nonsyndromic hearing loss. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside antibiotic therapy, and eventually to decrease the incidence of deafness.

关键词： gene Mitochondrial DNA Mutations Associated with Aminoglycoside Ototoxicity rRNA DNA

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Interactive effects of morphine and dopaminergic compounds on spatial working memory in rhesus monkeys

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Neuroscience Bulletin 2013年第1期29卷 37-46页

作者： Jian-Hong Wang Joshua Dominie Rizak Yan-Mei Chen Liang Li Xin-Tian Hu Yuan-Ye Ma State Key Laboratory of Brain and Cognitive Sciences Kunming Institute of Zoology Chinese Academy of Sciences Graduate University of Chinese Academy of Sciences Department of Psychology Speech and Hearing Research Center Key Laboratory on Machine Perception (Ministry of Education) Peking University

Opiates and dopamine （DA） play key roles in learning and memory in humans and animals. Although interactions between these neurotransmitters have been found, their functional roles remain to be fully elucidated, and their dysfunction may contribute to human diseases and addiction. Here we investigated the interactions of morphine and dopaminergic neurotransmitter systems with respect to learning and memory in rhesus monkeys by using the Wisconsin General Test Apparatus （WGTA） delayed-response task. Morphine and DA agonists （SKF-38393, apomorphine and bromocriptine） or DA antagonists （SKF-83566, haloperidol and sulpiride） were co-administered to the monkeys 30 min prior to the task. We found that dose-patterned co-administration of morphine with D1 or D2 antagonists or agonists reversed the impaired spatial working memory induced by morphine or the compounds alone. For example, morphine at 0.01 mg/kg impaired spatial working memory, while morphine （0.01 mg/kg） and apomorphine （0.01 or 0.06 mg/kg） co-treatment ameliorated this effect. Our findings suggest that the interactions between morphine and dopaminergic compounds influence spatial working memory in rhesus monkeys. A better understanding of these interactive relationships may provide insights into human addiction.

关键词： working memory morphine dopamine rhesus monkey

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m^(6)A modification of lncRNA in middle ear cholesteatoma

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中南大学学报（医学版） 2024年第5期49卷 667-678页

作者： HE Jun XIE Shumin JIN Li FU Jinfeng YUAN Qiulin LIU Wei Department of Otolaryngology-Head and Neck Surgery Second Xiangya HospitalCentral South UniversityChangsha 410011 Clinical Medical Research center for Otology in Hunan Province Changsha 410011 Department of Otolaryngology-Head and Neck Surgery Xiangya HospitalCentral South UniversityChangsha 410008 Otolaryngology Major Disease Research Key Laboratory of Hunan Province Changsha 410008 Clinical Research center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province Changsha 410008 National Clinical Research center for Geriatric Disorders Xiangya HospitalChangsha 410008China

Objective:Middle ear cholesteatoma is a non-tumorous condition that typically leads to hearing loss,bone destruction,and other severe *** surgery being the primary treatment,the recurrence rate remains ***,exploring the molecular mechanisms underlying cholesteatoma is crucial for discovering new therapeutic *** study aims to explore the involvement of N6-methyladenosine(m^(6)A)methylation in long non-coding RNAs(lncRNAs)in the biological functions and related pathways of middle ear ***:The m^(6)A modification patterns of lncRNA in middle ear cholesteatoma tissues(n=5)and normal post-auricular skin tissues(n=5)were analyzed using an lncRNA m^(6)A transcriptome *** Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were conducted to identify potential biological functions and signaling pathways involved in the pathogenesis of middle ear *** RNA immunoprecipitation(MeRIP)-PCR was used to validate the m^(6)A modifications in cholesteatoma and normal skin ***:Compared with normal skin tissues,1525 lncRNAs were differentially methylated in middle ear cholesteatoma tissues,with 1048 showing hypermethylation and 477 showing hypomethylation[fold change(FC)≥3 or<1/3,P<0.05].GO enrichment analysis indicated that hypermethylated lncRNAs were involved in protein phosphatase inhibitor activity,neuron-neuron synapse,and regulation ofα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)receptor *** lncRNAs were associated with mRNA methyltransferase activity,secretory granule membrane,and mRNA *** analysis revealed that hypermethylated lncRNAs were mainly associated with 5 pathways:the Hedgehog signaling pathway,viral protein interaction with cytokines and cytokine receptors,mitogen-activated protein kinase(MAPK)signaling pathway,cytokine-cytokine receptor interaction,and adrenergic signaling in ***

