Biomolecules
·
2024
·Vol. 14
·期 1
·95
·
IF 4.8
Fei Tan,Xuran Li,Xiao Li,Maoxiang Xu,Khawar Ali Shahzad,Lei Hou
Recent advances in cochlear implantology are exemplified by novel functional strategies such as bimodal electroacoustic stimulation, in which the patient has intact low-frequency hearing and profound high-frequency hearing pre-operatively. Therefore, the synergistic restoration of dysfunctional cochlear hair cells and the protection of hair cells from ototoxic insults have become a persistent target pursued for this hybrid system. In this study, we developed a composite GelMA/PEDOT:PSS conductive hydrogel that is suitable as a coating for the cochlear implant electrode for the potential local delivery of otoregenerative and otoprotective drugs. Various material characterization methods (e.g.,1H NMR spectroscopy, FT-IR, EIS, and SEM), experimental models (e.g., murine cochlear organoid and aminoglycoside-induced ototoxic HEI-OC1 cellular model), and biological analyses (e.g., confocal laser scanning microscopy, real time qPCR, flow cytometry, and bioinformatic sequencing) were used. The results demonstrated decent material properties of the hydrogel, such as mechanical (e.g., high tensile stress and Young’s modulus), electrochemical (e.g., low impedance and high conductivity), biocompatibility (e.g., satisfactory cochlear cell interaction and free of systemic toxicity), and biosafety (e.g., minimal hemolysis and cell death) features. In addition, the CDR medicinal cocktail sustainably released by the hydrogel not only promoted the expansion of the cochlear stem cells but also boosted the trans-differentiation from cochlear supporting cells into hair cells. Furthermore, hydrogel-based drug delivery protected the hair cells from oxidative stress and various forms of programmed cell death (e.g., apoptosis and ferroptosis). Finally, using large-scale sequencing, we enriched a complex network of signaling pathways that are potentially downstream to various metabolic processes and abundant metabolites. In conclusion, we present a conductive hydrogel-based local delivery of bifunctional drug cocktails, thereby serving as a potential solution to intracochlear therapy of bimodal auditory rehabilitation and diseases beyond.Keywords:conductive hydrogel;hair cell;hair cell regeneration;apoptosis;ferroptosis;cochlear implant;electroacoustic stimulation;GelMA;PEDOT:PSS
研究领域:
生物材料
·
生物医学工程
·
人工耳蜗学
·
再生医学
·
耳科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA OTO-LARYNGOLOGICA
·
2024
·
IF 1.2
Nishan Chen,Tongxiang Diao,Jilei Zhang,Lisheng Yu
Backgrounds Due to the therapeutic needs of inner ear diseases, a simple method of inner ear drug delivery has been under exploration. Postauricular administration, which involves injecting the drug through the middle of the retroauricular groove, is a potential novel approach, but its mechanisms remain unclear.Objectives To investigate threshold shifts in the auditory brainstem response (ABR), as well as the morphology and quantity of hair cells on the bilateral inner ear of guinea pigs after postauricular neomycin administration.Material and Methods Thirty healthy guinea pigs were divided randomly into two groups and administered either neomycin 200 mg/kg or saline 1 ml via daily postauricular injection for 10 days. Auditory threshold-shifts were examined by tests of the ABR. The quantity and morphology of hair cells in the organ of Corti were assessed by confocal laser scanning microscopy.Results The ABR results showed that at a frequency of 16 kHz, the threshold shift was 21.00 ± 14.49 dB in the neomycin injection side, 10.00 ± 16.67 dB in the contralateral side, and 0.50 ± 3.69 dB in the saline group. At a frequency of 24 kHz, the threshold shift was 37.00 ± 16.36 dB in the neomycin injection side, 14.50 ± 9.26 dB in the contralateral side, and 1.00 ± 2.11 dB in the saline group. Histopathological analysis revealed that the outer hair cells (OHCs) in the neomycin injection side suffered significant morphological and numerical loss, while the OHC loss in the contralateral ear was less severe than in the injection side but greater than in the saline group.Conclusions and Significance This study confirms that postauricular administration is a novel method of local drug delivery to the inner ear, which has practical value in future experimental modeling and the treatment of inner ear diseases.
