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
International Journal of Nanomedicine
·
2023
·
IF 8
Yuming Chen,Jiayi Gu,Jian Liu,Ling Tong,Fuxin Shi,Xiaoqin Wang,Xueling Wang,Dehong Yu,Hao Wu
Background: Cisplatin is an extensively used anti-neoplastic agent for the treatment of various solid tumors. However, a high incidence of severe ototoxicity is accompanied by its use in the clinic. Currently, no drugs or therapeutic strategies have been approved for the treatment of cisplatin-induced ototoxicity by the FDA.Purpose: The purpose of this study was to investigate the otoprotective effects of dexamethasone (DEX)-loaded silk-polyethylene hydrogel (DEX-SILK) following round window membrane administration in the cisplatin-induced ototoxicity mouse model.Methods: The morphology, gelation kinetics, viscosity and secondary structure of the DEX-SILK hydrogel were analyzed. DEX concentration in the perilymph was tested at different time points following hydrogel injection on the RWM niche. Cultured cells (HEI-OC1), organ of Corti explants (C57/BL6, P0-2), and cisplatin-induced hearing loss mice model (C57/BL6) were used as in vitro and in vivo models for investigating the otoprotective effects of DEX-SILK hydrogel against cisplatin.Results: Encapsulation of DEX with a loading of 8% (w/v) did not significantly change the silk gelation time, and DEX was evenly distributed in the Silk-PEG hydrogel as visualized by scanning electron microscopy (SEM). The concentration of Silk majorly influenced DEX distribution, morphological characteristics, viscosity, and gelation time. The optimized DEX-SILK hydrogel (8% w/v loading, 15% silk concentration, 10 μl) was administered directly onto the RWM of the guinea pigs. The DEX concentration in the perilymph was maintained above 1 μg/ml for at least 21 days for the DEX-SILK, while it was maintained for less than 6 h in the control sample of free DEX. DEX-SILK (5-60 ng/ml) exhibited significant protective effects against cisplatin-induced cellular ototoxicity and notably reduced the production of reactive oxygen species (ROS). Eventually, pretreatment with DEX-SILK effectively preserved outer hair cells in the cultured organ of Corti explants and demonstrated significant hearing protection at 4, 8, and 16 kHz in the cisplatin-induced hearing loss mice as compared to the effects noted following pretreatment with DEX.Conclusion: These results demonstrated the clinical value of DEX-SILK for the therapy of cisplatin-induced ototoxicity.
研究领域:
药理学
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耳鼻喉科学
·
材料科学
✓ 已验证
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
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2021
·
IF 4.374
Jiayi Gu,Ling Tong,Xin Lin,Yuming Chen,Hao Wu,Xueling Wang,Dehong Yu
The ototoxic mechanisms of cisplatin on the organ of Corti and spiral ganglion neurons have been extensively studied, while few studies have been focused on the stria vascularis (SV). Herein, we verified the functional and morphological impairment in SV induced by a single injection of cisplatin (12 mg/kg, I.P.), represented by a reduction in Endocochlear Potentials (EP) and strial atrophy, and explored underlying mechanisms. Our results revealed increased extravasation of chromatic tracers (Evans blue dye and FITC-dextran) around microvessels after cisplatin exposure. The increased vascular permeability could be attributed to changes of pericytes (PCs) and perivascular-resident macrophage-like melanocytes (PVM/Ms) in number or morphology, as well as the enhanced level of HIF-1α and downstream VEGF. This capillary leakage led to a high accumulation of cisplatin in the perivascular space in SV, and disrupted the integrity of blood-labyrinth barrier (BLB). Also, tight junction (ZO-1) loosening and Na + , K + -ATPase damage was considered to be other critical contributors of BLB breakdown, which resulted in EP drop and consequent hearing loss. This study explored the role of stria vascularis in cisplatin-induced ototoxicity in terms of BLB hyperpermeability and pointed to a novel therapeutic target for the prevention of cisplatin-related hearing loss.