关键词： long non-coding RNA m6A modifications middle ear cholesteatoma

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Electrically evoked auditory nerve responses in the cochlea with normal outer hair cells

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Journal of Otology 2009年第2期4卷 71-75页

作者： Josef M Miller Alfred L Nuttall Kresge hearing Research Institute The University of Michigan1150 West Medical Center DriveMS IIAnn ArborMichigan 48109-0506 Oregon hearing Research center(NRC04) Department of Otolaryngology and Head & Neck SurgeryOregon Health Science University3181 SW Sam Jackson Park RoadPortlandOregon97239-3098

As hybrid cochlear implant devices are increasingly used for restoring hearing in patients with residual hearing, it is important to understand electrically evoked responses in cochleae having functional hair cells. To test the hypothesis that extracochlear electrical stimulation (EES) from sinusoidal current can provoke an auditory nerve response with normal frequency selectivity, the EES-evoked compound action potential(ECAP) was investigated in this study. Brief sinusoidal electrical currents, delivered via a round window electrode, were used to evoke ECAP. The ECAP waveform was observed to be the same as the acoustically evoked CAP(ACAP), except for a shorter latency. The input/output and intensity/latency functions of ACAPs and ECAPs were also similar. The maximum acoustic masking for both ACAP and ECAP occurred near probe frequencies. Since the masked tuning curve of a CAP reflects the frequency selectivity of neural excitation, these data demonstrate a highly specific activation of the auditory nerve, which would result in high degree of frequency selectivity. This frequency selectivity likely results from the cochlear traveling wave caused by electrically stimulated outer hair cells.

关键词： Gerbil Cochlea Electrical stimulation hearing cochlear implant cochlear compound action potential

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Recent advances in the regulation mechanism of SOX10

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Journal of Otology 2022年第4期17卷 247-252页

作者： Jingcui Qi Long Ma Weiwei Guo Department of Otorhinolaryngology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina PLA Rocket Force Characteristic Medical center Department of Stomatology China College of Otolaryngology Head and Neck Surgery Chinese PLA General HospitalBeijing 100853China National Clinical Research center for Otolaryngologic Diseases BeijingChina Key Lab of hearing Science Ministry of EducationChina Beijing Key Lab of hearing Impairment for Prevention and Treatment BeijingChina

Neural crest(NC)is the primitive neural structure in embryonic stage,which develops from ectodermal neural plate cells and epithelial *** the neural fold forms into neural tube,neural crest also forms a cord like structure above the neural tube and below the *** crest cells(NCC)have strong migration and proliferation abilities.A number of tissue cells differentiate from neural crest cells,such as melanocytes,central and peripheral neurons,glial cells,craniofacial cells,osteoblasts,chondrocytes and smooth muscle *** migration and differentiation of neural crest cells are regulated by a gene network where a variety of genes,transcriptional factors,signal pathways and growth factors are involved.

关键词： neural facial crest

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Saccades of video head impulse test in Meniere's disease and Vestibular Migraine: What can we learn from?

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Journal of Otology 2023年第2期18卷 79-84页

作者： Yi Du Xingjian Liu Lili Ren Yu Wang Fei Ji Weiwei Guo Ziming Wu College of Otolaryngology Head and Neck Surgery Chinese PLA General HospitalChinese PLA Medical School28 Fuxing RoadBeijingChina National Clinical Research center for Otolaryngologic Diseases BeijingChina State Key Lab of hearing Science Ministry of EducationBeijingChina Beijing Key Lab of hearing Impairment Prevention and Treatment BeijingChina

Background:Saccades are often observed on video head impulse tests(vHIT)in patients with Meniere's Disease(MD)and Vestibular Migraine(VM).However,their saccadic features are not fully ***:This study aims to identify the saccades characteristics of MD and ***:75 VM patients and 103 definite unilateral MD patients were enrolled in this *** raw saccades were exported and *** VM patients were divided into left and right based on their ears,while the MD patients were separated into affected and unaffected subgroups based on their audiograms and ***:The MD patients have more saccades on the affected side(85%vs.69%),and saccade velocity is more consistent than the contralateral side(shown by the coefficient of variation).The saccades occurrence rates on both sides are similar in VM(77%vs.76%),as are other saccadic *** MD patients have more significant inter-aural differences than the VM patients,manifested in higher velocity(p-value 0.000),earlier arriving(p-value 0.010),and more time-domain gathered(p-value 0.003)on the affected ***:Bilateral saccades are commonly observed in MD and *** contrast to MD,saccades on VM are subtle,scattered,and ***,the MD patients showed inconsistent saccadic distribution with more velocity-uniform saccades on the affected side.