研究领域:
耳科学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Neurology
·
2025
·
IF 2.8
Renlong Ji,Yanchang Xu,Kang Li,Wen Jiang,Yuan Li,Jianwei Zeng,Wei Li,Caiji Wang,Zeqi Zhao,Yalan Li,Naveena Konduru,Wen Liu,Yuehua Qiao,Xuanyi Li
Objective: To investigate the effects of Zexie decoction on vestibular and auditory function in guinea pigs with endolymphatic hydrolysis induced by desmopressin. Methods: Sixty guinea pigs were randomly and evenly divided into four groups, each group has 15 guinea pigs: normal control group, DDAVP group, DDAVP modeling combined with Zexie Decoction group, and DDAVP combined with Double Zexie group. At 7 and 14 days, bone-conducted cervical vestibular evoked myogenic potential tests, auditory brainstem responses, and distortion-product otoacoustic emissions were conducted on each group of guinea pigs to evaluate their vestibular and auditory function quantitatively. After functional testing, the outer hair cells were observed by scanning electron microscope. On day 14, one guinea pig was randomly selected from both the normal control group and DDAVP group to verify the successful establishment of the model using gadolinium-enhanced magnetic resonance imaging of the inner ear.Results: We conducted BC-cVEMP, ABR, and DPOAE tests on guinea pigs, and the results showed that DDAVP did affect vestibular function and hearing in guinea pigs. Analyses were performed from those results that were statistically significant, Zexie Decoction improved DDAVP-induced vestibular dysfunction and hearing loss dose-dependently, though complete reversal was not achieved. About scanning electron microscopy, outer hair cells of the DDAVP group showed significant loss and cilia lodging, however, treatment with Zexie decoction can alleviate the loss of outer hair cells and the lodging of cilia. When the outer hair cells were exposed to DDAVP for a long time, the improvement effect of Zexie decoction was not as obvious as before.Conclusion: The extent of improvement correlates with the concentration and dosage of Zexie Decoction. Even at double the dosage, Zexie Decoction only partially mitigates the decline in vestibular and auditory function induced by DDAVP, falling short of complete reversal.
研究领域:
药理学
·
听力学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Metabolites
·
2021
·Vol. 11
·期 12
·873
·
IF 4.932
Fengjiao Chen,Ying Yang,Jianling Chen,Zihua Tang,Qian Peng,Jinfu Wang,Jie Ding
The Notch signaling pathway plays an important role in otic neurogenesis by regulating the differentiation of inner ear hair cells and supporting cells. Notch-regulated differentiation is required for the regeneration of hair cells in the inner ear. The temporal expression pattern of Notch ligands and receptors during in vitro hair cell-like cell differentiation from human embryonic stem cells (hESCs) was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Subsequently, pAJ-U6-shRNA-CMV-Puro/GFP recombinant lentiviral vectors encoding short hairpin RNAs were used to silence JAG-1, JAG-2, and DLL-1, according to the temporal expression pattern of Notch ligands. Then, the effect of each ligand on the in vitro differentiation of hair cells was examined by RT-PCR, immunofluorescence, and scanning electron microscopy (SEM). The results showed that the individual deletion of JAG-2 or DLL-1 had no significant effect on the differentiation of hair cell-like cells. However, the simultaneous inhibition of both DLL-1 and JAG-2 increased the number of hair cell-like cells and decreased the number of supporting cells. JAG-2 and DLL-1 may have a synergistic role in in vitro hair cell differentiation.Keywords:human embryonic stem cells;progenitor cells;hair cell-like cells;Notch signaling pathway;shRNA
研究领域:
干细胞生物学
·
分子生物学
·
发育生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
·
2025
·
IF 6.9
Tang Wei,Zong Shimin,Du Peiyu,Yu Xuan,Li Ting,Liu Bo,Zhong Yu,Lei Wenyang,Yu Wenting,Xiao Hongjun
Cochlear hair cell death is the primary cause of cisplatin-induced ototoxicity, currently lacking widely applicable clinical methods for effective prevention and treatment. In this study, an in vivo cisplatin-induced ototoxicity model was established by intraperitoneal injection of 12 mg/kg cisplatin. We found that ablation of SIRT3 exacerbates cisplatin-induced hearing loss and cochlear hair cell damage. An in vitro cisplatin-induced ototoxicity model was established using 5 µM cisplatin in cochlear explants and OC-1 cells. We found that the absence of SIRT3 impairs cochlear hair cell glycolytic metabolism, leading to excessive accumulation of ROS and significant reduction in MMP levels, thereby promoting apoptosis. In contrast, overexpression of SIRT3 in OC-1 cells promotes cochlear hair cell survival and reduces cochlear hair cell apoptosis. Inhibition of PFKFB3 reduces glycolytic metabolism in OC-1 cells, and the protective effect conferred by SIRT3 overexpression is lost. In summary, the protective effect of SIRT3 may be mediated by the regulation of PFKFB3-dependent glycolysis and the mitigation of cisplatin-induced excessive ROS accumulation.
