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Hearing Research Jun 2024Cisplatin, a highly effective chemotherapeutic drug for various human cancers, induces irreversible sensorineural hearing loss as a side effect. Currently there are no...
Cisplatin, a highly effective chemotherapeutic drug for various human cancers, induces irreversible sensorineural hearing loss as a side effect. Currently there are no highly effective clinical strategies for the prevention of cisplatin-induced ototoxicity. Previous studies have indicated that short-term cisplatin ototoxicity primarily affects the outer hair cells of the cochlea. Therefore, preventing the entry of cisplatin into hair cells may be a promising strategy to prevent cisplatin ototoxicity. This study aimed to investigate the entry route of cisplatin into mouse cochlear hair cells. The competitive inhibitor of organic cation transporter 2 (OCT2), cimetidine, and the sensory mechanoelectrical transduction (MET) channel blocker benzamil, demonstrated a protective effect against cisplatin toxicity in hair cells in cochlear explants. Sensory MET-deficient hair cells explanted from Tmc1;Tmc2 mice were resistant to cisplatin toxicity. Cimetidine showed an additive protective effect against cisplatin toxicity in sensory MET-deficient hair cells. However, in the apical turn, cimetidine, benzamil, or genetic ablation of sensory MET channels showed limited protective effects, implying the presence of other entry routes for cisplatin to enter the hair cells in the apical turn. Systemic administration of cimetidine failed to protect cochlear hair cells from ototoxicity caused by systemically administered cisplatin. Notably, outer hair cells in MET-deficient mice exhibited no apparent deterioration after systemic administration of cisplatin, whereas the outer hair cells in wild-type mice showed remarkable deterioration. The susceptibility of mouse cochlear hair cells to cisplatin ototoxicity largely depends on the sensory MET channel both ex vivo and in vivo. This result justifies the development of new pharmaceuticals, such as a specific antagonists for sensory MET channels or custom-designed cisplatin analogs which are impermeable to sensory MET channels.
Topics: Cisplatin; Animals; Ototoxicity; Mechanotransduction, Cellular; Organic Cation Transporter 2; Cimetidine; Antineoplastic Agents; Hair Cells, Auditory; Hair Cells, Auditory, Outer; Mice, Inbred C57BL; Mice; Membrane Proteins
PubMed: 38718672
DOI: 10.1016/j.heares.2024.109013 -
Hearing Research Jun 2024The disruption of ribbon synapses in the cochlea impairs the transmission of auditory signals from the cochlear sensory receptor cells to the auditory cortex. Although...
The disruption of ribbon synapses in the cochlea impairs the transmission of auditory signals from the cochlear sensory receptor cells to the auditory cortex. Although cisplatin-induced loss of ribbon synapses is well-documented, and studies have reported nitration of cochlear proteins after cisplatin treatment, yet the underlying mechanism of cochlear synaptopathy is not fully understood. This study tests the hypothesis that cisplatin treatment alters the abundance of cochlear synaptosomal proteins, and selective targeting of nitrative stress prevents the associated synaptic dysfunction. Auditory brainstem responses of mice treated with cisplatin showed a reduction in amplitude and an increase in latency of wave I, indicating cisplatin-induced synaptic dysfunction. The mass spectrometry analysis of cochlear synaptosomal proteins identified 102 proteins that decreased in abundance and 249 that increased in abundance after cisplatin treatment. Pathway analysis suggested that the dysregulated proteins were involved in calcium binding, calcium ion regulation, synapses, and endocytosis pathways. Inhibition of nitrative stress by co-treatment with MnTBAP, a peroxynitrite scavenger, attenuated cisplatin-induced changes in the abundance of 27 proteins. Furthermore, MnTBAP co-treatment prevented the cisplatin-induced decrease in the amplitude and increase in the latency of wave I. Together, these findings suggest a potential role of oxidative/nitrative stress in cisplatin-induced cochlear synaptic dysfunction.
Topics: Cisplatin; Animals; Cochlea; Evoked Potentials, Auditory, Brain Stem; Synapses; Proteomics; Synaptosomes; Oxidative Stress; Mice, Inbred CBA; Male; Ototoxicity; Mice
PubMed: 38705005
DOI: 10.1016/j.heares.2024.109022 -
Hearing Research Jun 2024Understanding the complex pathologies associated with hearing loss is a significant motivation for conducting inner ear research. Lifelong exposure to loud noise,... (Review)
Review
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.