关键词： Meniere's disease Vestibular migraine Saccades Video head impulse test Differential diagnosis

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Analysis of video head impulse test saccades data in patients with vestibular migraine or probable vestibular migraine

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Journal of Otology 2022年第4期17卷 197-202页

作者： Yi Du Xingjian Liu Lili Ren Yu Wang Ziming Wu College of Otolaryngology Head and Neck Sury Chinese PLA General HospitalChinese PLA Medical School28 Fuxing RoadBeijingChina National Clinical Research center for Otolaryngologic Diseases BeijingChina State Key Lab of hearing Science Ministry of EducationBeijingChina Beijing Key Lab of hearing Impairment Prevention and Treatment BeijingChina

Objective:Saccades accompanied by normal gain in video head impulse tests(vHIT)are often observed in patients with vestibular migraine(VM).However,they are not considered as an independent indicator,reducing their utility in diagnosing *** better understand clinical features of VM,it is necessary to understand raw saccades ***:Fourteen patients with confirmed VM,45 patients with probable VM(p-VM)and 14 agematched healthy volunteers were included in this *** findings related to spontaneous nystagmus(SN),positional nystagmus(PN),head-shaking nystagmus(HSN),caloric test and vHIT were *** saccades data were exported and numbered by their sequences,and their features ***:VM patients showed no SN,PN or HSN,and less than half of them showed unilateral weakness(UW)on caloric *** first saccades from lateral semicircular canal stimulation were the most predominant for both left and right *** velocity nor time parameters were significantly different when compared between the two *** VM patients(86%)exhibited small saccades,around 35%of the head peak velocity,with a latency of 200e400 *** of saccades were similar in patients with *** four normal subjects showed saccades,all unilateral and seemingly ***:Small saccades involving bilateral semicircular canals with a scattered distribution pattern are common in patients with VM and p-VM.

关键词： Vestibular migraine Probable vestibular migraine Video head impulse test Saccade Data analysis

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Signal Transduction and Targeted Therapy 2022年第7期7卷 2533-2544页

作者： Xi Shi Zihao Wang Wei Ren Long Chen Cong Xu Menghua Li Shiyong Fan Yuru Xu Mengbing Chen Fanjun Zheng Wenyuan Zhang Xinbo Zhou Yue Zhang Shiwei Qiu Liyuan Wu Peng Zhou Xinze Lv Tianyu Cui Yuehua Qiao Hui Zhao Weiwei Guo Wei Chen Song Li Wu Zhong Jian Lin Shiming Yang Department of Pharmacy Peking University Third HospitalBeijingChina Artificial Auditory Laboratory of Jiangsu Province Xuzhou Medical UniversityXuzhouChina National Engineering Research center for the Emergency Drug Beijing Institute of Pharmacology and ToxicologyBeijingChina College of Otolaryngology Head and Neck Surgery Chinese PLA General HospitalBeijingChina National Clinical Research center for Otolaryngologic Diseases BeijingChina Key Lab of hearing Science Ministry of EducationBeijingChina Beijing Key Lab of hearing Impairment for Prevention and Treatment BeijingChina Synthetic and Functional Biomolecules center Beijing National Laboratory for Molecular SciencesKey Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of EducationCollege of Chemistry and Molecular EngineeringInnovation Center for GenomicsPeking UniversityBeijingChina

Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people ***,the presence of the blood-labyrinth barrier(BLB)on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability,which restricts the entry of most drug compounds from the bloodstream into the inner ear ***,we report the finding of a novel receptor,low-density lipoprotein receptor-related protein 1(LRP1),that is expressed on the BLB,as a potential target for shuttling therapeutics across this *** a proof-ofconcept,we developed an LRP1-binding peptide,IETP2,and covalently conjugated a series of model small-molecule compounds to it,including potential drugs and imaging *** compounds were successfully delivered into the inner ear and inner ear lymph,indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the *** discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.