研究领域:
耳鼻喉科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Jie Tang,Bairu Chen,Fang Yu,Long Xu,Muxin Yu,Chunji Wang,Fang Zhang,Li Zhang,Yujia Yang,Jiani Hou,Xingfei Li,Weihao Xu,Nenghua Zhang
Increasing evidence links hearing loss to environmental pollutant exposure, with cochlear hair cell being a key target. Bisphenol A (BPA) has been suggested to cause ototoxicity, but its mechanism is not fully understood. In this study, cell viability was assessed by varying concentrations of BPA (0–150 μM) exposed to mouse cochlear hair cells (HEI-OC1), followed by RNA transcriptome sequencing to identify the possible molecular mechanisms. Results showed that BPA above 50 μM reduced cell viability in a dose-dependent manner. RNA sequencing identified 1764 differentially-expressed genes, comprised of 1152 up-regulated and 612 down-regulated genes. Notably, estrogen receptor-related genes were enriched, with a marked up-regulation of estrogen receptor α (ER-α) at both mRNA and protein levels. GO and KEGG analyses revealed the main pathway involvement for oxidative damage, lipid metabolism, protein phosphorylation, and DNA damage. STRING analyses constructed gene networks to identify functionally interacting genes correlated with pyroptotic pathways. BPA exposure induced pyroptosis-like morphological changes characterized by cell swelling, rounding, and membrane blebbing. Increased intracellular ROS and mitochondrial superoxide (MitoSOX) levels, reduced mitochondrial membrane potential ( ΔΨm ), and elevated intracellular calcium (Ca²⁺) levels were observed. Flow cytometry showed an increased proportion of apoptotic and necrotic cells. Pyroptosis-related genes, including caspase-3, caspase-8, caspase-9, and GSDME, were down-regulated, while IL-1β and IL-18 were up-regulated. Protein expressions of caspase-3, caspase-8, caspase-9, and GSDME were decreased, while cleaved caspase-3 and N-terminal GSDME (GSDME-NT) were increased. Furthermore, ROS inhibitor N-acetylcysteine (NAC) and the ER-α antagonist fulvestrant alleviated BPA-induced cell death, and suppressed the protein expressions of the pyroptotic pathway. These results demonstrate that BPA exposure induces ototoxicity possibly through activating ER-α and triggering mitochondrial ROS that contributes to pyroptosis.
研究领域:
毒理学
·
耳科学
·
分子生物学
·
环境健康
·
细胞死亡机制
·
内分泌干扰物
✓ 已验证
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2018
·
IF 4.427
Jieyi Li,Yuhang Ling,Wenhao Huang,Limei Sun,Yanyan Li,Caihong Wang,Yuhuan Zhang,Xuedong Wang,Randy A. Dahlgren,Huili Wang
Chronic ototoxicity of β-diketone antibiotics ( DKAs) to zebrafish ( Danio rerio ) was explored in detail by following abnormal expressions of two hearing-related miRNAs. Dose-dependent down-regulation of miR-96 and miR-184 was observed in otoliths during embryonic-larval development. Continuous DKA exposure to 120-hpf larva decreased sensitivity to acoustic stimulation. Development of otolith was delayed in treatment groups, showing unclear boundaries and vacuolization at 72-hpf, and utricular enlargement as well as decreased saccular volume in 96-hpf or latter larval otoliths. If one miRNA was knocked-down and another over-expressed, only a slight influence on morphological development of the otic vesicle occurred, but knocked-down or over-expressed miRNA both significantly affected zebrafish normal development. Injection of miR-96, miR-184 or both micRNA mimics to yolk sac resulted in marked improvement of otic vesicle phenotype. However, hair cell staining showed that only the injected miR-96 mimic restored hair cell numbers after DKA exposure, demonstrating that miR-96 played an important role in otic vesicle development and formation of hearing, while miR-184 was only involved in otic vesicle construction during embryonic development . These observations advance our understanding of hearing loss owing to acute antibiotic exposure and provide theoretical guidance for early intervention and gene therapy for drug-induced diseases.
