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Shen P, Hu D, Shen M, Du T, Zhao L, Han M, Song R, Guo R, Lu X, Liu S, Shen X. Association of mixed polycyclic aromatic hydrocarbons exposure with hearing loss and the mediating role of blood cell markers of inflammation in U.S. adults. Front Public Health 2024; 12:1410601. [PMID: 39664550 PMCID: PMC11631931 DOI: 10.3389/fpubh.2024.1410601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
Introduction Studies on the effects of polycyclic aromatic hydrocarbons (PAHs) on hearing loss (HL) are limited and often focus on individual PAH compounds. The present study aimed to explore the individual and combined effects of PAH exposure on hearing loss, with a focus on the mediating role of inflammatory blood cell markers. Methods This cross-sectional study included 1,409 participants from 3 cycles of the National Health and Nutrition Examination Survey (2001-2002, 2003-2004, and 2011-2012). Seven monohydroxylated PAH metabolites (OH-PAHs) in the urine were measured. Multivariable logistic regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were applied to assess both the individual and combined effects of OH-PAHs on hearing loss. Moreover, mediation analysis was employed to examine the mediating role of inflammatory blood cell markers in these associations. Results Among the 1,409 participants, 59.1% had hearing loss. The WQS model revealed a positive association between PAH mixtures and HL (OR: 1.290; 95% CI: 1.042, 1.597), LFHL (OR: 1.363; 95% CI: 1.130, 1.644), and HFHL (OR: 1.299; 95% CI: 1.022, 1.626). Additionally, the WQS model identified hydroxynaphthalene (1-OHNAP) primarily contributed to HL and LFHL, while 2-hydroxyfluorene (2-OHFLU) was the primary contributor to HFHL. BKMR analysis demonstrated positive associations between PAH mixtures and all three types of hearing loss. Mediation analysis revealed that the association between OH-PAHs and LFHL was mediated by neutrophil (NEU) and basophil (BAS) counts. Discussion These results confirmed that exposure to PAH mixtures was positively associated with the odds of hearing loss and that inflammatory blood cell markers mediated this association.
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Affiliation(s)
- Peixuan Shen
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
| | - Dan Hu
- Licang District Center for Disease Control and Prevention, Qingdao, China
| | - Meiyue Shen
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
| | - Tingwei Du
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
| | - Longzhu Zhao
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
| | - Miaomiao Han
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
| | - Ruihan Song
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
| | - Rongrong Guo
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
| | - Xiaochuan Lu
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
| | - Shengnan Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
| | - Xiaoli Shen
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao, China
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Dai D, Chen C, Lu C, Guo Y, Li Q, Sun C. Apoptosis, autophagy, ferroptosis, and pyroptosis in cisplatin-induced ototoxicity and protective agents. Front Pharmacol 2024; 15:1430469. [PMID: 39380912 PMCID: PMC11459463 DOI: 10.3389/fphar.2024.1430469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 09/04/2024] [Indexed: 10/10/2024] Open
Abstract
Cisplatin is widely used to treat various solid tumors. However, its toxicity to normal tissues limits its clinical application, particularly due to its ototoxic effects, which can result in hearing loss in patients undergoing chemotherapy. While significant progress has been made in preclinical studies to elucidate the cellular and molecular mechanisms underlying cisplatin-induced ototoxicity (CIO), the precise mechanisms remain unclear. Moreover, the optimal protective agent for preventing or mitigating cisplatin-induced ototoxicity has yet to be identified. This review summarizes the current understanding of the roles of apoptosis, autophagy, ferroptosis, pyroptosis, and protective agents in cisplatin-induced ototoxicity. A deeper understanding of these cell death mechanisms in the inner ear, along with the protective agents, could facilitate the translation of these agents into clinical therapeutics, help identify new therapeutic targets, and provide novel strategies for cisplatin-based cancer treatment.
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Affiliation(s)
- Dingyuan Dai
- Department of Otolaryngology Head and Neck Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chao Chen
- Department of Otolaryngology Head and Neck Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chen Lu
- Department of Otolaryngology Head and Neck Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Guo
- Department of Otolaryngology Head and Neck Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qi Li
- Department of Otolaryngology Head and Neck Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Nanjing Medical University, Nanjing, Jiangsu, China
- Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Chen Sun
- Department of Otolaryngology Head and Neck Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Maraslioglu-Sperber A, Blanc F, Heller S. Murine cochlear damage models in the context of hair cell regeneration research. Hear Res 2024; 447:109021. [PMID: 38703432 DOI: 10.1016/j.heares.2024.109021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 04/16/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024]
Abstract
Understanding the complex pathologies associated with hearing loss is a significant motivation for conducting inner ear research. Lifelong exposure to loud noise, ototoxic drugs, genetic diversity, sex, and aging collectively contribute to human hearing loss. Replicating this pathology in research animals is challenging because hearing impairment has varied causes and different manifestations. A central aspect, however, is the loss of sensory hair cells and the inability of the mammalian cochlea to replace them. Researching therapeutic strategies to rekindle regenerative cochlear capacity, therefore, requires the generation of animal models in which cochlear hair cells are eliminated. This review discusses different approaches to ablate cochlear hair cells in adult mice. We inventoried the cochlear cyto- and histo-pathology caused by acoustic overstimulation, systemic and locally applied drugs, and various genetic tools. The focus is not to prescribe a perfect damage model but to highlight the limitations and advantages of existing approaches and identify areas for further refinement of damage models for use in regenerative studies.
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Affiliation(s)
- Ayse Maraslioglu-Sperber
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Fabian Blanc
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Otolaryngology - Head & Neck Surgery, University Hospital Gui de Chauliac, University of Montpellier, Montpellier, France
| | - Stefan Heller
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Thakur NS, Rus I, Sparks E, Agrahari V. Dual stimuli-responsive and sustained drug delivery NanoSensoGel formulation for prevention of cisplatin-induced ototoxicity. J Control Release 2024; 368:66-83. [PMID: 38331002 DOI: 10.1016/j.jconrel.2024.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 02/06/2024] [Indexed: 02/10/2024]
Abstract
Cisplatin (CisPt)-induced ototoxicity (CIO) is delineated as a consequence of CisPt-induced intracellular generation of reactive oxygen species (ROS) which can be circumvented by Bucillamine (BUC; an antioxidant drug with sulfhydryl groups) and Diltiazem (DLT, L-type calcium channel blocker). However, its effective accumulation in the Organ of Corti and cell cytoplasm is desired. Therefore, a biocompatible BUC- and DLT-nanoparticles (NPs)-impregnated dual stimuli-responsive formulation (NanoSensoGel) presented here with ROS- and thermo-responsive properties for the sustained and receptive delivery of drugs. The ROS-responsive polypropylene sulfide- methyl polyethylene glycol-2000 (PPS-mPEG2000) polymer was rationally designed, synthesized, and characterized to fabricate BUC- and DLT-loaded PPS-mPEG2000-NPs (BUC- and DLT-NPs). The fabricated BUC- and DLT-NPs showed efficient cellular uptake, intracellular delivery, ROS responsiveness, and cytoprotective effect which was characterized using cellular internalization, intracellular ROS, mitochondrial superoxide, and Caspase 3/7 assays on the House Ear Institute-Organ of Corti-1 (HEI-OC1) cells. The composite NanoSensoGel (i.e., ROS-responsive BUC- and DLT-NPs suspended in the thermo-responsive hydrogel) present in a sol state at room temperature and turned to gel above 33°C, which could be essential for retaining the formulation at the target site for long-term release. The NanoSensoGel showed sustained release of BUC and DLT following Fickian release diffusion kinetics. Overall, a novel NanoSensoGel formulation developed in this study has demonstrated its great potential in delivering therapeutics in the inner ear for prophylactic treatment of CIO, and associated hearing loss.
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Affiliation(s)
- Neeraj S Thakur
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Iulia Rus
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Ethan Sparks
- Department of Integrative Biology, Oklahoma State University, Stillwater, OK 74078, USA
| | - Vibhuti Agrahari
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
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Tan F, Li X, Li X, Xu M, Shahzad KA, Hou L. GelMA/PEDOT:PSS Composite Conductive Hydrogel-Based Generation and Protection of Cochlear Hair Cells through Multiple Signaling Pathways. Biomolecules 2024; 14:95. [PMID: 38254695 PMCID: PMC10812993 DOI: 10.3390/biom14010095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 12/18/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
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.
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Affiliation(s)
- Fei Tan
- Department of ORL-HNS, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200070, China; (X.L.); (M.X.); (K.A.S.)
- Plasma Medicine and Surgical Implants Center, School of Medicine, Tongji University, Shanghai 200070, China
- Department of ORL-HNS, The Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland
- Department of ORL-HNS, The Royal College of Surgeons of England, London WC2A 3PE, UK
| | - Xuran Li
- Department of ORL-HNS, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200070, China; (X.L.); (M.X.); (K.A.S.)
- Plasma Medicine and Surgical Implants Center, School of Medicine, Tongji University, Shanghai 200070, China
| | - Xiao Li
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology & Center for Advanced Low-Dimension Materials, Donghua University, Shanghai 200051, China; (X.L.); (L.H.)
| | - Maoxiang Xu
- Department of ORL-HNS, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200070, China; (X.L.); (M.X.); (K.A.S.)
- Plasma Medicine and Surgical Implants Center, School of Medicine, Tongji University, Shanghai 200070, China
| | - Khawar Ali Shahzad
- Department of ORL-HNS, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200070, China; (X.L.); (M.X.); (K.A.S.)
- Plasma Medicine and Surgical Implants Center, School of Medicine, Tongji University, Shanghai 200070, China
| | - Lei Hou
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology & Center for Advanced Low-Dimension Materials, Donghua University, Shanghai 200051, China; (X.L.); (L.H.)
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Song J, Ouyang F, Xiong Y, Luo Q, Jiang H, Fan L, Zhang Z. Reassessment of oxidative stress in idiopathic sudden hearing loss and preliminary exploration of the effect of physiological concentration of melatonin on prognosis. Front Neurol 2023; 14:1249312. [PMID: 37745649 PMCID: PMC10511764 DOI: 10.3389/fneur.2023.1249312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Background and purpose The pathogenesis of idiopathic sudden sensorineural hearing loss (ISSNHL) is still unclear, and there is no targeted treatment. This research aimed to verify the role of oxidative stress in ISSNHL and explore whether melatonin has a protective effect on hearing. Materials and methods A total of 43 patients with ISSNHL and 15 healthy controls were recruited to detect the level of melatonin, reactive oxygen species (ROS), and total antioxidant capacity (TAC) in the blood and compared before and after treatment. Multivariate logistic regression models were performed to assess the factors relevant to the occurrence and improvement of ISSNHL. Results The patients with ISSNHL showed significantly higher ROS levels than controls (4.42 ± 4.40 vs. 2.30 ± 0.59; p = 0.031). The levels of basal melatonin were higher (1400.83 ± 784.89 vs. 1095.97 ± 689.08; p = 0.046) and ROS levels were lower (3.05 ± 1.81 vs. 5.62 ± 5.56; p = 0.042) in the effective group as compared with the ineffective group. Logistic regression analysis showed that melatonin (OR = 0.999, 95% CI 0.997-1.000, p = 0.049), ROS (OR = 1.154, 95% CI 1.025-2.236, p = 0.037), and vertigo (OR = 3.011, 95% CI 1.339-26.983, p = 0.019) were independent factors associated with hearing improvement. Besides, the level of melatonin (OR = 0.999, 95% CI 0.998-1.000, p = 0.023) and ROS (OR = 3.248, 95% CI 1.109-9.516, p = 0.032) were associated with the occurrence of ISSNHL. Conclusion Our findings may suggest oxidative stress involvement in ISSNHL etiopathogenesis. The level of melatonin and ROS, and vertigo appear to be predictive of the effectiveness of hearing improvement following ISSNHL treatment.