研究领域:
耳鼻喉科学
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药理学
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毒理学
✓ 已验证
产品关联
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
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发育生物学
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药理学
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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
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耳鼻喉科学
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纳米技术
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
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IF 4.8
Wenxin Zhang,Hongbo Teng,Tianyi Zhao,Roberts I. Eglitis,Xv Wang,Zhengxuan Yu,Shurong Qu,Haijing Wang,Yaru Zhao,Bowen Fan,Shuangli Liu,Yan Zhao
Introduction: Cisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from Acanthopanax sessiliflorus has abundant activity against CIO.Methods: In this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin—induced HEI—OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence.Results: It was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy.Discussion: These findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss.
研究领域:
药理学
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肿瘤学
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分子生物学
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2020
·Vol. 22
·期 6
·5053-5068
·
IF 2.1
Guofang Guan,Xiao He,Jingjing Chen,Li Bin,Xuxia Tang
Sensorineural hearing loss is prevalent in patients receiving cisplatin therapy. Tetramethylpyrazine (Tet) and tanshinone IIA (Tan IIA) have protective roles against hearing impairment or ototoxicity. The present study aimed to investigate the molecular mechanisms underlying cisplatin‑induced ototoxicity and the protective effect of Tet and Tan IIA against it. House Ear Institute‑Organ of Corti 1 auditory cells were treated with titrating doses of Tan IIA, Tet, and cisplatin. In a cell viability assay, cisplatin, Tan IIA and Tet had IC50 values of 42.89 µM, 151.80 and 1.04x103 mg/l, respectively. Tan IIA augmented cisplatin‑induced cytotoxicity. However, Tet concentrations <75 mg/l attenuated cisplatin‑induced cytotoxicity and apoptosis. Moreover, RNA sequencing analysis was carried out on auditory cells treated for 30 h with 30 µM cisplatin alone for 48 h or combined with 37.5 mg/l Tet for 30 h. Differentially expressed genes (DEGs) induced in these conditions were identified and examined using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Cisplatin increased the expression of genes related to the p53 and FoxO pathways, such as Fas, p21/CDKN1A, and Bcl‑2 binding component 3, but decreased the expression of insulin‑like growth factor 1 (IGF1), as well as genes in the histone (Hist)1 and Hist2 clusters. Treatment with Tet downregulated FOXO3 and Bcl‑2 binding component 3, and increased the expression of IGF1. Moreover, Tet upregulated genes associated with Wnt signaling, but not p53‑related genes. Thus, the otoprotective properties of Tet might be mediated by activation of Wnt and IGF1 signaling, and inhibition of FoxO signaling.
研究领域:
药理学
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耳鼻喉科学
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分子生物学
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基因组学
✓ 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
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环境健康
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2022
·
IF 5.364
Xiaozhu Chen,Hong Zhang,Chu Wang,Yue Su,Min Xiong,Xiaohua Feng,Daishi Chen,Zhaoyang Ke,Lu Wen,Gang Chen
Overexpression of apoptotic factors in the inner ear is generally proven to induce ototoxicity. This has aroused research interest in various antiapoptotic drugs, the most representative of which is curcumin (CUR). In this study, two nanoformulations of CUR were developed with sustained-release behavior to improve their protective effects against ototoxic hearing loss (HL), which were the nanoparticles of CUR-loaded poly(lactic acid–glycolic acid) (CUR-PLGA NPs) and CUR-loaded chitosan-coated PLGA NPs (CUR-CS/PLGA NPs). The obtained results revealed that both CUR-NPs provided otoprotection in vitro and in vivo, and their effective doses in guinea pigs were much less than that of dexamethasone, which was clinically used to treat HL. Moreover, relative to CUR and CUR-PLGA NPs, CUR-CS/PLGA NPs exhibited the highest accumulation in HEI-OC1 cells and guinea pigs’ cochlea. In pharmacodynamic experiments, the optimal administration timing was investigated, and CUR-CS/PLGA NPs showed sustained efficacy and the best hearing improvement at all tested sound frequencies. Lastly, the protective effect of CUR nanoformulations was further validated via inhibition of Caspase-3 and Bax activation, thereby reducing the concentration of reactive oxygen species and protecting mitochondrial integrity in hair cells. Collectively, CUR-CS/PLGA NPs demonstrated potent and lasting effects against ototoxic HL, making our novel formulation a promising candidate for the alleviation of sensorineural HL.