关键词： drugs prevention barrier

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Shrinkage of ipsilateral taste buds and hyperplasia of contralateral taste buds following chorda tympani nerve transection

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Neural Regeneration Research 2015年第6期10卷 989-995页

作者： Yi-ke Li Juan-mei Yang Yi-bo Huang Dong-dong Ren Fang-lu Chi Department of Otology and Skull Base Surgery Eye Ear Nose & Throat HospitalFudan University Shanghai Auditory Medical center Key Laboratory of hearing Science Ministry of Health Department of hearing and Speech Sciences Vanderbilt University

The morphological changes that occur in the taste buds after denervation are not well under- stood in rats, especially in the contralateral tongue epithelium. In this study, we investigated the time course of morphological changes in the taste buds following unilateral nerve transection. The role of the trigeminal component of the lingual nerve in maintaining the structural integrity of the taste buds was also examined. Twenty-four Sprague-Dawley rats were randomly divided into three groups： control, unilateral chorda tympani nerve transection and unilateral chorda tympani nerve transection ＋ lingual nerve transection. Rats were allowed up to 42 days of re- covery before being euthanized. The taste buds were visualized using a cytokeratin 8 antibody. Taste bud counts, volumes and taste receptor cell numbers were quantified and compared among groups. No significant difference was detected between the chorda tympani nerve transection and chorda tympani nerve transection ＋ lingual nerve transection groups. Taste bud counts, volumes and taste receptor cell numbers on the ipsilateral side all decreased significantly compared with control. On the contralateral side, the number of taste buds remained unchanged over time, but they were larger, and taste receptor cells were more numerous postoperatively. There was no evidence for a role of the trigeminal branch of the lingual nerve in maintaining the structural integrity of the anterior taste buds.

关键词： nerve regeneration gustation cytokeratin tongue epithelium immunohistochemistry taste bud trigeminal nerve disorder NSFC grants neural regeneration

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Modulation of copper transporters in protection against cisplatin-induced cochlear hair cell damage

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Journal of Otology 2011年第2期6卷 51-59页

作者： Richard Salvi center for hearing and Deafness Department of Communicative Disorders and SciencesState University of New York at Buffalo137 Cary Hall3435 Main StreetBuffaloNY 14214 USA

Cisplatin belongs to platinum-based drugs and is widely used in cancer *** is one of the major dose limiting side-effects of *** toxicity to occur cisplatin must first be transported from the bloodstream into cochlear *** copper transporters are considered pathways for regulating the uptake and translocation of cisplatin into cells:Ctr1,ATP7A and *** recent study with cochlear organotypic cultures shows that cochlear hair cells can be destroyed by cisplatin at low concentrations from 10μm to 100μ***,high doses of cisplatin cannot damage hair cells,maybe due to intrinsic feedback reactions that increase export of platinum by ATP7B when the platinum concentration is high in extracellular *** is a specific copper transporter inhibitor that can block the entrance of copper and platinum,and may prevent cisplatin-induced cochlear hair cell *** evaluate this hypothesis,we treated cochlear organotypic cultures with cisplatin (10 μm or 50 μm) alone,or cisplatin combined with cimitidine at concentrations ranging from 10-2000 μm for 48 *** at 10 μm damaged about 20% hair *** contrast,when cimitidine (10 μm,100 μm and 2000 μm) was added to the culture,near 100% cochlear hair cell *** higher concentration (50 μm),cisplatin destroyed about 80% of cochlear hair ***,100 μmcimitidine rescued about 50% hair cells from cisplatin damage,and 2000μm cimitidine protected about 80% hair *** data of western blot showed that CTR1 and ATP7B expressions were increased in cisplatin treated cochlear tissue,but cimitidine significantly reduced CTR1 and *** addition,ATP7A expression was depressed a little after cisplatin *** that Ctr1 is involved in copper and platinum influx,but the ATP7A and ATP7B are copper export transporters,the results suggest that cimitidine can effectively block the entrance by copper transporters and stop the influx of cisplatin.

关键词： cisplatin copper transporter ototoxicity cochlear hair cell

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