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Affiliation(s)
- Jianxiong Song
- Department of Otolaryngology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fang Ouyang
- Department of Endocrinology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yuanping Xiong
- Department of Otolaryngology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qing Luo
- Department of Otolaryngology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hongqun Jiang
- Department of Otolaryngology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Li Fan
- Department of Otolaryngology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhiyuan Zhang
- Department of Otolaryngology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Le Prell CG. Preclinical prospects of investigational agents for hearing loss treatment. Expert Opin Investig Drugs 2023; 32:685-692. [PMID: 37695693 DOI: 10.1080/13543784.2023.2253141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/25/2023] [Indexed: 09/13/2023]
Abstract
INTRODUCTION : Hearing loss has a high prevalence, with aging, noise exposure, ototoxic drug therapies, and genetic mutations being some of the leading causes of hearing loss. Health conditions such as cardiovascular disease and diabetes are associated with hearing loss, perhaps due to shared vascular pathology in the ear and in other tissues. AREAS COVERED : Issues in the design of preclinical research preclude the ability to make comparisons regarding the relative efficacy of different drugs of interest for possible hearing loss prevention or hearing restoration. This has not slowed the advancement of candidate therapeutics into human clinical testing. There is a robust pipeline with drugs that have different mechanisms of action providing diverse candidate therapies and opportunities for combination therapies to be considered. EXPERT OPINION : Much of the preclinical research literature lacks standard study design elements such as dose response testing, and lack of standardization of test protocols significantly limits conclusions regarding relative efficacy. Nonetheless, the many positive results to date have supported translation of preclinical efforts into clinical trials assessing potential human benefits. Approval of the first hearing loss prevention therapeutic is a major success, providing a pathway for other drugs to follow.
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Affiliation(s)
- Colleen G Le Prell
- Department of Speech, Language, and Hearing, University of Texas at Dallas, Richardson, TX, USA
- Callier Center for Communication Disorders, University of Texas at Dallas, Dallas, TX, USA
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Zhang G, Gao Y, Zhao Z, Pyykko I, Zou J. Low-Molecular-Weight Hyaluronic Acid Contributes to Noise-Induced Cochlear Inflammation. Audiol Neurootol 2023; 28:380-393. [PMID: 37231777 DOI: 10.1159/000530280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 03/16/2023] [Indexed: 05/27/2023] Open
Abstract
INTRODUCTION Our previous work indicated that the activation of the Toll-like receptor (TLR) 4 signaling pathway contributed to noise-induced cochlear inflammation. Previous studies have reported that low-molecular-weight hyaluronic acid (LMW-HA) accumulates during aseptic trauma and promotes inflammation by activating the TLR4 signaling pathway. We hypothesized that LMW-HA or enzymes synthesizing or degrading HA might be involved in noise-induced cochlear inflammation. METHODS The present study included two arms. The first arm was the noise exposure study, in which TLR4, proinflammatory cytokines, HA, hyaluronic acid synthases (HASs), and hyaluronidases (HYALs) in the cochlea as well as auditory brainstem response (ABR) thresholds were measured before and after noise exposure. The second arm was analysis of HA delivery-induced reactions, in which control solution, high-molecular-weight HA (HMW-HA), or LMW-HA was delivered into the cochlea by cochleostomy or intratympanic injection. Then, the ABR threshold and cochlear inflammation were measured. RESULTS After noise exposure, the expression of TLR4, proinflammatory cytokines, HAS1, and HAS3 in the cochlea significantly increased over the 3rd to 7th day post-noise exposure (PE3, PE7). The expression of HYAL2 and HYAL3 dramatically decreased immediately after noise exposure, gradually increased thereafter to levels significantly greater than the preexposure level on PE3, and then rapidly returned to the preexposure level on PE7. The expression of HA, HAS2, and HYAL1 in the cochlea remained unchanged after exposure. After cochleostomy or intratympanic injection, both the hearing threshold shifts and the expression of TLR4, TNF-α, and IL-1β in the cochleae of the LMW-HA group were obviously greater than those of the control group and HMW-HA group. The expression of proinflammatory cytokines in the LMW-HA and control groups on the 7th day (D7) after cochleostomy tended to increase compared to that on the 3rd day (D3), whereas levels in the HMW-HA group tended to decrease on D7 compared to D3. CONCLUSION HAS1, HAS3, HYAL2, and HYAL3 in the cochlea are involved in acoustic trauma-induced cochlear inflammation through the potential proinflammatory function of LMW-HA.
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Affiliation(s)
- Guoping Zhang
- Department of Otolaryngology-Head and Neck Surgery, Centre for Otolaryngology-Head and Neck Surgery of the Chinese PLA, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yiling Gao
- Department of Otolaryngology-Head and Neck Surgery, Centre for Otolaryngology-Head and Neck Surgery of the Chinese PLA, Changhai Hospital, Second Military Medical University, Shanghai, China
- Department of Otolaryngology-Head and Neck Surgery, Shidong Hospital, Shanghai, China
| | - Zhen Zhao
- Department of Otolaryngology-Head and Neck Surgery, Centre for Otolaryngology-Head and Neck Surgery of the Chinese PLA, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Ilmari Pyykko
- Hearing and Balance Research Unit, Field of Otolaryngology, School of Medicine, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Jing Zou
- Department of Otolaryngology-Head and Neck Surgery, Centre for Otolaryngology-Head and Neck Surgery of the Chinese PLA, Changhai Hospital, Second Military Medical University, Shanghai, China
- Department for Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Gill NB, Dowker-Key PD, Hubbard K, Voy BH, Whelan J, Hedrick M, Bettaieb A. Ginsenoside Rc from Panax Ginseng Ameliorates Palmitate-Induced UB/OC-2 Cochlear Cell Injury. Int J Mol Sci 2023; 24:7345. [PMID: 37108509 PMCID: PMC10139021 DOI: 10.3390/ijms24087345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/03/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
By 2050, at least 700 million people will require hearing therapy while 2.5 billion are projected to suffer from hearing loss. Sensorineural hearing loss (SNHL) arises from the inability of the inner ear to convert fluid waves into neural electric signals because of injury to cochlear hair cells that has resulted in their death. In addition, systemic chronic inflammation implicated in other pathologies may exacerbate cell death leading to SNHL. Phytochemicals have emerged as a possible solution because of the growing evidence of their anti-inflammatory, antioxidant, and anti-apoptotic properties. Ginseng and its bioactive molecules, ginsenosides, exhibit effects that suppress pro-inflammatory signaling and protect against apoptosis. In the current study, we investigated the effects of ginsenoside Rc (G-Rc) on UB/OC-2 primary murine sensory hair cell survival in response to palmitate-induced injury. G-Rc promoted UB/OC-2 cell survival and cell cycle progression. Additionally, G-Rc enhanced the differentiation of UB/OC-2 cells into functional sensory hair cells and alleviated palmitate-induced inflammation, endoplasmic reticulum stress, and apoptosis. The current study offers novel insights into the effects of G-Rc as a potential adjuvant for SNHL and warrants further studies elucidating the molecular mechanisms.
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Affiliation(s)
- Nicholas B. Gill
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-1920, USA
| | - Presley D. Dowker-Key
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-1920, USA
| | - Katelin Hubbard
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-1920, USA
| | - Brynn H. Voy
- Department of Animal Science, University of Tennessee Institute of Agriculture, Knoxville, TN 37996-0840, USA
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN 37996-0840, USA
| | - Jay Whelan
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-1920, USA
| | - Mark Hedrick
- Department of Audiology and Speech Pathology, The University of Tennessee Health Science Center, Knoxville, TN 37996-0240, USA
| | - Ahmed Bettaieb
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-1920, USA
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN 37996-0840, USA
- Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996-0840, USA
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Recoding of Nonsense Mutation as a Pharmacological Strategy. Biomedicines 2023; 11:biomedicines11030659. [PMID: 36979640 PMCID: PMC10044939 DOI: 10.3390/biomedicines11030659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/18/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Approximately 11% of genetic human diseases are caused by nonsense mutations that introduce a premature termination codon (PTC) into the coding sequence. The PTC results in the production of a potentially harmful shortened polypeptide and activation of a nonsense-mediated decay (NMD) pathway. The NMD pathway reduces the burden of unproductive protein synthesis by lowering the level of PTC mRNA. There is an endogenous rescue mechanism that produces a full-length protein from a PTC mRNA. Nonsense suppression therapies aim to increase readthrough, suppress NMD, or are a combination of both strategies. Therefore, treatment with translational readthrough-inducing drugs (TRIDs) and NMD inhibitors may increase the effectiveness of PTC suppression. Here we discuss the mechanism of PTC readthrough and the development of novel approaches to PTC suppression. We also discuss the toxicity and bioavailability of therapeutics used to stimulate PTC readthrough.
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Kishimoto-Urata M, Urata S, Fujimoto C, Yamasoba T. Role of Oxidative Stress and Antioxidants in Acquired Inner Ear Disorders. Antioxidants (Basel) 2022; 11:1469. [PMID: 36009187 PMCID: PMC9405327 DOI: 10.3390/antiox11081469] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/25/2022] [Accepted: 07/25/2022] [Indexed: 01/27/2023] Open
Abstract
Oxygen metabolism in the mitochondria is essential for biological activity, and reactive oxygen species (ROS) are produced simultaneously in the cell. Once an imbalance between ROS production and degradation (oxidative stress) occurs, cells are damaged. Sensory organs, especially those for hearing, are constantly exposed during daily life. Therefore, almost all mammalian species are liable to hearing loss depending on their environment. In the auditory pathway, hair cells, spiral ganglion cells, and the stria vascularis, where mitochondria are abundant, are the main targets of ROS. Excessive generation of ROS in auditory sensory organs is widely known to cause sensorineural hearing loss, and mitochondria-targeted antioxidants are candidates for treatment. This review focuses on the relationship between acquired hearing loss and antioxidant use to provide an overview of novel antioxidants, namely medicines, supplemental nutrients, and natural foods, based on clinical, animal, and cultured-cell studies.
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Affiliation(s)
| | | | | | - Tatsuya Yamasoba
- Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo, Tokyo 1138655, Japan; (M.K.-U.); (S.U.); (C.F.)
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Chen SL, Ho CY, Chin SC. Effects of oral N-acetylcysteine combined with oral prednisolone on idiopathic sudden sensorineural hearing loss. Medicine (Baltimore) 2022; 101:e29792. [PMID: 35777063 PMCID: PMC9239607 DOI: 10.1097/md.0000000000029792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Idiopathic sudden sensorineural hearing loss (ISSNHL) is an acute condition that presents with sudden hearing loss, for which steroids remain the main treatment. N-acetylcysteine (NAC), as a precursor of glutathione, can reduce the production of reactive oxygen species to protect hair cells in the inner ear from damage. However, data regarding the therapeutic outcomes of oral steroid combined with oral NAC for ISSNHL are still limited. This study was performed to investigate this issue. METHODS Between June 2016 and October 2021, 219 patients (219 ears) diagnosed with ISSNHL and treated with oral prednisolone were enrolled in this retrospective study. Oral NAC was prescribed to 94 of these patients (NAC group) but not to the remaining 125 patients (non-NAC group). The clinical and audiological findings were assessed. RESULTS The NAC group showed a mean hearing level gain of 29.5 ± 21.8 dB, speech reception threshold (SRT) gain of 26.2 ± 34.4 dB, and speech discrimination score (SDS) gain of 25.5 ± 30.4%. Although the NAC group had better mean hearing level, SRT, and SDS gains than the non-NAC group, the differences were not statistically significant (all P > .05). The only significant difference between the NAC and non-NAC groups was the posttreatment pure tone audiometry (PTA) thresholds at 8 kHz, which were 54.2 ± 24.4 and 60.9 ± 34.1 dB, respectively (P = .046). CONCLUSIONS This study demonstrated the effect of oral steroid combined with oral NAC for ISSNHL. Both the NAC and non-NAC groups showed obvious improvement in all PTA thresholds, as well as mean hearing level, SRT, and SDS gains. The NAC group showed significantly better PTA performance at a high frequency (8 kHz) than the non-NAC group. Therefore, for oral treatment of ISSNHL, we advocate concurrent use of oral prednisolone and oral NAC.
