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Methylmercury induces hair cell loss requiring production of hydrogen peroxide and leukocytes in the zebrafish embryos

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Methylmercury induces hair cell loss requiring production of...

In vitro Differentiation of Adipose-Derived Stem cells into hair cell-Like cells in Guinea Pigs

中国毒理学会环境与生态毒理学专业委员会第七届学术研讨会

作者：杨立新中国环境科学研究院

Hearing impairment and deafness is frequently observed as one of the neurological signs in patients with Minamata disease caused by methylmercury(MeHg) poisoning. Loss of hair cells in humans and animals is a consequence of MeHg poisoning. However, it is still not clear how MeHg causes these hearing deficits. We employed hair cells of lateral line system of the zebrafish embryos as model to explore this question. We exposed zebrafish embryos to MeHg(30-360mg/L) at the different stages, and scored the numbers of hair cells. We find that MeHg-induced reduction of hair cells is in a concentration dependent manner. Loss of hair cells involves the action of leukocytes. Moreover, hair cell loss is attenuated by co-treating MeHg-exposed embryos with pharmacological inhibitors of NADPH oxidases. This is the first evidence that hydrogen peroxide(HO) is a causative mediator of the toxic effect of MeHg in hair cells. In situ gene expression analysis showed that genes encoding the SQSTM1-Keap1-Nrf2 systems involved in combating oxidative stress and immune responses are highly expressed in lateral line organs of embryos exposed to MeHg. This suggests that induction of hydrogen peroxide(HO) is the primary effect of MeHg on hair cells. Genes induced by MeHg are also involved in regeneration of hair cells. These features are likely related to the capacity of the zebrafish to regenerate lost hair cells.

关键词： Zebrafish MeHg hair cell hydrogen peroxide gene expression oxidative stress

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Journal of Otology 2007年第2期2卷 97-101页

作者： WANG Ying1, DONG Min-min1, YANG Hai-bo2, GAO Song-tao3 1 Department of Otolaryngology, the First Affiliated Hospital of Zhengzhou University, China 2 Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, China 3 Department of orthopaedics, Xiangya Hospital of Central South University, China Department of Otolaryngology the First Affiliated Hospital of Zhengzhou University China Department of Cardiology The First Affiliated Hospital of Zhengzhou University China Department of orthopaedics Xiangya Hospital of Central South University China

Objective Adipose-derived stem cells(ADSCs) are suggested to possess a highly plastic ability to differentiate into several specific cell types in addition to adipocyte lineages, including germ layer tissue-specific cell lineages such as chondrocyte, myocyte, neuronal, and osteoblast lineages. The aim of this study is to establish an in vitro culture technique for ADSCs in an adult guinea pig model that facilitate their differentiation into hair cell-like cells. Materials and Methods cells from inguinal fat pads in adult guinea pigs were cultured with β-mercaptoethanol, RA, Forskorin, Heregulin, bFGF, BDNF and EGF. cellular differentiation was examined using immunocytochemistry techniques. Results The ADSCs demonstrated hair cell immunophenotypes with expression of epitopes of the hair cell marker protein myosin Ⅶa. Conclusion ADSCs from adult guinea pig adipose tissue can differentiate into hair cell-like cells when cultured in vitro. ADSCs may serve as seed cells for tissue engineering.

关键词： adipose-derived stem cell hair cell differentiate guinea pig

Inhibition of histone methyltransferase PRMT5 attenuates cisplatininduced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway

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Journal of Pharmaceutical Analysis 2023年第6期13卷 590-602页

作者： Zhiwei Zheng Benyu Nan Chang Liu Dongmei Tang Wen Li Liping Zhao Guohui Nie Yingzi He ENT Institute and Department of Otorhinolaryngology Eye&ENT HospitalState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceNHC Key Laboratory of Hearing Medicine(Fudan University)Fudan UniversityShanghai200031China Department of Otorhinolaryngology-Head and Neck Surgery The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000ZhejiangChina Department of Otolaryngology-Head and Neck Surgery The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou510630China Department of Otolaryngology Shenzhen Institute of Translational MedicineShenzhen Second People's HospitalThe First Affiliated Hospital of Shenzhen UniversityShenzhen518035GuangdongChina

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.

关键词： Protein arginine methyltransferase 5 (PRMT5) LLY-283 Cisplatin Hearing loss hair cell Spiral ganglion neuron

The role of Rho GTPase family in cochlear hair cells and hearing

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Neural Regeneration Research 2023年第10期18卷 2167-2172页

作者： Yu-Bei Dai Xiang Gao Dong Liu Jie Gong School of Life Science Nantong Laboratory of Development and DiseasesKey Laboratory of Neuroregeneration of Jiangsu and Ministry of EducationCo-innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina

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.

关键词： actin assembly auditory sensory neurons cell polarity cell proliferation electromotility hair cell hearing loss morphogenesis Rho GTPases stereocilia

Inhibiting DNA methylation alleviates cisplatininduced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1305-1321页

作者： Yingzi He Zhiwei Zheng Chang Liu Wen Li Liping Zhao Guohui Nie Huawei Li ENT Institute and Otorhinolaryngology Department of Eye&ENT Hospital State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceFudan UniversityShanghai 200031China NHC Key Laboratory of Hearing Medicine(Fudan University) Shanghai 200031China Department of Otolaryngology and Institute of Translational Medicine Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science CenterShanghai 200032China Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science Fudan UniversityShenzhen 518035China

Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss.This study aimed to assess the potential effect of the DNA methyltransferase(DNMT)inhibitor RG108 on cisplatin-induced ototoxicity.Immunohistochemistry,apoptosis assay,and auditory brainstem response(ABR)were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells(HCs)and spiral ganglion neurons(SGNs).Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential(MMP)assessment.Reactive oxygen species(ROS)amounts were evaluated by cellrox green and Mitosox-red probes.Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates(OCRs).The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs,and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation.Furthermore,RG108 upregulated BCL-2 and downregulated APAF1,BAX,and BAD in HEI-OC1 cells,and triggered the PI3K/AKT pathway.Decreased expression of low-density lipoprotein receptor-related protein 1(LRP1)and high methylation of the LRP1 promoter were observed after cisplatin treatment.RG108 treatment can increase LRP1expression and decrease LRP1 promoter methylation.In conclusion,RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.