研究领域:
分子生物学
·
发育生物学
·
药理学
·
遗传学
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2018
·
IF 4.37
Xueling Wang,Yuming Chen,Yong Tao,Yunge Gao,Dehong Yu,Hao Wu
Background The delivery of treatment agents to inner ear with drug delivery system (DDS) has been under investigation to overcome the limitations of the conventional therapeutic agents in curing or alleviating the cisplatin ototoxicity. Methods In the present study, a novel targeted dexamethasone (DEX)-loaded DDS, A666-DEX-NP, was constructed for prevention from cisplatin-induced hearing loss. A666-(CLEPRWGFGWWLH) peptides specifically bind to prestin, which is limited to the outer hair cells (OHCs). HEI-OC1 and cisplatin-treated guinea pigs (12 mg/kg, intraperitoneal) were used as in vitro and in vivo models for investigating the targeting and protective efficiency against cisplatin. Results As expected, compared to A666-unconjugated nanoparticles (NP), A666-conjugated coumarin 6-labeled NP showed active targeting to OHCs. Furthermore, A666-coumarin 6-labeled NP could be significantly internalized by HEI-OC1 cells via the A666–prestin interaction. This facilitated the uptake of cells pretreated with A666-DEX-NP, followed by the cisplatin-treated group, which led to enhanced cell viability, reduced apoptotic properties, and decreased reactive oxygen species levels as compared to cells pretreated with DEX or DEX-NP, 4 hours in advance of cisplatin treatment. In cisplatin-treated guinea pigs, pretreatment with A666-DEX-NP effectively preserved OHCs and showed significant hearing protection at 4, 8, and 16 kHz as compared to pretreatment with saline, DEX, or DEX-NP formulation. Conclusion This OHC-targeting DDS provides a novel strategy for DEX application that can be potentially used to combat cisplatin ototoxicity.
研究领域:
药理学
·
耳鼻喉科学
·
纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2021
·Vol. 129
·期 4
·308-318
·
IF 4.084
Xinjia Zhou,Yuan Gao,Yue Hu,Xiulan Ma
Hearing loss positively links with cigarette smoking. However, the involved mechanism and treatment strategies are largely unrevealed. This study aimed to investigate the damaging effect of nicotine on cochlear hair cells, reveal the underlying mechanism and evaluate the therapeutic effect of melatonin on nicotine-induced injury. The results showed that nicotine induced cytotoxicity of House Ear Institute-Organ of Corti 1 (HEI-OC1) cochlear hair cells in a dose-dependent manner (0, 2.5, 5, 10, 20, 40 and 80 μM). Functional investigations showed that nicotine (10 μM) stimulation dramatically promoted apoptosis, inflammatory response, oxidative stress and endoplasmic reticulum stress in HEI-OC1 cells. Moreover, melatonin treatment dose-dependently alleviated the nicotine-induced cytotoxicity in HEI-OC1 cells (0, 10 25, 50 and 100 μM). Further investigation showed that melatonin (100 μM) effectively attenuated the nicotine-induced apoptosis, inflammation, oxidative stress and endoplasmic reticulum stress in HEI-OC1 cells. Collectively, we demonstrated that nicotine induced apoptosis, inflammation, oxidative stress and endoplasmic reticulum stress of cochlear hair cells in an in vitro cell model. Melatonin showed protective effect on these aspects, suggesting that melatonin may be a potential agent for treating smoking-induced hearing loss.
研究领域:
药理学
·
毒理学
·
神经科学
·
耳鼻喉科
✓ 已验证
DOI
PubMed
高影响因子
Autophagy
·
2022
·
IF 13.391
Yuhua Zhang,Qiaojun Fang,Hongfeng Wang,Jieyu Qi,Shan Sun,Menghui Liao,Yunhao Wu,Yangnan Hu,Pei Jiang,Cheng Cheng,Xiaoyun Qian,Mingliang Tang,Wei Cao,Shang Xiang,Chen Zhang,Jianming Yang,Xia Gao,Zheng Ying,Renjie Chai
Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of Pink1 expression, the key initiator of mitophagy. Moreover, we found that neomycin impaired mitophagy by inducing ATF3 expression. Importantly, treatment with a mitophagy activator could rescue neomycin-treated hair cells by increasing mitophagy, indicating that genetic modulation or drug intervention in mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss.Abbreviations: AAV: adeno-associated virus; ABR: auditory brainstem response; ATF3: activating transcription factor 3; ATOH1/MATH1: atonal bHLH transcription factor 1; BafA1: bafilomycin A1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; COX4I1/COXIV: cytochrome c oxidase subunit 4I1; CTBP2/RIBEYE: C-terminal binding protein 2; DFP: deferiprone; EGFP: enhanced green fluorescent protein; FOXO3: forkhead box O3; GRIA2/GLUR2: glutamate receptor, ionotropic, AMPA2 (alpha 2); HC: hair cell; HSPD1/HSP60: heat shock protein 1 (chaperonin); IHC: inner hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MYO7A: myosin VIIA; OPTN: optineurin; OMM: outer mitochondrial membrane; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RT-qPCR: real-time quantitative polymerase chain reaction; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUNEL: Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling; USP30: ubiquitin specific peptidase 30; XBP1: X-box binding protein 1.