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Affiliation(s)
- Shih-Lung Chen
- Department of Otorhinolaryngology and Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
- *Correspondence: Shih-Lung Chen, MD, Department of Otorhinolaryngology and Head and Neck Surgery, Chang Gung Memorial Hospital, No. 5, Fu-Shin Street, Kwei-Shan, Taoyuan, Taiwan, 333 (e-mail: )
| | - Chia-Ying Ho
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Shy-Chyi Chin
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Taiwan
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13
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Gong L, Chen B, Chen J, Li Y. Protective Effects of Vitamin C against Neomycin-Induced Apoptosis in HEI-OC1 Auditory Cell. Neural Plast 2022; 2022:1298692. [PMID: 35601667 PMCID: PMC9117069 DOI: 10.1155/2022/1298692] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/15/2022] [Accepted: 04/18/2022] [Indexed: 11/18/2022] Open
Abstract
Ototoxic hearing loss results from hair cell death via reactive oxygen species (ROS) overproduction and consequent apoptosis. We investigated the effects of vitamin C (VC) on neomycin-induced HEI-OC1 cell damage, as well as the mechanism of inhibition. HEI-OC1 cells were treated with neomycin or with vitamin C (VC). The results indicated that VC had a protective effect on neomycin-induced HEI-OC1 cell death. Mechanistically, VC decreased neomycin-induced ROS generation, suppressed cell death, and increased cell viability. VC inhibited neomycin-induced apoptosis, ameliorated neomycin reduced antiapoptotic Bcl-2 expression, and suppressed neomycin increased expression of proapoptotic Bax, caspase-3 cleavage and caspase-8. TUNEL labeling demonstrated that VC blocked neomycin-induced apoptosis. Further study revealed that the effect of VC on neomycin-induced hair cell death was through interference with JNK activation and p38 phosphorylation. These results indicate that VC via suppressed ROS generation, which inhibited cell death by counteracting apoptotic signaling induced by neomycin in cells. Hence, VC is a potential candidate for protection agent against neomycin-induced HEI-OC1 cell ototoxicity.
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Affiliation(s)
- Liang Gong
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China
| | - Biao Chen
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China
| | - Jingyuan Chen
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China
| | - Yongxin Li
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China
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Lin JN, Wang JS, Lin CC, Lin HY, Yu SH, Wen YH, Tseng GF, Hsu CJ, Wu HP. Ameliorative effect of taxifolin on gentamicin-induced ototoxicity via down-regulation of apoptotic pathways in mouse cochlear UB/OC-2 cells. J Chin Med Assoc 2022; 85:617-626. [PMID: 35286283 DOI: 10.1097/jcma.0000000000000708] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Taxifolin is a flavanonol with efficacious cytoprotective properties, such as anti-inflammatory, antioxidant, anticancer, hepatoprotective, and nephroprotective effects. However, the potential protective effects of taxifolin against gentamicin-induced ototoxicity have not been confirmed. In this study, the possible mechanisms underlying the effects of taxifolin on gentamicin-induced death of UB/OC-2 cochlear cells were investigated. METHODS Mouse cochlear UB/OC-2 cells with or without taxifolin pretreatment were exposed to gentamicin, and the effects on cytotoxicity, reactive oxygen species (ROS) production, mitochondrial permeability transition, and apoptotic marker expression were examined using biochemical techniques, flow cytometry, western blotting, and fluorescent staining. RESULTS Little or no apparent effect of taxifolin on cell viability was observed at concentrations less than 40 μM. Further investigations showed that gentamicin significantly inhibited cell viability in a concentration-dependent manner. Pretreatment with taxifolin attenuated gentamicin-induced lactate dehydrogenase release, as well as cellular cytotoxicity. In addition, taxifolin significantly prevented gentamicin-induced cell damage by decreasing ROS production, stabilizing mitochondrial membrane potential, and downregulating the mitochondrial pathway of apoptosis. CONCLUSION In summary, pretreatment with taxifolin is effective for mitigating gentamicin-induced apoptotic cell death mediated by the mitochondrial pathway. Our data suggest that taxifolin provides a new approach to combat gentamicin-induced ototoxicity.
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Affiliation(s)
- Jia-Ni Lin
- Department of Otolaryngology, Head and Neck Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan, ROC
| | - Jen-Shu Wang
- Department of Chinese Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan, ROC
- School of Medicine, Tzu Chi University, Hualien, Taiwan, ROC
| | - Chung-Ching Lin
- Department of Otolaryngology, Head and Neck Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan, ROC
| | - Hui-Yi Lin
- School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC
| | - Szu-Hui Yu
- Department of Music, Tainan University of Technology, Tainan, Taiwan, ROC
| | - Yu-Hsuan Wen
- School of Medicine, Tzu Chi University, Hualien, Taiwan, ROC
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, ROC
- Department of Otolaryngology, Head and Neck Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC
| | - Guo-Fang Tseng
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, ROC
- Department of Anatomy, Tzu Chi University, Hualien, Taiwan, ROC
| | - Chuan-Jen Hsu
- Department of Otolaryngology, Head and Neck Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan, ROC
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - Hung-Pin Wu
- Department of Otolaryngology, Head and Neck Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan, ROC
- School of Medicine, Tzu Chi University, Hualien, Taiwan, ROC
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, ROC
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Blood Transcriptome Analysis Reveals Gene Expression Differences between Yangtze Finless Porpoises from Two Habitats: Natural and Ex Situ Protected Waters. FISHES 2022. [DOI: 10.3390/fishes7030096] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis, YFP) is a critically endangered small odontocete species, mainly distributed in the middle and lower reaches of the Yangtze River, Poyang Lake, and Dongting Lake. Under the influence of human activities, many factors are threatening the survival and reproduction of YFPs in their natural habitat. Ex situ conservation is of great significance to strengthen the rescuing conservation of YFPs by providing suitable alternative habitats and promoting the reproduction and growth of the ex situ population. To reveal the differences in gene expression of YFPs in natural and ex situ protected waters, and to investigate the effects of environmental factors on YFPs and their mechanisms, we performed transcriptome sequencing for blood tissues of YFPs collected from natural waters and ex situ protected waters. Using RNA-seq we identified 4613 differentially expressed genes (DEGs), of which 4485 were up-regulated and 128 were down-regulated in the natural population. GO analysis showed that DEGs were significantly enriched in entries related to binding, catalytic activity, and biological regulation; KEGG analysis showed that DEGs were enriched mainly in signal transduction, endocrine system, immune system, and sensory system-related pathways. Further analysis revealed that water pollution in natural waters may affect the hormone secretion of YFPs by altering the expression pattern of endocrine genes, thus interfering with normal endocrine activities; noise pollution may induce oxidative stress and inflammatory responses in YFPs, thus impairing the auditory function of YFPs. This study provides a new perspective for further research on the effect of habitat conditions on the YFPs and suggests that improving the habitat environment may help in the conservation of YFPs.
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Chen BC, Lin LJ, Lin YC, Lee CF, Hsu WC. Optimal N-acetylcysteine concentration for intratympanic injection to prevent cisplatin-induced ototoxicity in guinea pigs. Acta Otolaryngol 2022; 142:127-131. [PMID: 35287541 DOI: 10.1080/00016489.2022.2038796] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
BACKGROUND Cisplatin is a chemotherapy drug that can induce sensorineural hearing loss. At present, no otoprotective agent is approved for use. OBJECTIVES This study investigated the optimal concentration of intratympanic N-acetylcysteine (NAC) to prevent cisplatin-induced ototoxicity in a guinea pig model. MATERIALS AND METHODS Guinea pigs (n = 64) were treated with a single intratympanic injection containing different NAC concentrations or saline (control) 3 days prior to intraperitoneal injection with cisplatin. The threshold change in the auditory brainstem response was assessed. RESULTS Four weeks after intraperitoneal cisplatin injection, only the group that received 2% NAC exhibited significant otoprotection (p < .05) compared with the control. Otoprotection was observed at all the frequencies tested (1k, 2k, 4k, and 8k Hz). The 2% NAC group also exhibited significant otoprotection (p < .05) compared with the other NAC groups (at 1k, 2k, 4k, and 8k Hz). The 4% NAC group exhibited significantly reduced hearing capacity (p < .05) in the fourth week compared with controls. CONCLUSIONS AND SIGNIFICANCE Intratympanic NAC administration is an efficient and safe means of preventing cisplatin-induced ototoxicity. In our animal model, the optimal intratympanic NAC concentration was 2%; concentrations of 4% loss of otoprotection.
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Affiliation(s)
- Bo-Cheng Chen
- Department of Otolaryngology, Hualien Tzu Chi Hospital, Medical Foundation, Hualien, Taiwan
| | - Lian-Jie Lin
- Department of Otolaryngology, Hualien Tzu Chi Hospital, Medical Foundation, Hualien, Taiwan
| | - Yi-Chen Lin
- Department of Otolaryngology, Hualien Tzu Chi Hospital, Medical Foundation, Hualien, Taiwan
| | - Chia-Fone Lee
- Department of Otolaryngology, Hualien Tzu Chi Hospital, Medical Foundation, Hualien, Taiwan
- Department of otolaryngology Head and Neck Surgery, School of Medicine, Chi University, Hualien, Taiwan
| | - Wei-Chung Hsu
- Department of Otolaryngology, Head and Neck Surgery, National Taiwan, University Hospital, Taipei, Taiwan
- Department of Otolaryngology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Bile acid-permeation enhancement for inner ear cochlear drug - pharmacological uptake: bio-nanotechnologies in chemotherapy-induced hearing loss. Ther Deliv 2021; 12:807-819. [PMID: 34761700 DOI: 10.4155/tde-2021-0048] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Ototoxicity is the damage to inner ear sensory epithelia due to exposure to certain medications and chemicals. This occurs when toxins enter the tightly controlled inner ear environment inducing hair cell death, resulting in hearing loss. Recent studies have explored hydrogel-based bio-nanotechnologies and new drug delivery formulations to prevent drug-induced hearing loss, with much attention given to administration of antioxidant drugs. Bile acids have been recognized as promising excipients due to their biocompatibility and unique physiochemical properties. As yet bile acids have not been explored in improving drug delivery to the inner ear despite improving drug stability and delivery in other systems and demonstrating positive biological effects in their own right.