Topics: Animals; Hair Cells, Auditory; Disease Models, Animal; Regeneration; Mice; Cochlea; Humans; Hearing; Hearing Loss, Noise-Induced; Hearing Loss; Acoustic Stimulation
PubMed: 38703432
DOI: 10.1016/j.heares.2024.109021 -
Investigational New Drugs Jun 2024MET exon 14 skipping alterations and MET amplifications are recognized as oncogenic and targetable genetic changes in cancer patients. The treatment of MET-selective...
MET exon 14 skipping alterations and MET amplifications are recognized as oncogenic and targetable genetic changes in cancer patients. The treatment of MET-selective tyrosine kinase inhibitors (TKIs) in this specific population has shown encouraging therapeutic results. However, a comprehensive understanding of the potential toxicities linked to these agents is still lacking. The present pharmacovigilance analysis was carried out using the FDA Adverse Event Reporting System database to assess notable adverse events associated with MET-selective TKIs. Gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and disturbances in metabolism and nutrition demonstrated a substantial prevalence and significance among the adverse event (AE) categories. Particularly notable were the occurrences of peripheral oedema, nausea, dysphagia, fatigue, and dyspnoea, which emerged as the foremost five reported AEs. The majority of these AEs were observed within the initial months of initiating treatment with MET-selective TKIs and persistently thereafter. Notably, our investigation unveiled a significant correlation between the usage of capmatinib and the incidence of hearing loss and difficulty in swallowing. Diligent monitoring and the implementation of supportive care strategies are essential in managing the toxicities associated with MET-selective TKIs, particularly those related to gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and ototoxicity.
Topics: Humans; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Male; Pharmacovigilance; Female; Middle Aged; Aged; Adverse Drug Reaction Reporting Systems; Adult; Neoplasms; Antineoplastic Agents; Benzamides; Aged, 80 and over; Triazines; Tyrosine Kinase Inhibitors; Imidazoles
PubMed: 38700578
DOI: 10.1007/s10637-024-01437-z -
Annals of Neurosciences Apr 2024Hypertension (HTN) has a genetic predisposition and it also impairs microcirculation, thereby, affecting the well vascularized structures like the brainstem and causing...
BACKGROUND
Hypertension (HTN) has a genetic predisposition and it also impairs microcirculation, thereby, affecting the well vascularized structures like the brainstem and causing changes in Brainstem Auditory Evoked Potentials (BAEPs).
PURPOSE
To find out the usefulness of BAEPs as a screening tool in apparently healthy individuals with a family history of HTN.
METHODS
One hundred and ten volunteers, aged 17 to 23 years, were enrolled in the study as participants with proper consent. After excluding the subjects with existing diseases or co-morbidities (e.g. diabetes, HTN, schizophrenia, neuropathy, etc.), those on ototoxic or neurotoxic drugs, a preliminary physical examination was performed, following which BAEPs were recorded with a proper device. Statistical analysis is done with SPSS 2016 software using the chi-square test.
RESULTS
A consistent distortion in the inter-peak latency of III-V waves is noted when a family history of HTN is present in either parent or maternal grandparents. Other statistically significant findings are present in V/I% (HTN in mother), wave I (HTN in paternal grandfather), wave III (HTN in maternal grandfather), and inter-peak latency I-V (HTN in maternal grandmother).
CONCLUSION
BAEP may be used as a screening tool in individuals with a family history of HTN with supportive evidence from further studies in the near future.
PubMed: 38694718
DOI: 10.1177/09727531231184680 -
Toxicology and Applied Pharmacology May 2024SERCA2, one of the P-type pumps encoded by gene ATP2A2, is the only calcium reflux channel of the endoplasmic reticulum (ER) and participates in maintaining calcium...
AIMS
SERCA2, one of the P-type pumps encoded by gene ATP2A2, is the only calcium reflux channel of the endoplasmic reticulum (ER) and participates in maintaining calcium homeostasis. The present study was designed to explore SERCA2 expression pattern in auditory hair cells and the possible mechanism underlying the effects of SERCA2 on cisplatin-induced ototoxicity.
MAIN METHODS
The SERCA2 expression pattern in cochlea hair cells and HEI-OC1 cells was measured by Western blot (WB) and immunofluorescence staining. The apoptosis and its related factors were detected by TUNEL assay and WB. The expression levels of ER stress-related factors, ATF6, PERK, IRE1α, and GRP78, were measured via WB. As for the determination of SERCA2 overexpression and knockdown, plasmids and lentiviral vectors were constructed, respectively.