研究领域:
药理学
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纳米医学
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耳科学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Fengqiu Chen,Qingjun Jiang,Baoying Xu,Yuqi Huang,Ke Xu,Xiaoju Xu,Dehong Yu,Yu Chen,Xueling Wang
Sensorineural hearing loss (SNHL) represents a significant clinical challenge, predominantly attributed to oxidative stress-related mechanisms. In this work, we report an innovative antioxidant strategy for mitigating SNHL, utilizing synthetically engineered allomelanin nanoparticles (AMNPs). Empirical evidence elucidates AMNPs’ profound capability in free radical neutralization, substantiated by a significant decrement in reactive oxygen species (ROS) levels within HEI-OC1 auditory cells exposure to cisplatin or hydrogen peroxide (H2O2). Comparative analyses reveal that AMNPs afford protection against cisplatin-induced and noise-induced auditory impairments, mirroring the effect of dexamethasone (DEX), a standard pharmacological treatment for acute SNHL. AMNPs exhibit notable cytoprotective properties for auditory hair cells (HCs), effectively preventing ototoxicity from cisplatin or H2O2 exposure, as confirmed by both in vitro assays and cultured organ of Corti studies. Further in vivo research corroborates AMNPs’ ability to reverse auditory brainstem response (ABR) threshold shifts resulting from acoustic injury, concurrently reducing HCs loss, ribbon synapse depletion, and spiral ganglion neuron degeneration. The therapeutic benefits of AMNPs are attributed to mitigating oxidative stress and inflammation within the cochlea, with transcriptome analysis indicating downregulated gene expression related to these processes post-AMNPs treatment. The pronounced antioxidative and anti-inflammatory effects of AMNPs position them as a promising alternative to DEX for SNHL treatment.
研究领域:
药理学
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生物医学工程
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耳鼻喉科
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-17
·
IF 9.429
Gu Jiayi,Wang Xueling,Chen Yuming,Xu Ke,Yu Dehong,Wu Hao
Background Excessive accumulation of reactive oxygen species (ROS) has been documented as the crucial cellular mechanism of cisplatin-induced ototoxicity. However, numerous antioxidants have failed in clinical studies partly due to inefficient drug delivery to the cochlea. A drug delivery system is an attractive strategy to overcome this drawback.Methods and resultsIn the present study, we proposed the combination of antioxidant astaxanthin (ATX) and ROS-responsive/consuming nanoparticles (PPS-NP) to combat cisplatin-induced ototoxicity. ATX-PPS-NP were constructed by the self-assembly of an amphiphilic hyperbranched polyphosphoester containing thioketal units, which scavenged ROS and disintegrate to release the encapsulated ATX. The ROS-sensitivity was confirmed by 1H nuclear magnetic resonance spectroscopy, transmission electron microscopy and an H2O2 ON/OFF stimulated model. Enhanced release profiles stimulated by H2O2 were verified in artificial perilymph, the HEI-OC1 cell line and guinea pigs. In addition, ATX-PPS-NP efficiently inhibited cisplatin-induced HEI-OC1 cell cytotoxicity and apoptosis compared with ATX or PPS-NP alone, suggesting an enhanced effect of the combination of the natural active compound ATX and ROS-consuming PPS-NP. Moreover, ATX-PPS-NP attenuated outer hair cell losses in cultured organ of Corti. In guinea pigs, NiRe-PPS-NP verified a quick penetration across the round window membrane and ATX-PPS-NP showed protective effect on spiral ganglion neurons, which further attenuated cisplatin-induced moderate hearing loss. Further studies revealed that the protective mechanisms involved decreasing excessive ROS generation, reducing inflammatory chemokine (interleukin-6) release, increasing antioxidant glutathione expression and inhibiting the mitochondrial apoptotic pathway.Conclusion sThus, this ROS-responsive nanoparticle encapsulating ATX has favorable potential in the prevention of cisplatin-induced hearing loss.Graphical Abstract
研究领域:
药学
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纳米技术
·
耳科学
·
药物递送系统
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抗氧化治疗
✓ 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）