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18
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Le Prell CG. Investigational Medicinal Products for the Inner Ear: Review of Clinical Trial Characteristics in ClinicalTrials.gov. J Am Acad Audiol 2021; 32:670-694. [PMID: 35609594 PMCID: PMC9129919 DOI: 10.1055/s-0041-1735522] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/21/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND The previous 30 years have provided information on the mechanisms of cell death in the inner ear after noise exposure, ototoxic drug injury, and during aging, and clinical trials have emerged for all of these acquired forms of hearing loss. Sudden hearing loss is less well understood, but restoration of hearing after sudden hearing loss is also a long-standing drug target, typically using steroids as an intervention but with other agents of interest as well. PURPOSE The purpose of this review was to describe the state of the science regarding clinical testing of investigational medicinal products for the inner ear with respect to treatment or prevention of acquired hearing loss. DATA COLLECTION AND ANALYSIS Comprehensive search and summary of clinical trials listed in the National Library of Medicine (www. CLINICALTRIALS gov) database identified 61 clinical trials. RESULTS Study phase, status, intervention, and primary, secondary, and other outcomes are summarized for studies assessing prevention of noise-induced hearing loss, prevention of drug-induced hearing loss, treatment of stable sensorineural hearing loss, and treatment of sudden sensorineural hearing loss. CONCLUSION This review provides a comprehensive summary of the state of the science with respect to investigational medicinal products for the inner ear evaluated in human clinical trials, and the current challenges for the field.
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MESH Headings
- Cell Death/drug effects
- Cell Death/physiology
- Deafness/chemically induced
- Deafness/drug therapy
- Deafness/prevention & control
- Ear, Inner/pathology
- Hearing Loss, Noise-Induced/drug therapy
- Hearing Loss, Noise-Induced/pathology
- Hearing Loss, Noise-Induced/prevention & control
- Hearing Loss, Sensorineural/chemically induced
- Hearing Loss, Sensorineural/drug therapy
- Hearing Loss, Sensorineural/pathology
- Hearing Loss, Sensorineural/prevention & control
- Hearing Loss, Sudden/chemically induced
- Hearing Loss, Sudden/drug therapy
- Hearing Loss, Sudden/pathology
- Hearing Loss, Sudden/prevention & control
- Humans
- United States
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Affiliation(s)
- Colleen G. Le Prell
- Department of Speech, Language, and Hearing, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas
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Theophylline alleviates gentamicin-induced cytotoxicity to sensory hair cells by maintaining HDAC2 expression. Acta Histochem 2021; 123:151696. [PMID: 33652374 DOI: 10.1016/j.acthis.2021.151696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 02/13/2021] [Accepted: 02/18/2021] [Indexed: 11/22/2022]
Abstract
Sensorineural hearing loss is a health problem with global prevalence. Aminoglycoside antibiotics, for instance gentamicin, may cause ototoxicity in mammals as a result of apoptosis and elevated oxidative stress in cochlear hair cells. Our study aimed to examine the potential effects of theophylline, an HDAC2 agonist, on gentamicin-induced cytotoxicity to sensory hair cells. Mouse cochlear explants and HEI-OC1 cells were in vitro cultured and challenged by gentamicin to induce ototoxicity, with or without theophylline. Cochlear hair cells were evaluated by fluorescent microscopy, and their mechanotransduction was assessed by electrophysiology. Expression levels of HDAC2 and apoptosis pathway factors were also evaluated following gentamicin and theophylline treatments. The functional role of HDAC2 in this setting was investigated by siRNA targeted silencing. Theophylline protected cochlear hair cells from ototoxicity induced by gentamicin, in terms of preserving cochlear structure and mechanotransduction ability, and preventing the activation of the intrinsic apoptosis pathway dose-dependently. HDAC2 expression was downregulated by gentamicin, which could be restored by theophylline. HDAC2 silencing in HEI-OC1 cells negated the beneficial effect of theophylline against gentamicin-induced growth defect and apoptosis activation. Theophylline protects sensory hair cells from gentamicin ototoxicity by maintaining HDAC2 expression. Our study thereby discovers a critical role of HDAC2 in gentamicin-induced ototoxicity, which could shine light on potential therapeutic options for treatment against sensorineural hearing loss.
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Tang Q, Wang X, Jin H, Mi Y, Liu L, Dong M, Chen Y, Zou Z. Cisplatin-induced ototoxicity: Updates on molecular mechanisms and otoprotective strategies. Eur J Pharm Biopharm 2021; 163:60-71. [PMID: 33775853 DOI: 10.1016/j.ejpb.2021.03.008] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/20/2021] [Accepted: 03/15/2021] [Indexed: 02/06/2023]
Abstract
Cisplatin is a highly effective antitumor drug generally used in the treatment of solid malignant tumors. However, cisplatin causes severe side effects such as bone marrow depression, nephrotoxicity, and ototoxicity, thus limiting its clinical application. The incidence of ototoxicity induced by cisplatin ranges from 20% to 70%, and it usually manifests as a progressive, bilateral and irreversible hearing loss. Although the etiology of cisplatin-induced ototoxicity remains unclear, an increasing body of evidence suggests that the ototoxicity of cisplatin is mainly related to the production of reactive oxygen species and activation of apoptotic pathway in cochlear tissues. Many drugs have been well proved to protect cisplatin-induced hearing loss in vitro and in vivo. However, the anti-tumor effect of cisplatin is also weakened by systemic administration of those drugs for hearing protection, especially antioxidants. Therefore, establishing a local administration strategy contributes to the otoprotection without affecting the effect of cisplatin. This review introduces the pathology of ototoxicity caused by cisplatin, and focuses on recent developments in the mechanisms and protective strategies of cisplatin-induced ototoxicity.
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Affiliation(s)
- Qing Tang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Xianren Wang
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Huan Jin
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Yanjun Mi
- Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research and Thoracic Tumor Diagnosis & Treatment, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, China
| | - Lingfeng Liu
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Mengyuan Dong
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Yibing Chen
- Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China.
| | - Zhengzhi Zou
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
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Zhao Z, Han Z, Naveena K, Lei G, Qiu S, Li X, Li T, Shi X, Zhuang W, Li Y, Qiao Y, Liu H. ROS-Responsive Nanoparticle as a Berberine Carrier for OHC-Targeted Therapy of Noise-Induced Hearing Loss. ACS APPLIED MATERIALS & INTERFACES 2021; 13:7102-7114. [PMID: 33528239 DOI: 10.1021/acsami.0c21151] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Overproduction of reactive oxygen species (ROS) and inflammation are two key pathogeneses of noise-induced hearing loss (NIHL), which leads to outer hair cell (OHC) damage and hearing loss. In this work, we successfully developed ROS-responsive nanoparticles as berberine (BBR) carriers (PL-PPS/BBR) for OHC-targeted therapy of NIHL: Prestin-targeting peptide 2 (PrTP2)-modified nanoparticles (PL-PPS/BBR), which effectively accumulated in OHC areas, and poly(propylene sulfide)120 (PPS120), which scavenged ROS and converted to poly(propylene sulfoxide)120 in a ROS environment to disintegrate and provoke the rapid release of BBR with anti-inflammatory and antioxidant effects. In this study, satisfactory anti-inflammatory and antioxidant effects of PL-PPS/BBR were confirmed. Immunofluorescence and scanning electron microscopy (SEM) images showed that PL-PPS/BBR effectively accumulated in OHCs and protected the morphological integrity of OHCs. The auditory brainstem response (ABR) results demonstrated that PL-PPS/BBR significantly improved hearing in NIHL guinea pigs after noise exposure. This work suggested that PL-PPS/BBR may be a new potential treatment for noise-associated injury with clinical application.
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Affiliation(s)
- Zeqi Zhao
- Institute of Audiology and Balance Science, Xuzhou Medical University, Xuzhou 221002, PR China
- Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, PR China
- Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou 221002, PR China
| | | | - Konduru Naveena
- Institute of Audiology and Balance Science, Xuzhou Medical University, Xuzhou 221002, PR China
| | - Guanxiong Lei
- Key Laboratory of Medical Imaging and Artifical Intelligence of Hunan Province, Xiangnan University, Chenzhou 423000, PR China
- Clinical College, Xiangnan University, Chenzhou 423000, PR China
| | - Shiwei Qiu
- Institute of Audiology and Balance Science, Xuzhou Medical University, Xuzhou 221002, PR China
| | - Xuanyi Li
- Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, PR China
| | - Ting Li
- Institute of Audiology and Balance Science, Xuzhou Medical University, Xuzhou 221002, PR China
| | - Xi Shi
- Institute of Audiology and Balance Science, Xuzhou Medical University, Xuzhou 221002, PR China
| | - Wei Zhuang
- Institute of Audiology and Balance Science, Xuzhou Medical University, Xuzhou 221002, PR China
| | - Yalan Li
- Institute of Audiology and Balance Science, Xuzhou Medical University, Xuzhou 221002, PR China
| | - Yuehua Qiao
- Institute of Audiology and Balance Science, Xuzhou Medical University, Xuzhou 221002, PR China
- Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, PR China
- Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou 221002, PR China
| | - Hongmei Liu
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, PR China
- Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, PR China
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Abstract
The delivery of therapies to the cochlea is notoriously challenging. It is an organ protected by a number of barriers that need to be overcome in the drug delivery process. Additionally, there are multiple sites of possible damage within the cochlea. Despite the many potential sites of damage, acquired otologic insults preferentially damage a single location. While progress has been made in techniques for inner ear drug delivery, the current techniques remain non-specific and our ability to deliver therapies in a cell-specific manner are limited. Fortunately, there are proteins specific to various cell-types within the cochlea (e.g., hair cells, spiral ganglion cells, stria vascularis) that function as biomarkers of site-specific damage. These protein biomarkers have potential to serve as targets for cell-specific inner ear drug delivery. In this manuscript, we review the concept of biomarkers and targeted- inner ear drug delivery and the well-characterized protein biomarkers within each of the locations of interest within the cochlea. Our review will focus on targeted drug delivery in the setting of acquired otologic insults (e.g., ototoxicity, noise-induce hearing loss). The goal is not to discuss therapies to treat acquired otologic insults, rather, to establish potential concepts of how to deliver therapies in a targeted, cell-specific manner. Based on our review, it is clear that future of inner ear drug delivery is a discipline filled with potential that will require collaborative efforts among clinicians and scientists to optimize treatment of otologic insults.
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Wu J, Ye J, Kong W, Zhang S, Zheng Y. Programmed cell death pathways in hearing loss: A review of apoptosis, autophagy and programmed necrosis. Cell Prolif 2020; 53:e12915. [PMID: 33047870 PMCID: PMC7653260 DOI: 10.1111/cpr.12915] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/23/2020] [Accepted: 09/09/2020] [Indexed: 02/05/2023] Open
Abstract
Programmed cell death (PCD)—apoptosis, autophagy and programmed necrosis—is any pathological form of cell death mediated by intracellular processes. Ototoxic drugs, ageing and noise exposure are some common pathogenic factors of sensorineural hearing loss (SNHL) that can induce the programmed death of auditory hair cells through different pathways, and eventually lead to the loss of hair cells. Furthermore, several mutations in apoptotic genes including DFNA5, DFNA51 and DFNB74 have been suggested to be responsible for the new functional classes of monogenic hearing loss (HL). Therefore, in this review, we elucidate the role of these three forms of PCD in different types of HL and discuss their guiding significance for HL treatment. We believe that further studies of PCD pathways are necessary to understand the pathogenesis of HL and guide scientists and clinicians to identify new drug targets for HL treatment.