KEY FINDINGS
We found that SERCA2 was highly expressed in cochlea hair cells and HEI-OC1 cells. Of note, the level of SERCA2 expression in neonatal mice was remarkably higher than that in adult mice. Under the exposure of 30 μM cisplatin, SERCA2 was down-regulated significantly compared with the control group. In addition, cisplatin administration triggered the occurrence of ER stress and apoptosis. Those events were reversed by overexpressing SERCA2. On the contrary, SERCA2 knockdown could aggravate the above processes.
SIGNIFICANCE
The findings from the present study disclose, for the first time, that SERCA2 is abundantly expressed in cochlea hair cells, and the suppression of SERCA2 caused by cisplatin could trigger ER homeostasis disruption, thereby implying that SERCA2 might be a promising target to prevent cisplatin-induced cytotoxicity of hair cells.
Topics: Cisplatin; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Animals; Endoplasmic Reticulum Stress; Endoplasmic Reticulum Chaperone BiP; Mice; Apoptosis; Hair Cells, Auditory; Cell Line; Antineoplastic Agents; Male; Ototoxicity
PubMed: 38688426
DOI: 10.1016/j.taap.2024.116947 -
Zhonghua Wai Ke Za Zhi [Chinese Journal... Jun 2024To investigate the clinical effect of intraarticular vancomycin on early periprosthetic joint infection (PJI) in knee arthroplasty and the incidence of postoperative...
To investigate the clinical effect of intraarticular vancomycin on early periprosthetic joint infection (PJI) in knee arthroplasty and the incidence of postoperative complications. This is a retrospective cohort study. The clinical data of 1 867 patients who underwent primary knee arthroplasty at Department of Joint Surgery, the Affiliated Hospital of Qingdao University from April 2022 to June 2023 were retrospectively analysed, including total knee arthroplasty (TKA), robotic-assisted total knee arthroplasty (RA-TKA) and unicondylar knee arthroplasty (UKA). There were 687 males and 1 180 females, aged (68.0±11.2)years(range:45 to 87 years). Patients were divided into the vancomycin group and the control group according to whether or not intra-articular injection of 1 g of vancomycin powder dissolved in 30 ml of saline was performed after intraoperative joint capsule closure. In the vancomycin group, 925 patients were included, including 782 TKA, 27 RA-TKA and 116 UKA.In the control group, 942 patients were included, including 767 TKA, 99 RA-TKA and 76 UKA. Early PJI, wound complications, and vancomycin-related toxicity including acute renal collapse, ototoxicity, and allergic reactions were assessed within 3 months postoperatively. The data were compared using the independent sample test, ² test, and Fisher's exact probability method, as appropriate. Major Extremity Trauma Research Consortium (METRC). No PJI was found in all patients in the vancomycin group.Five cases (0.7%,5/767) of early PJI were found in TKA patients in the control group, with a statistically significant difference (=0.030); 1 case of early PJI was found in each RA-TKA and UKA patients, with non-significant difference compared with vancomycin group (all >0.05). Two cases (0.3%,2/782) of incisional complications were found in TKA patients in the vancomycin group, and 4 cases (0.5%, 4/767) of incisional complications were found in TKA patients in the control group, with non-significant difference(=0.449); no incisional complication was found in RA-TKA patients in the vancomycin group, and 1 case (1.0%,1/99) of incisional complications were found in RA-TKA patients in the control group, the difference was not statistically significant (>0.05); no incisional complication was found in both groups of UKA patients.No vancomycin-related acute kidney injury, ototoxicity, or allergic reactions was observed in all patients. Intra-articular injection of 1 g of vancomycin suspension after arthrotomy closure during TKA maybe lower the risk of early PJI without increasing the risk of wound complication and vancomycin-associated systemic toxicity.