研究领域:
细胞生物学
·
神经科学
·
耳科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Hanyu Liao,Xue Li,Huiming Zhang,Shanshan Yin,Yu Hong,Rong Chen,Fei Gui,Lei Yang,Jun Yang,Jianyun Zhang
Hearing loss is a common chronic sensory deficit that affects millions of people worldwide and has emerged as a significant public health concern. The association between environmental exposure to chemicals and the prevalence of hearing impairment has recently attracted increased attention. Chlorinated paraffins (CPs) are a type of chemical compound that has been widely used and commonly detected in samples of both environmental and human origin. The knowledge of the toxicological effects of CPs, particularly its ototoxicity, remains limited at present. In this study, six commercial CPs were selected and evaluated using cochlea hair HEI-OC1 cells for their cytotoxicity, apoptosis, DNA damage, reactive oxygen species (ROS) accumulation and oxidative response. The cytotoxicity was observed after CPs exposure at high concentrations except for C-40 and was positively related to the chlorine content (Cl-content) in both CCK-8 and trypan blue assays. All 6 CPs induced cells apoptosis through caspase-dependent apoptotic pathway. CPs exposure induced DNA damage and stimulated ROS overproduction. Antioxidant N-acetyl-L-cysteine (NAC) could reverse the cytotoxicity and ROS accumulation caused by CPs exposure. The overexpression of ATF4 and CHOP indicated that endoplasmic reticulum (ER) stress was involved in the CPs induced cytotoxicity. Thus, CPs induced cytotoxicity and apoptosis via ROS accumulation, ER stress and DNA damage and positively related to the Cl-content and our findings indicate that CPs may pose a risk of ototoxicity at environmental relevant exposure levels.
研究领域:
毒理学
·
环境健康
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2021
·
IF 6.543
Yanzhuo Zhang,Zhe Lv,Yudong Liu,Huan Cao,Jianwang Yang,Baoshan Wang
A growing amount of evidence has confirmed the crucial role of the prolyl isomerase PIN1 in aging and age-related diseases. However, the mechanism of PIN1 in age-related hearing loss (ARHL) remains unclear. Pathologically, ARHL is primarily due to the loss and dysfunction of hair cells (HCs) and spiral ganglion cells (SGCs) in the cochlea. Therefore, in this study, we aimed to investigate the role of PIN1 in protecting hair cells and auditory HEI-OC1 cells from senescence. Enzyme-linked immunosorbent assays, immunohistochemistry, and immunofluorescence were used to detect the PIN1 protein level in the serum of ARHL patients and C57BL/6 mice in different groups, and in the SGCs and HCs of young and aged C57BL/6 mice. In addition, a model of HEI-OC1 cell senescence induced by H2O2 was used. Adult C57BL/6 mice were treated with juglone, or juglone and NAC, for 4 weeks. Interestingly, we found that the PIN1 protein expression decreased in the serum of patients with ARHL, in senescent HEI-OC1 cells, and in the cochlea of aged mice. Moreover, under H2O2 and juglone treatment, a large amount of ROS was produced, and phosphorylation of p53 was induced. Importantly, PIN1 expression was significantly increased by treatment with the p53 inhibitor pifithrin-α. Overexpression of PIN1 reversed the increased level of p-p53 and rescued HEI-OC1 cells from senescence. Furthermore, PIN1 mediated cellular senescence by the PI3K/Akt/mTOR signaling pathway. In vivo data from C57BL/6 mice showed that treatment with juglone led to hearing loss. Taken together, these findings demonstrated that PIN1 may act as a vital modulator in hair cell and HEI-OC1 cell senescence.
研究领域:
衰老
·
听力科学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）