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Affiliation(s)
- Junhao Wu
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Ye
- College of Biomedical Engineering, Sichuan University, Chengdu, China
| | - Weili Kong
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Shouyue Zhang
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Yun Zheng
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, China
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24
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Noise-Induced Hearing Loss and its Prevention: Current Issues in Mammalian Hearing. CURRENT OPINION IN PHYSIOLOGY 2020; 18:32-36. [PMID: 32984667 DOI: 10.1016/j.cophys.2020.07.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Noise-induced hearing loss (NIHL) has been well investigated across diverse mammalian species and the potential for prevention of NIHL is of broad interest. To most efficiently develop novel therapeutic interventions, a good understanding of the current state of knowledge regarding mechanisms of injury is essential. The overarching goals of this review are to 1) concisely summarize the current state of knowledge, and 2) provide opinions on the most significant future trends and developments.
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25
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Otoprotective Effect of 2,3,4',5-Tetrahydroxystilbene-2- O-β-d-Glucoside on Gentamicin-Induced Apoptosis in Mouse Cochlear UB/OC-2 Cells. Molecules 2020; 25:molecules25133070. [PMID: 32640539 PMCID: PMC7412181 DOI: 10.3390/molecules25133070] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/03/2020] [Accepted: 07/05/2020] [Indexed: 02/06/2023] Open
Abstract
Excessive levels of reactive oxygen species (ROS) lead to mitochondrial damage and apoptotic cell death in gentamicin-induced ototoxicity. 2,3,4',5-Tetrahydroxystilbene-2-O-β-d-glucoside (THSG), a bioactive constituent, isolated from Polygonum multiflorum Thunb., exhibits numerous biological benefits in treating aging-related diseases by suppressing oxidative damage. However, its protective effect on gentamicin-induced ototoxicity remains unexplored. Therefore, here, we aimed to investigate the otoprotective effect of THSG on gentamicin-induced apoptosis in mouse cochlear UB/OC-2 cells. We evaluated the effect of gentamicin and THSG on the ROS level, superoxide dismutase (SOD) activity, mitochondrial membrane potential, nuclear condensation, and lactate dehydrogenase (LDH) release, and the expression of apoptosis-related proteins was assessed to understand the molecular mechanisms underlying its preventive effects. The findings demonstrated that gentamicin increased ROS generation, LDH release, and promoted apoptotic cell death in UB/OC-2 cells. However, THSG treatment reversed these effects by suppressing ROS production and downregulating the mitochondrial-dependent apoptotic pathway. Additionally, it increased the SOD activity, decreased the expression of apoptosis-related proteins, alleviated the levels of the apoptotic cells, and impaired cytotoxicity. To the best of our knowledge, this is the first study to demonstrate that THSG could be a potential therapeutic option to attenuate gentamicin-induced ototoxicity.
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Reynolds R, Garner A, Norton J. Sound and Vibration as Research Variables in Terrestrial Vertebrate Models. ILAR J 2020; 60:159-174. [PMID: 32602530 DOI: 10.1093/ilar/ilaa004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 12/31/2022] Open
Abstract
Sound and vibration have been shown to alter animal behavior and induce physiological changes as well as to cause effects at the cellular and molecular level. For these reasons, both environmental factors have a considerable potential to alter research outcomes when the outcome of the study is dependent on the animal existing in a normal or predictable biological state. Determining the specific levels of sound or vibration that will alter research is complex, as species will respond to different frequencies and have varying frequencies where they are most sensitive. In consideration of the potential of these factors to alter research, a thorough review of the literature and the conditions that likely exist in the research facility should occur specific to each research study. This review will summarize the fundamental physical properties of sound and vibration in relation to deriving maximal level standards, consider the sources of exposure, review the effects on animals, and discuss means by which the adverse effects of these factors can be mitigated.
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Affiliation(s)
- Randall Reynolds
- Duke University School of Medicine, Department of Pathology and Division of Laboratory Animal Resources, Durham, NC
| | - Angela Garner
- Duke University School of Medicine, Division of Laboratory Animal Resources, Durham, NC
| | - John Norton
- Duke University School of Medicine, Pathology and Division of Laboratory Animal Resources
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27
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Cortada M, Wei E, Jain N, Levano S, Bodmer D. Telmisartan Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro. Audiol Neurootol 2020; 25:297-308. [PMID: 32369826 DOI: 10.1159/000506796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 02/13/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Telmisartan is an angiotensin II receptor blocker that has pleiotropic effects and protective properties in different cell types. Moreover, telmisartan has also shown partial agonism on the peroxisome proliferator-activated receptor γ (PPAR-γ). Auditory hair cells (HCs) express PPAR-γ, and the protective role of PPAR-γ agonists on HCs has been shown. OBJECTIVES The objective of this study was to investigate the effects of telmisartan on gentamicin-induced ototoxicity in vitro. METHODS Cochlear explants were exposed to gentamicin with or without telmisartan, and/or GW9662, an irreversible PPAR-γ antagonist. RESULTS Telmisartan protected auditory HCs against gentamicin-induced ototoxicity. GW9662 completely blocked this protective effect, suggesting that it was mediated by PPAR-γ signaling. Exposure to GW9662 or telmisartan alone was not toxic to auditory HCs. CONCLUSIONS We found that telmisartan, via PPAR-γ signaling, protects auditory HCs from gentamicin-induced ototoxicity. Therefore, telmisartan could potentially be used in the future to prevent or treat sensorineural hearing loss.
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Affiliation(s)
- Maurizio Cortada
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Eric Wei
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Neha Jain
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Soledad Levano
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Daniel Bodmer
- Clinic for Otolaryngology, Head and Neck Surgery, University of Basel Hospital, Basel, Switzerland,
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28
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Liu ZG, Li Y, Jiao JH, Long H, Xin ZY, Yang XY. MicroRNA regulatory pattern in spinal cord ischemia-reperfusion injury. Neural Regen Res 2020; 15:2123-2130. [PMID: 32394971 PMCID: PMC7716024 DOI: 10.4103/1673-5374.280323] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
After spinal cord injury, dysregulated miRNAs appear and can participate in inflammatory responses, as well as the inhibition of apoptosis and axon regeneration through multiple pathways. However, the functions of miRNAs in spinal cord ischemia-reperfusion injury progression remain unclear. miRCURY LNATM Arrays were used to analyze miRNA expression profiles of rats after 90 minutes of ischemia followed by reperfusion for 24 and 48 hours. Furthermore, subsequent construction of aberrantly expressed miRNA regulatory patterns involved cell survival, proliferation, and apoptosis. Remarkably, the mitogen-activated protein kinase (MAPK) signaling pathway was the most significantly enriched pathway among 24- and 48-hour groups. Bioinformatics analysis and quantitative reverse transcription polymerase chain reaction confirmed the persistent overexpression of miR-22-3p in both groups. These results suggest that the aberrant miRNA regulatory network is possibly regulated MAPK signaling and continuously affects the physiological and biochemical status of cells, thus participating in the regulation of spinal cord ischemia-reperfusion injury. As such, miR-22-3p may play sustained regulatory roles in spinal cord ischemia-reperfusion injury. All experimental procedures were approved by the Animal Ethics Committee of Jilin University, China [approval No. 2020 (Research) 01].
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Affiliation(s)
- Zhi-Gang Liu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yin Li
- School of Public Health, Jilin University, Changchun, Jilin Province, China
| | - Jian-Hang Jiao
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Hao Long
- Pain Clinic, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Zhuo-Yuan Xin
- The Key Laboratory of Zoonosis Search, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin Province, China
| | - Xiao-Yu Yang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin Province, China
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Miao L, Ji J, Wan L, Zhang J, Yin L, Pu Y. An overview of research trends and genetic polymorphisms for noise-induced hearing loss from 2009 to 2018. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2019; 26:34754-34774. [PMID: 31696427 DOI: 10.1007/s11356-019-06470-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 09/09/2019] [Indexed: 05/27/2023]
Abstract
Recently, there has been increased studies in noise-induced hearing loss (NIHL). We aimed to make an overview of research trends and genetic polymorphisms for NIHL from 2009 to 2018 with VOSviewer software. A total of 2391 papers were identified for research trends analysis in NIHL and 33 studies identified for a brief review of genetic polymorphisms in human NIHL. The number of publications has been increasing over the past decade. The journal Hearing Research published the most articles (218). The USA contributed the largest number of papers (1042; 43.58%), with the most citations (18,987) and the highest H-index (60). The University of Washington was the most contributive institution. Liberman MC published the most articles (32), and Kujawa SG possessed the highest co-citations (584). Except for high-frequency keywords identified by the software, "prevalence," "oxidative stress," "hair cells," and "cochlear implant" were also the latest research frontiers. HSPA1A rs1043618, HSPA1L rs2227956, PON2 rs12026 and rs7785846, SOD2 rs2855116, KCNE1 rs2070358, KCNQ4 rs34287852, GJB2 rs3751385, PCDH15 rs7095441 and rs11004085, GRHL2 rs1981361, ITGA8 rs10508489, MYH14 rs667907, and POU4F3 rs891969 were the research hotspots and were replicated in independent samples. Inflammation response underlying NIHL has emerged and should be considered as a pioneering field in the future for the prevention of NIHL and conservation of hearing.
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Affiliation(s)
- Long Miao
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, People's Republic of China
| | - Jiahui Ji
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, People's Republic of China
| | - Liu Wan
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, People's Republic of China
| | - Juan Zhang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, People's Republic of China
| | - Lihong Yin
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, People's Republic of China
| | - Yuepu Pu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, People's Republic of China.
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Naert G, Pasdelou MP, Le Prell CG. Use of the guinea pig in studies on the development and prevention of acquired sensorineural hearing loss, with an emphasis on noise. THE JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA 2019; 146:3743. [PMID: 31795705 PMCID: PMC7195866 DOI: 10.1121/1.5132711] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 07/30/2019] [Accepted: 08/12/2019] [Indexed: 05/10/2023]
Abstract
Guinea pigs have been used in diverse studies to better understand acquired hearing loss induced by noise and ototoxic drugs. The guinea pig has its best hearing at slightly higher frequencies relative to humans, but its hearing is more similar to humans than the rat or mouse. Like other rodents, it is more vulnerable to noise injury than the human or nonhuman primate models. There is a wealth of information on auditory function and vulnerability of the inner ear to diverse insults in the guinea pig. With respect to the assessment of potential otoprotective agents, guinea pigs are also docile animals that are relatively easy to dose via systemic injections or gavage. Of interest, the cochlea and the round window are easily accessible, notably for direct cochlear therapy, as in the chinchilla, making the guinea pig a most relevant and suitable model for hearing. This article reviews the use of the guinea pig in basic auditory research, provides detailed discussion of its use in studies on noise injury and other injuries leading to acquired sensorineural hearing loss, and lists some therapeutics assessed in these laboratory animal models to prevent acquired sensorineural hearing loss.
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Affiliation(s)
| | | | - Colleen G Le Prell
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, Texas 75080, USA
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31
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Gittleman SN, Le Prell CG, Hammill TL. Octave band noise exposure: Laboratory models and otoprotection efforts. THE JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA 2019; 146:3800. [PMID: 31795706 PMCID: PMC7195864 DOI: 10.1121/1.5133393] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 05/21/2019] [Indexed: 05/05/2023]
Abstract
With advances in the understanding of mechanisms of noise injury, the past 30 years have brought numerous efforts to identify drugs that prevent noise-induced hearing loss (NIHL). The diverse protocols used across investigations have made comparisons across drugs difficult. A systematic review of the literature by Hammill [(2017). Doctoral thesis, The University of Texas at Austin] identified original reports of chemical interventions to prevent or treat hearing loss caused by noise exposure. An initial search returned 3492 articles. After excluding duplicate articles and articles that did not meet the systematic review inclusion criteria, a total of 213 studies published between 1977 and 2016 remained. Reference information, noise exposure parameters, species, sex, method of NIHL assessment, and pharmaceutical intervention details for these 213 studies were entered into a database. Frequency-specific threshold shifts in control animals (i.e., in the absence of pharmaceutical intervention) are reported here. Specific patterns of hearing loss as a function of species and noise exposure parameters are provided to facilitate the selection of appropriate pre-clinical models. The emphasis of this report is octave band noise exposure, as this is one of the most common exposure protocols across pharmacological otoprotection studies.