Topics: Humans; Vancomycin; Male; Arthroplasty, Replacement, Knee; Female; Retrospective Studies; Aged; Middle Aged; Prosthesis-Related Infections; Aged, 80 and over; Injections, Intra-Articular; Anti-Bacterial Agents; Treatment Outcome
PubMed: 38682631
DOI: 10.3760/cma.j.cn112139-20231116-00224 -
International Journal of Molecular... Apr 2024Hearing is essential for communication, and its loss can cause a serious disruption to one's social life. Hearing loss is also recognized as a major risk factor for... (Review)
Review
Hearing is essential for communication, and its loss can cause a serious disruption to one's social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant type of hearing loss, is mainly due to damage to the inner ear along with a variety of pathologies including ischemia, noise, trauma, aging, and ototoxic drugs. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies. The cochlea, which plays a major role in auditory function, requires high-energy metabolism and is, therefore, highly susceptible to oxidative stress, particularly in the mitochondria. Based on these pathological findings, the potential of antioxidants for the treatment of hearing loss has been demonstrated in several animal studies. However, results from human studies are insufficient, and future clinical trials are required. This review discusses the relationship between sensorineural hearing loss and reactive oxidative species (ROS), with particular emphasis on age-related hearing loss, noise-induced hearing loss, and ischemia-reperfusion injury. Based on these mechanisms, the current status and future perspectives of ROS-targeted therapy for sensorineural hearing loss are described.
Topics: Humans; Oxidative Stress; Hearing Loss, Sensorineural; Animals; Reactive Oxygen Species; Antioxidants; Cochlea; Hearing Loss, Noise-Induced; Reperfusion Injury; Mitochondria
PubMed: 38673731
DOI: 10.3390/ijms25084146 -
BMJ Case Reports Apr 2024Mycetoma is a chronic granulomatous infectious disease with a triad of subcutaneous swelling, discharging sinuses and the presence of granules. The infection may occur...
Mycetoma is a chronic granulomatous infectious disease with a triad of subcutaneous swelling, discharging sinuses and the presence of granules. The infection may occur following minor trauma or penetrating thorn injury. We report a case of a man in his 40s with a history of thorn prick 9 years ago, followed by the formation of painless discharging sinuses on the right foot for the past 2 years. Clinical, local epidemiological, histopathological examination and Gram stain confirmed the diagnosis of actinomycetoma. Prior to initiating the Welsh regimen, a pretreatment assessment of the patient's auditory function was conducted through pure tone audiometry, indicating the existence of pre-existing high-frequency bilateral sensorineural hearing loss. The patient was treated with linezolid as an alternative to amikacin, at a dosage of 600 mg two times per day, leading to complete resolution within 3 weeks. This underscores linezolid's efficacy as a safe and cost-effective alternative for actinomycetoma, without causing ototoxic side effects.
Topics: Humans; Linezolid; Male; Hearing Loss, Sensorineural; Mycetoma; Adult; Anti-Bacterial Agents; Treatment Outcome
PubMed: 38663898
DOI: 10.1136/bcr-2023-258686 -
Environmental Toxicology Jul 2024Platinum-based antineoplastic drugs, including cisplatin, carboplatin, and oxaliplatin, are widely used in the treatment of various cancers. Ototoxicity is a common...
Platinum-based antineoplastic drugs, including cisplatin, carboplatin, and oxaliplatin, are widely used in the treatment of various cancers. Ototoxicity is a common adverse effect of platinum-based drugs. Ototoxicity leads to irreversible hearing impairment. We hypothesize that different platinum-based drugs exhibit varying ototoxic concentrations, time effects, and ototoxic mechanisms. We tested this hypothesis by using a zebrafish model (pvalb3b: TagGFP) to assess the viability of hair cells collected from zebrafish larvae. Cisplatin, carboplatin, and oxaliplatin were administered at dosages of 100, 200, or 400 μM, and the ototoxic effects of these drugs were assessed 1, 2, or 3 h after administration. Fm4-64 and a TUNEL assay were used to label the membranes of living hair cells and to detect cell apoptosis, respectively. We observed that >50% of hair cells were damaged at 1 h after cisplatin (100 μM) exposure, and this ototoxic effect increased at higher dosages and over time. Owing to the smaller ototoxic effects of carboplatin and oxaliplatin, we conducted higher-strength and longer-duration experiments with these drugs. Neither carboplatin nor oxaliplatin was obviously ototoxic, even at 1600 μM and after 6 h. Moreover, only cisplatin damaged the membranes of the hair cells. Cell apoptosis and significantly increased antioxidant gene expression were observed in only the cisplatin group. In conclusion, cisplatin significantly damages sensory hair cells and has notable dosage and time effects. Carboplatin and oxaliplatin are less ototoxic than cisplatin, likely due to having different ototoxic mechanisms than cisplatin.
Topics: Animals; Zebrafish; Cisplatin; Oxaliplatin; Carboplatin; Ototoxicity; Antineoplastic Agents; Apoptosis; Hair Cells, Auditory; Larva
PubMed: 38661261
DOI: 10.1002/tox.24285