关键词： Cisplatin DNMT Apoptosis hair cell Spiral ganglion neurons RG108 Mitochondrial dysfunction ROS

Phosphatidylinositol 4-kinase β is required for the ciliogenesis of zebrafish otic vesicle

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Journal of Genetics and Genomics 2020年第10期47卷 627-636页

作者： Yufei Feng Ping Yu Jingyu Li Ying Cao Jingjing Zhang Affiliated Hospital of Guangdong Medical University&Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University Zhanjiang 524001China Clinical and Translational Research Center Shanghai First Maternity and Infant HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China

The primary cilium,an important microtubule-based organelle,protrudes from nearly all the vertebrate cells.The motility of cilia is necessary for various developmental and physiological processes.Phosphoinositides(PIs)and its metabolite,Ptd Ins(4,5)P2,have been revealed to contribute to cilia assembly and disassembly.As an important kinase of the PI pathway and signaling,phosphatidylinositol 4-kinaseβ(PI4 KB)is the one of the most extensively studied phosphatidylinositol 4-kinase isoform.However,its potential roles in organ development remain to be characterized.To investigate the developmental role of Pi4 kb,especially its function on zebrafish ciliogenesis,we generated pi4 kb deletion mutants using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9 technique.The homozygous pi4 kb mutants exhibit an absence of primary cilia in the inner ear,neuromasts,and pronephric ducts accompanied by severe edema in the eyes and other organs.Moreover,smaller otic vesicle,malformed semicircular canals,and the insensitivity on sound stimulation were characteristics of pi4 kb mutants.At the protein level,both in vivo and in vitro analyses revealed that synthesis of Pi4 p was greatly reduced owing to the loss of Pi4 kb.In addition,the expression of the Pi4 kb-binding partner of neuronal calcium sensor-1,as well as the phosphorylation of phosphatidylinositol-4-phosphate downstream effecter of Akt,was significantly inhibited in pi4 kb mutants.Taken together,our work uncovers a novel role of Pi4 kb in zebrafish inner ear development and the functional formation of hearing ability by determining hair cell ciliogenesis.

关键词： Ciliogenesis Pi4kb hair cell Hearing loss Zebrafish

Glucose Protects Cochlear hair cells Against Oxidative Stress and Attenuates Noise-Induced Hearing Loss in Mice

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Neuroscience Bulletin 2021年第5期37卷 657-668页

作者： Hao Xiong Lan Lai Yongyi Ye Yiqing Zheng Department of Otolaryngology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Institute of Hearing and Speech-Language Science Sun Yat-sen UniversityGuangzhou 510120China

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.

关键词： Oxidative stress Glucose Cochlea hair cell Hearing loss

Dissection of voltage-gated sodium channels in developing cochlear sensory epithelia

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Protein & cell 2015年第6期6卷 458-462页

作者： You Zhou Fang-Hao Fang Zhi-Rui Liu Yong-Hua Ji Laboratory of Neuropharmacology and Neurotoxicology ShanghaiUniversity Shanghai 200436 China

Dear Editor hair cells （HCs） clustered produce spontaneous spike n cochlear sensory epithelia and evoked action potentials during the developmental stage of auditory, which rely on many ion channels, such as Ca2＋ channels, K＋ channels and Na＋ channels （Housley et al., 2006; Marcotti et al., 2003）. As the dominant molecule acting in action potentials in most of excitable cells, Na＋ channels （VGSCs） were deemed to be indispensable in the spontaneous and evoked action po- tentials of HCs （Marcotti et al., 2003）.

关键词： Alternative Splice hair cell Editing Site Intracellular Loop Sensory Epithelium

Notch pathway inhibitor DAPT enhances Atoh1 activity to generate new hair cells in situ in rat cochleae

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Neural Regeneration Research 2017年第12期12卷 2092-2099页

作者： Wen-wei Luo Zhao Han Dong-dong Ren Xin-wei Wang Fang-lu Chi Juan-mei Yang Department of Otolaryngology Eye & ENT Hospital of Fudan University Research Institute of Otolaryngology Fudan University

Atoh1 overexpression in cochlear epithelium induces new hair cell formation. Use of adenovirus-mediated Atoh1 overexpression has mainly focused on the rat lesser epithelial ridge and induces ectopic hair cell regeneration. The sensory region of rat cochlea is difficult to transfect, thus new hair cells are rarely produced in situ in rat cochlear explants. After culturing rat cochleae in medium containing 10% fetal bovine serum, adenovirus successfully infected the sensory region as the width of the supporting cell area was significantly increased. Adenovirus encoding Atoh1 infected the sensory region and induced hair cell formation in situ. Combined application of the Notch inhibitor DAPT and Atoh1 increased the Atoh1 expression level and decreased hes1 and hes5 levels, further promoting hair cell generation. Our results demonstrate that DAPT enhances Atoh1 activity to promote hair cell regeneration in rat cochlear sensory epithelium in vitro.

关键词： nerve regeneration Atoh 1 DAPT. transdifferentiation gamma secretase inhibitor cochlea sensory epithelium fetal bovine serum hair cell supporting cell hair cell regeneration neural regeneration