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Affiliation(s)
- Sarah N Gittleman
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, Texas 75080, USA
| | - Colleen G Le Prell
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, Texas 75080, USA
| | - Tanisha L Hammill
- Department of Defense, Defense Health Agency, Falls Church, Virginia 22042, USA
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32
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Hong H, Budhathoki C, Farley JE. Increased risk of aminoglycoside-induced hearing loss in MDR-TB patients with HIV coinfection. Int J Tuberc Lung Dis 2019; 22:667-674. [PMID: 29862952 DOI: 10.5588/ijtld.17.0830] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
SETTING A high proportion of individuals with multidrug-resistant tuberculosis (MDR-TB) develop permanent hearing loss due to ototoxicity caused by injectable aminoglycosides (AGs). The prevalence of AG-induced hearing loss is greatest in tuberculosis (TB) and human immunodeficiency virus (HIV) endemic countries in sub-Saharan Africa. However, whether HIV coinfection is associated with a higher incidence of AG-induced hearing loss during MDR-TB treatment is controversial. OBJECTIVE To evaluate the impact of HIV coinfection on AG-induced hearing loss among individuals with MDR-TB in sub-Saharan Africa. DESIGN This was a meta-analysis of articles published in PubMed, Embase, Scopus, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Cochrane Review, and reference lists using search terms 'hearing loss', 'aminoglycoside', and 'sub-Saharan Africa'. RESULTS Eight studies conducted in South Africa, Botswana and Namibia and published between 2012 and 2016 were included. As the included studies were homogeneous (χ2 = 8.84, df = 7), a fixed-effects model was used. Individuals with MDR-TB and HIV coinfection had a 22% higher risk of developing AG-induced hearing loss than non-HIV-infected individuals (pooled relative risk 1.22, 95%CI 1.10-1.36) during MDR-TB treatment. CONCLUSION This finding is critical for TB programs with regard to the expansion of injectable-sparing regimens. Our findings lend credibility to using injectable-sparing regimens and more frequent hearing monitoring, particularly in resource-limited settings for HIV-coinfected individuals.
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Affiliation(s)
- H Hong
- Department of Community-Public Health
| | | | - J E Farley
- Department of Community-Public Health, REACH Initiative, Johns Hopkins University School of Nursing, Baltimore, Maryland, USA
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33
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Hong H, Dooley KE, Starbird LE, Francis HW, Farley JE. Adverse outcome pathway for aminoglycoside ototoxicity in drug-resistant tuberculosis treatment. Arch Toxicol 2019; 93:1385-1399. [PMID: 30963202 DOI: 10.1007/s00204-019-02407-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 02/06/2019] [Indexed: 12/22/2022]
Abstract
Individuals treated for multidrug-resistant tuberculosis (MDR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss. However, AG ototoxicity has never been conceptually integrated or causally linked to MDR-TB patients' pre-treatment health condition. We sought to develop a framework that examines the relationships between pre-treatment conditions and AG-induced hearing loss among MDR-TB-infected individuals in sub-Saharan Africa. The adverse outcome pathway (AOP) approach was used to develop a framework linking key events (KEs) within a biological pathway that results in adverse outcomes (AO), which are associated with chemical perturbation of a molecular initiating event (MIE). This AOP describes pathways initiating from AG accumulation in hair cells, sound transducers of the inner ear immediately after AG administration. After administration, the drug catalyzes cellular oxidative stress due to overproduction of reactive oxygen species. Since oxidative stress inhibits mitochondrial protein synthesis, hair cells undergo apoptotic cell death, resulting in irreversible hearing loss (AO). We identified the following pre-treatment conditions that worsen the causal linkage between MIE and AO: HIV, malnutrition, aging, noise, smoking, and alcohol use. The KEs are: (1) nephrotoxicity, pre-existing hearing loss, and hypoalbuminemia that catalyzes AG accumulation; (2) immunodeficiency and antioxidant deficiency that trigger oxidative stress pathways; and (3) co-administration of mitochondrial toxic drugs that hinder mitochondrial protein synthesis, causing apoptosis. This AOP clearly warrants the development of personalized interventions for patients undergoing MDR-TB treatment. Such interventions (i.e., choosing less ototoxic drugs, scheduling frequent monitoring, modifying nutritional status, avoiding poly-pharmacy) will be required to limit the burden of AG ototoxicity.
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Affiliation(s)
- Hyejeong Hong
- Johns Hopkins University School of Nursing, 525 North Wolfe Street, Baltimore, MD, 21205, USA. .,Johns Hopkins University School of Nursing, The REACH Initiative, 855 N. Wolfe Street, 21205, Baltimore, MD, USA.
| | - Kelly E Dooley
- Divisions of Clinical Pharmacology and Infectious Disease, Johns Hopkins University School of Medicine, 600 North Wolfe Street, 21205, Baltimore, MD, USA
| | - Laura E Starbird
- Center for Health Policy, Columbia University School of Nursing, 560 W 168 St, 10032, New York, NY, USA
| | - Howard W Francis
- Division of Head and Neck Surgery and Communication Sciences, Duke University School of Medicine, 40 Duke Medicine Circle, 27710, Durham, NC, USA
| | - Jason E Farley
- Johns Hopkins University School of Nursing, 525 North Wolfe Street, Baltimore, MD, 21205, USA.,Johns Hopkins University School of Nursing, The REACH Initiative, 855 N. Wolfe Street, 21205, Baltimore, MD, USA
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Blood Pressure Variability Is Associated with Hearing and Hearing Loss: A Population-Based Study in Males. Int J Hypertens 2019; 2019:9891025. [PMID: 30863629 PMCID: PMC6377956 DOI: 10.1155/2019/9891025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 01/12/2019] [Accepted: 01/20/2019] [Indexed: 01/03/2023] Open
Abstract
Blood pressure (BP) has been well documented to be associated with hearing loss previously. However, the role of blood pressure variability (BPV, representing BP fluctuation over a time period) on hearing remains unknown. We aimed to evaluate the relationship between BPV and hearing in Chinese population. We included 8646 male subjects from a population-based study (the Kailuan study). BP was measured every two years at routine physical examinations from 2006 to 2015. Based on five annual BP measurements, BPV was estimated by standard deviation of BP (SD), coefficient of the variation of BP (CV), and variation independent of mean of BP (VIM). Hearing was estimated by pure-tone average threshold (PTA) at low, intermediate, and high frequencies in the year of 2014. Regression models were used to evaluate the relationship between BPV and hearing. The results showed that PTAs and percentages of hearing loss at low, intermediate, and high frequencies grew gradually with increasing systolic SD (SSD) (p<0.05). After adjusting for multiple covariates, multivariate regression analyses demonstrated that variations of SBP (SSD, SCV, and VIMSBP) were all positively correlated with PTA at intermediate and high frequencies (p<0.05). Each SD increase in SSD, SCV, and VIMSBP was also positively associated with hearing loss at intermediate and high frequencies. No significant correlation was observed between variations of DBP and hearing. These findings suggest that increase in long-term BPV is associated with hearing and hearing loss. Trial registration number: Kailuan study (ChiCTRTNC-11001489).
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35
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Yu Y, Hu B, Bao J, Mulvany J, Bielefeld E, Harrison RT, Neton SA, Thirumala P, Chen Y, Lei D, Qiu Z, Zheng Q, Ren J, Perez-Flores MC, Yamoah EN, Salehi P. Otoprotective Effects of Stephania tetrandra S. Moore Herb Isolate against Acoustic Trauma. J Assoc Res Otolaryngol 2018; 19:653-668. [PMID: 30187298 PMCID: PMC6249158 DOI: 10.1007/s10162-018-00690-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 07/08/2018] [Indexed: 01/10/2023] Open
Abstract
Noise is the most common occupational and environmental hazard, and noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit. Although therapeutics that target the free-radical pathway have shown promise, none of these compounds is currently approved against NIHL by the United States Food and Drug Administration. The present study has demonstrated that tetrandrine (TET), a traditional Chinese medicinal alkaloid and the main chemical isolate of the Stephania tetrandra S. Moore herb, significantly attenuated NIHL in CBA/CaJ mice. TET is known to exert antihypertensive and antiarrhythmic effects through the blocking of calcium channels. Whole-cell patch-clamp recording from adult spiral ganglion neurons showed that TET blocked the transient Ca2+ current in a dose-dependent manner and the half-blocking concentration was 0.6 + 0.1 μM. Consistent with previous findings that modulations of calcium-based signaling pathways have both prophylactic and therapeutic effects against neural trauma, NIHL was significantly diminished by TET administration. Importantly, TET has a long-lasting protective effect after noise exposure (48 weeks) in comparison to 2 weeks after noise exposure. The otoprotective effects of TET were achieved mainly by preventing outer hair cell damage and synapse loss between inner hair cells and spiral ganglion neurons. Thus, our data indicate that TET has great potential in the prevention and treatment of NIHL.
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Affiliation(s)
- Yan Yu
- The First People’s Hospital of Zhangjiagang, 68 W Jiyang Road, Zhangjiagang City, 215600 Jiangsu China
- Translational Research Center, Northeast Ohio Medical University, Rootstown, OH 44272 USA
| | - Bing Hu
- Translational Research Center, Northeast Ohio Medical University, Rootstown, OH 44272 USA
- Department of Otolaryngology-Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA
- Department of Otolaryngology Head and Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, 440011 Hunan China
| | - Jianxin Bao
- Translational Research Center, Northeast Ohio Medical University, Rootstown, OH 44272 USA
- Department of Research and Development, Gateway Biotechnology Inc., Rootstown, OH 44272 USA
| | - Jessica Mulvany
- Translational Research Center, Northeast Ohio Medical University, Rootstown, OH 44272 USA
- Department of Research and Development, Gateway Biotechnology Inc., Rootstown, OH 44272 USA
| | - Eric Bielefeld
- Department of Speech and Hearing Science, Ohio State University, Columbus, OH 43210 USA
| | - Ryan T. Harrison
- Department of Speech and Hearing Science, Ohio State University, Columbus, OH 43210 USA
| | - Sarah A. Neton
- Department of Speech and Hearing Science, Ohio State University, Columbus, OH 43210 USA
| | - Partha Thirumala
- The University of Pittsburgh Medical Center, Suite B-400, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Yingying Chen
- Translational Research Center, Northeast Ohio Medical University, Rootstown, OH 44272 USA
| | - Debin Lei
- Translational Research Center, Northeast Ohio Medical University, Rootstown, OH 44272 USA
| | - Ziyu Qiu
- Department of Research and Development, Gateway Biotechnology Inc., Rootstown, OH 44272 USA
| | - Qingyin Zheng
- Department of Otolaryngology-Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA
| | - Jihao Ren
- Department of Otolaryngology Head and Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, 440011 Hunan China
| | - Maria Cristina Perez-Flores
- Department of Physiology and Cell Biology, University of Nevada Reno, 1664 North Virginia St, Reno, NV 89557 USA
| | - Ebenezer N. Yamoah
- Department of Physiology and Cell Biology, University of Nevada Reno, 1664 North Virginia St, Reno, NV 89557 USA
| | - Pezhman Salehi
- Translational Research Center, Northeast Ohio Medical University, Rootstown, OH 44272 USA
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Wang X, Chen Y, Tao Y, Gao Y, Yu D, Wu H. A666-conjugated nanoparticles target prestin of outer hair cells preventing cisplatin-induced hearing loss. Int J Nanomedicine 2018; 13:7517-7531. [PMID: 30532536 PMCID: PMC6241721 DOI: 10.2147/ijn.s170130] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
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.
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Affiliation(s)
- Xueling Wang
- Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China, ;
| | - Yuming Chen
- Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China, ;
| | - Yong Tao
- Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China, ;
| | - Yunge Gao
- Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China, ;
| | - Dehong Yu
- Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China, ;
| | - Hao Wu
- Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China, ; .,Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China, ;
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Desa DE, Nichols MG, Smith HJ. Aminoglycosides rapidly inhibit NAD(P)H metabolism increasing reactive oxygen species and cochlear cell demise. JOURNAL OF BIOMEDICAL OPTICS 2018; 24:1-14. [PMID: 30411553 PMCID: PMC6225535 DOI: 10.1117/1.jbo.24.5.051403] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Accepted: 09/21/2018] [Indexed: 06/04/2023]
Abstract
Despite causing permanent hearing loss by damaging inner ear sensory cells, aminoglycosides (AGs) remain one of the most widely used classes of antibiotics in the world. Although the mechanisms of cochlear sensory cell damage are not fully known, reactive oxygen species (ROS) are clearly implicated. Mitochondrial-specific ROS formation was evaluated in acutely cultured murine cochlear explants exposed to gentamicin (GM), a representative ototoxic AG antibiotic. Superoxide (O2·-) and hydrogen peroxide (H2O2) were measured using MitoSOX Red and Dihydrorhodamine 123, respectively, in sensory and supporting cells. A 1-h GM exposure significantly increased O2·- formation in IHCs and increased H2O2 formation in all cell types. At the same time point, GM significantly increased manganese superoxide dismutase (MnSOD) levels while significantly decreasing copper/zinc superoxide dismutase (CuZnSOD) in cochlear sensory cells. This suggests (1) a rapid conversion of highly reactive O2·- to H2O2 during the acute stage of ototoxic antibiotic exposure and (2) that the endogenous antioxidant system is significantly altered by AGs. Fluorescence intensity-based measurements of reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] and mitochondrial membrane potential were measured to determine if increases in GM-induced ROS production were correlated with changes in mitochondrial metabolism. This project provides a basis for understanding the mechanisms of mitochondrial ROS production in cochlear cells exposed to ototoxic antibiotics. Understanding the nature of ototoxic antibiotic-induced changes in mitochondrial metabolism is critical for developing hearing loss treatment and prevention strategies.
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Affiliation(s)
- Danielle E. Desa
- University of Rochester, Department of Biomedical Engineering, Rochester, New York, United States
| | - Michael G. Nichols
- Creighton University, Department of Physics, Omaha, Nebraska, United States
- Creighton University, Department of Biomedical Sciences, Omaha, Nebraska, United States
| | - Heather Jensen Smith
- University of Nebraska Medical Center, The Eppley Institute for Cancer and Allied Diseases, Omaha, Nebraska, United States
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Ralli M, Rolesi R, Anzivino R, Turchetta R, Fetoni AR. Acquired sensorineural hearing loss in children: current research and therapeutic perspectives. ACTA OTORHINOLARYNGOLOGICA ITALICA 2018; 37:500-508. [PMID: 29327735 PMCID: PMC5782428 DOI: 10.14639/0392-100x-1574] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 05/02/2017] [Indexed: 01/03/2023]
Abstract
The knowledge of mechanisms responsible for acquired sensorineural hearing loss in children, such as viral and bacterial infections, noise exposure, aminoglycoside and cisplatin ototoxicity, is increasing and progressively changing the clinical management of affected patients. Viral infections are by far the most relevant cause of acquired hearing loss, followed by aminoglycoside and platinum derivative ototoxicity; moreover, cochlear damage induced by noise overexposure, mainly in adolescents, is an emerging topic. Pharmacological approaches are still challenging to develop a truly effective cochlear protection; however, the use of steroids, antioxidants, antiviral drugs and other small molecules is encouraging for clinical practice. Most of evidence on the effectiveness of antioxidants is still limited to experimental models, while the use of corticosteroids and antiviral drugs has a wide correspondence in literature but with controversial safety. Future therapeutic perspectives include innovative strategies to transport drugs into the cochlea, such as molecules incorporated in nanoparticles that can be delivered to a specific target. Innovative approaches also include the gene therapy designed to compensate for abnormal genes or to make proteins by introducing genetic material into cells; finally, regenerative medicine (including stem cell approaches) may play a central role in the upcoming years in hearing preservation and restoration even if its role in the inner ear is still debated.
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Affiliation(s)
- M Ralli
- Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Italy
| | - R Rolesi
- Department of Otolaryngology, Catholic University of Sacred Heart, Rome, Italy
| | - R Anzivino
- Department of Otolaryngology, Catholic University of Sacred Heart, Rome, Italy
| | - R Turchetta
- Department of Sense Organs, Sapienza University of Rome, Italy
| | - A R Fetoni
- Department of Otolaryngology, Catholic University of Sacred Heart, Rome, Italy
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Eshraghi AA, Aranke M, Salvi R, Ding D, Coleman JK, Ocak E, Mittal R, Meyer T. Preclinical and clinical otoprotective applications of cell-penetrating peptide D-JNKI-1 (AM-111). Hear Res 2018; 368:86-91. [DOI: 10.1016/j.heares.2018.03.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 02/07/2018] [Accepted: 03/02/2018] [Indexed: 01/12/2023]
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Dabrowski M, Bukowy-Bieryllo Z, Zietkiewicz E. Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons. Mol Med 2018; 24:25. [PMID: 30134808 PMCID: PMC6016875 DOI: 10.1186/s10020-018-0024-7] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 05/01/2018] [Indexed: 12/31/2022] Open
Abstract
Premature termination codons (PTCs) in the coding regions of mRNA lead to the incorrect termination of translation and generation of non-functional, truncated proteins. Translational readthrough of PTCs induced by pharmaceutical compounds is a promising way of restoring functional protein expression and reducing disease symptoms, without affecting the genome or transcriptome of the patient. While in some cases proven effective, the clinical use of readthrough-inducing compounds is still associated with many risks and difficulties. This review focuses on problems directly associated with compounds used to stimulate PTC readthrough, such as their interactions with the cell and organism, their toxicity and bioavailability (cell permeability; tissue deposition etc.). Various strategies designed to overcome these problems are presented.
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Affiliation(s)
- Maciej Dabrowski
- Institute of Human Genetics; Polish Academy of Sciences, Poznan, Poland
| | | | - Ewa Zietkiewicz
- Institute of Human Genetics; Polish Academy of Sciences, Poznan, Poland.
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Importance of Perimodiolar Electrode Position for Psychoacoustic Discrimination in Cochlear Implantation. Otol Neurotol 2017; 38:e429-e437. [PMID: 29135866 DOI: 10.1097/mao.0000000000001594] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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42
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Martín-Saldaña S, Palao-Suay R, Aguilar MR, García-Fernández L, Arévalo H, Trinidad A, Ramírez-Camacho R, San Román J. pH-sensitive polymeric nanoparticles with antioxidant and anti-inflammatory properties against cisplatin-induced hearing loss. J Control Release 2017; 270:53-64. [PMID: 29197586 DOI: 10.1016/j.jconrel.2017.11.032] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 11/17/2017] [Accepted: 11/20/2017] [Indexed: 11/28/2022]
Abstract
Polymeric nanoparticles (NPs) based on smart synthetic amphiphilic copolymers are used to transport and controlled release dexamethasone in the inner ear to protect against the ototoxic effect of cisplatin. The NPs were based on a mixture of two pseudo-block polymer drugs obtained by free radical polymerization: poly(VI-co-HEI) and poly(VP-co-MVE) or poly(VP-co-MTOS), being VI 1-vinylimidazole, VP N-vinylpyrrolidone, and HEI, MVE and MTOS the methacrylic derivatives of ibuprofen, α-tocopherol and α-tocopheryl succinate, respectively. The NPs were obtained by nanoprecipitation with appropriate hydrodynamic properties, and isoelectric points that matched the pH of inflamed tissue. The NPs were tested both in vitro (using HEI-OC1 cells) and in vivo (using a murine model) with good results. Although the concentration of dexamethasone administered in the NPs is around two orders of magnitude lower that the conventional treatment for intratympanic administration, the NPs protected from the cytotoxic effect of cisplatin when the combination of the appropriate properties in terms of size, zeta potential, encapsulation efficiency and isoelectric point were achieved. To the best of our knowledge this is the first time that pH sensitive NPs are used to protect from cisplatin-induced hearing loss by intratympanic administration.
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Affiliation(s)
- Sergio Martín-Saldaña
- Grupo de Biomateriales, Departamento de Nanomateriales Poliméricos y Biomateriales, Instituto de Ciencia y Tecnología de Polímeros, ICTP-CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain; Ear Research Group, Hospital UniversitarioPuerta de Hierro Majadahonda, Health Research Institute Puerta de Hierro, Madrid, Spain
| | - Raquel Palao-Suay
- Grupo de Biomateriales, Departamento de Nanomateriales Poliméricos y Biomateriales, Instituto de Ciencia y Tecnología de Polímeros, ICTP-CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain
| | - María Rosa Aguilar
- Grupo de Biomateriales, Departamento de Nanomateriales Poliméricos y Biomateriales, Instituto de Ciencia y Tecnología de Polímeros, ICTP-CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain.
| | - Luis García-Fernández
- Grupo de Biomateriales, Departamento de Nanomateriales Poliméricos y Biomateriales, Instituto de Ciencia y Tecnología de Polímeros, ICTP-CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain
| | - Humberto Arévalo
- Grupo de Biomateriales, Departamento de Nanomateriales Poliméricos y Biomateriales, Instituto de Ciencia y Tecnología de Polímeros, ICTP-CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain
| | - Almudena Trinidad
- Ear Research Group, Hospital UniversitarioPuerta de Hierro Majadahonda, Health Research Institute Puerta de Hierro, Madrid, Spain
| | - Rafael Ramírez-Camacho
- Ear Research Group, Hospital UniversitarioPuerta de Hierro Majadahonda, Health Research Institute Puerta de Hierro, Madrid, Spain
| | - Julio San Román
- Grupo de Biomateriales, Departamento de Nanomateriales Poliméricos y Biomateriales, Instituto de Ciencia y Tecnología de Polímeros, ICTP-CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain
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Victores AJ, Chen M, Smith A, Lane AP. Olfactory loss in chronic rhinosinusitis is associated with neuronal activation of c-Jun N-terminal kinase. Int Forum Allergy Rhinol 2017; 8:415-420. [PMID: 29193850 DOI: 10.1002/alr.22053] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 10/22/2017] [Accepted: 11/07/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND Olfactory inflammation in chronic rhinosinusitis (CRS) is associated with cytokines that may result in the death of olfactory sensory neurons. The principal signaling molecules involved in the apoptotic pathway are c-Jun N-terminal kinases (JNK). Although the JNK pathway has emerged as a key player in programmed cell death in neuroinflammation, its specific role in CRS-associated olfactory loss has not been thoroughly investigated. METHODS JNK activation was studied in human tissue samples from 9 control and 11 CRS patients by immunohistochemical staining for phosphorylated c-Jun. A mouse model of inducible olfactory cytokine expression was used to experimentally control inflammation and assess JNK activation over time. RESULTS In patients with CRS, activation of c-Jun is significantly increased relative to non-CRS control subjects, and there is an associated loss of sensory neurons. In the olfactory inflammation mouse model, prolonged induction of inflammation results in elevation of c-Jun expression and neuronal apoptosis. CONCLUSION Activation of neuronal JNK is a feature of chronic olfactory inflammation that is associated with neuronal apoptosis. Given that inhibition of JNK activity is neuroprotective in other settings, antagonism of this pathway may have therapeutic potential in the management of inflammatory olfactory loss or other disorders linked to olfactory neuronal apoptosis.
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Affiliation(s)
- Andrew J Victores
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Mengfei Chen
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Amy Smith
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Andrew P Lane
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
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Antibiotics Reduce Retinal Cell Survival In Vitro. Neurotox Res 2017; 33:781-789. [PMID: 29098663 DOI: 10.1007/s12640-017-9826-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 09/24/2017] [Accepted: 10/05/2017] [Indexed: 10/18/2022]
Abstract
Antibiotics such as gentamicin (an aminoglycoside) and penicillin (a beta-lactam antibiotic) are routinely used in retinal cell and explant cultures. In many cases, these in vitro systems are testing parameters regarding photoreceptor transplantation or preparing cells for transplantation. In vivo, milligram doses of gentamicin are neurotoxic to the retina. However, little is known about the effects of antibiotics to retina in vitro and whether smaller doses of gentamicin are toxic to retinal cells. To test toxicity, retinal cells were dissociated from tiger salamander, placed in culture, and treated with either 20 μg/ml gentamicin, 100 μg/ml streptomycin, 100 U/ml antibiotic/antimycotic, 0.25 μg/ml amphotericin B, or 100 U/ml penicillin G. All dosages were within manufacturer's recommended levels. Control cultures had defined medium only. Cells were fixed at 2 h or 7 days. Three criteria were used to assess toxicity: (1) survival of retinal neurons, (2) neuritic growth of photoreceptors assessed by the development of presynaptic varicosities, and (3) survival and morphology of Mueller cells. Rod cells were immunolabeled for rod opsin, Mueller cells for glial fibrillary acidic protein, and varicosities for synaptophysin. Neuronal cell density was reduced with all pharmacological treatments. The number of presynaptic varicosities was also significantly lower in both rod and cone photoreceptors in treated compared to control cultures; further, rods were more sensitive to gentamicin than cones. Penicillin G (100 U/ml) was overall the least inhibitory and amphotericin B the most toxic of all the agents to photoreceptors. Mueller cell survival was reduced with all treatments; reduced survival was accompanied by the appearance of proportionally fewer stellate and more rounded glial morphologies. These findings suggest that even microgram doses of antibiotic and antimycotic drugs can be neurotoxic to retinal cells and reduce neuritic regeneration in cell culture systems.
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Gu L, Cui X, Wei W, Yang J, Li X. Ferulic acid promotes survival and differentiation of neural stem cells to prevent gentamicin-induced neuronal hearing loss. Exp Cell Res 2017; 360:257-263. [DOI: 10.1016/j.yexcr.2017.09.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 09/06/2017] [Accepted: 09/08/2017] [Indexed: 01/15/2023]
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The Effect of Systemic Steroid on Hearing Preservation After Cochlear Implantation via Round Window Approach: A Guinea Pig Model. Otol Neurotol 2017; 38:962-969. [DOI: 10.1097/mao.0000000000001453] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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47
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Noise-induced cochlear synaptopathy: Past findings and future studies. Hear Res 2017; 349:148-154. [DOI: 10.1016/j.heares.2016.12.008] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 11/08/2016] [Accepted: 12/08/2016] [Indexed: 01/12/2023]
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Martín-Saldaña S, Palao-Suay R, Aguilar MR, Ramírez-Camacho R, San Román J. Polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate to prevent cisplatin-induced ototoxicity. Acta Biomater 2017; 53:199-210. [PMID: 28213099 DOI: 10.1016/j.actbio.2017.02.019] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 01/23/2017] [Accepted: 02/11/2017] [Indexed: 12/20/2022]
Abstract
The aim of this work is the development of highly protective agents to be administered locally within the middle ear to avoid cisplatin-induced ototoxicity, which affects to 100% of the clinical patients at ultra-high concentrations (16mg/kg). The protective agents are based on polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate as anti-inflammarory and anti-apoptotic molecules. Dexamethasone and α-tocopheryl succinate are poorly soluble in water and present severe side effects when systemic administered during long periods of time. Their incorporation in the hydrophobic core of nanoparticles with the appropriate hydrodynamic properties provides the desired effects in vitro (lower cisplatin-induced toxicity, decreasing of caspase 3/7 activity, and lower IL-1β release) and in vivo (reducing the hearing loss at the local level). The local administration of the nanoparticles by bullostomy provides an adequate dose of drug without systemic interference with the chemotherapeutic effect of cisplatin. STATEMENT OF SIGNIFICANCE 100% of the cancer patients receiving ultra-high doses of CDDP (16mg/kg) suffer severe hearing loss, being a limiting factor in antineoplastic treatments. In this paper we describe the application of polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate to palliate the cisplatin ototoxicity derived from chemotherapy treatment. These new nanoparticles, that encapsulate, transport, and deliver dexamethasone or α-tocopheryl succinate in the middle ear, are able to partially prevent ototoxicity derived from high doses of CDDP. This is an interdisciplinary study in which in vitro and in vivo experiments are described and extensively discussed. The importance of the results opens an excellent opportunity to the translation to the clinic.
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Affiliation(s)
- Sergio Martín-Saldaña
- Department of Otorhinolaryngology, Puerta de Hierro Majadahonda University Hospital, C/ Manuel de Falla, 1, 28222 Majadahonda, Spain; Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/ Juan de la Cierva, 3, 28006 Madrid, Spain
| | - Raquel Palao-Suay
- Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/ Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain
| | - María Rosa Aguilar
- Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/ Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain.
| | - Rafael Ramírez-Camacho
- Department of Otorhinolaryngology, Puerta de Hierro Majadahonda University Hospital, C/ Manuel de Falla, 1, 28222 Majadahonda, Spain; Universidad Autónoma de Madrid, Cantoblanco Campus University, 28049 Madrid, Spain
| | - Julio San Román
- Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/ Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain
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Fuentes-Santamaría V, Alvarado JC, Melgar-Rojas P, Gabaldón-Ull MC, Miller JM, Juiz JM. The Role of Glia in the Peripheral and Central Auditory System Following Noise Overexposure: Contribution of TNF-α and IL-1β to the Pathogenesis of Hearing Loss. Front Neuroanat 2017; 11:9. [PMID: 28280462 PMCID: PMC5322242 DOI: 10.3389/fnana.2017.00009] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 02/09/2017] [Indexed: 12/12/2022] Open
Abstract
Repeated noise exposure induces inflammation and cellular adaptations in the peripheral and central auditory system resulting in pathophysiology of hearing loss. In this study, we analyzed the mechanisms by which noise-induced inflammatory-related events in the cochlea activate glial-mediated cellular responses in the cochlear nucleus (CN), the first relay station of the auditory pathway. The auditory function, glial activation, modifications in gene expression and protein levels of inflammatory mediators and ultrastructural changes in glial-neuronal interactions were assessed in rats exposed to broadband noise (0.5-32 kHz, 118 dB SPL) for 4 h/day during 4 consecutive days to induce long-lasting hearing damage. Noise-exposed rats developed a permanent threshold shift which was associated with hair cell loss and reactive glia. Noise-induced microglial activation peaked in the cochlea between 1 and 10D post-lesion; their activation in the CN was more prolonged reaching maximum levels at 30D post-exposure. RT-PCR analyses of inflammatory-related genes expression in the cochlea demonstrated significant increases in the mRNA expression levels of pro- and anti-inflammatory cytokines, inducible nitric oxide synthase, intercellular adhesion molecule and tissue inhibitor of metalloproteinase-1 at 1 and 10D post-exposure. In noise-exposed cochleae, interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α) were upregulated by reactive microglia, fibrocytes, and neurons at all time points examined. In the CN, however, neurons were the sole source of these cytokines. These observations suggest that noise exposure causes peripheral and central inflammatory reactions in which TNF-α and IL-1β are implicated in regulating the initiation and progression of noise-induced hearing loss.
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Affiliation(s)
- Verónica Fuentes-Santamaría
- Instituto de Investigación en Discapacidades NeurológicasAlbacete, Spain; Facultad de Medicina, Universidad de Castilla-La ManchaAlbacete, Spain
| | - Juan Carlos Alvarado
- Instituto de Investigación en Discapacidades NeurológicasAlbacete, Spain; Facultad de Medicina, Universidad de Castilla-La ManchaAlbacete, Spain
| | - Pedro Melgar-Rojas
- Instituto de Investigación en Discapacidades NeurológicasAlbacete, Spain; Facultad de Medicina, Universidad de Castilla-La ManchaAlbacete, Spain
| | - María C Gabaldón-Ull
- Instituto de Investigación en Discapacidades NeurológicasAlbacete, Spain; Facultad de Medicina, Universidad de Castilla-La ManchaAlbacete, Spain
| | - Josef M Miller
- Center for Hearing and Communication Research and Department of Clinical Neuroscience, Karolinska InstitutetStockholm, Sweden; Kresge Hearing Research Institute, University of MichiganAnn Arbor, MI, USA
| | - José M Juiz
- Instituto de Investigación en Discapacidades NeurológicasAlbacete, Spain; Facultad de Medicina, Universidad de Castilla-La ManchaAlbacete, Spain
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Huang X, Chen M, Ding Y, Wang Q. Arctigenin protects against neuronal hearing loss by promoting neural stem cell survival and differentiation. Genesis 2016; 55. [PMID: 28026149 DOI: 10.1002/dvg.23016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 12/13/2016] [Accepted: 12/16/2016] [Indexed: 11/10/2022]
Abstract
Neuronal hearing loss has become a prevalent health problem. This study focused on the function of arctigenin (ARC) in promoting survival and neuronal differentiation of mouse cochlear neural stem cells (NSCs), and its protection against gentamicin (GMC) induced neuronal hearing loss. Mouse cochlea was used to isolate NSCs, which were subsequently cultured in vitro. The effects of ARC on NSC survival, neurosphere formation, differentiation of NSCs, neurite outgrowth, and neural excitability in neuronal network in vitro were examined. Mechanotransduction ability demonstrated by intact cochlea, auditory brainstem response (ABR), and distortion product optoacoustic emissions (DPOAE) amplitude in mice were measured to evaluate effects of ARC on GMC-induced neuronal hearing loss. ARC increased survival, neurosphere formation, neuron differentiation of NSCs in mouse cochlear in vitro. ARC also promoted the outgrowth of neurites, as well as neural excitability of the NSC-differentiated neuron culture. Additionally, ARC rescued mechanotransduction capacity, restored the threshold shifts of ABR and DPOAE in our GMC ototoxicity murine model. This study supports the potential therapeutic role of ARC in promoting both NSCs proliferation and differentiation in vitro to functional neurons, thus supporting its protective function in the therapeutic treatment of neuropathic hearing loss in vivo.
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Affiliation(s)
- Xinghua Huang
- Department of Ultrasound Diagnosis, the Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Mo Chen
- Department of Otolaryngology-Head and Neck Surgery, the Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Yan Ding
- Department of Otolaryngology-Head and Neck Surgery, the Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Qin Wang
- Department of Otolaryngology-Head and Neck Surgery, the Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
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