Although cisplatin is a widely used chemotherapeutic agent, it is severely toxic and causes irreversible hearing loss, restricting its application in clinical settings. This study aimed to determine the molecular mechanism underlying cisplatin-induced ototoxicity. Here, we established in vitro and in vivo ototoxicity models of cisplatin-induced hair cell loss, and our results showed that reducing STING levels decreased inflammatory factor expression and hair cell death. In addition, we found that cisplatin-induced mitochondrial dysfunction was accompanied by cytosolic DNA, which may act as a critical linker between the cyclic GMP-AMP synthesis-stimulator of interferon genes (cGAS-STING) pathway and the pathogenesis of cisplatin-induced hearing loss. H-151, a specific inhibitor of STING, reduced hair cell damage and ameliorated the hearing loss caused by cisplatin in vivo. This study underscores the role of cGAS-STING in cisplatin ototoxicity and presents H-151 as a promising therapeutic for hearing loss.
Cisplatin/toxicity* ; Animals ; Nucleotidyltransferases/antagonists & inhibitors* ; Membrane Proteins/antagonists & inhibitors* ; Signal Transduction/drug effects* ; Mice ; Hair Cells, Auditory, Inner/pathology* ; Antineoplastic Agents/toxicity* ; Mice, Inbred C57BL ; Hearing Loss/metabolism* ; Male ; Ototoxicity/metabolism*

As an indispensable trace element in the human body,copper plays an important role in various physiological and biochemical reactions.The dyshomeostasis of copper leads to the disorder of copper metabolism and the occurrence of related diseases.Cuproptosis,a newly proposed regulatory cell death mode,is different from the known apoptosis,pyroptosis,necroptosis,and ferroptosis.Recent studies have found that the dyshomeostasis of copper has been observed in a variety of cancers.Therefore,targeting copper for disease treatment may become a new strategy and a new idea.This article systematically summarizes the fundamental properties of copper,copper dyshomeostasis-related diseases (Menkes syndrome,Wilson's disease,and cancer) and their treatment,and reviews the research progress in cuproptosis.
Humans ; Copper/metabolism* ; Homeostasis ; Neoplasms/metabolism* ; Hepatolenticular Degeneration/metabolism* ; Menkes Kinky Hair Syndrome/metabolism*

The cochlear auditory epithelium contains two types of sound receptors, inner hair cells (IHCs) and outer hair cells (OHCs). Mouse models for labelling juvenile and adult IHCs or OHCs exist; however, labelling for embryonic and perinatal IHCs or OHCs are lacking. Here, we generated a new knock-in Fgf8^P2A-3×GFP/+ (Fgf8^GFP/+) strain, in which the expression of a series of three GFP fragments is controlled by endogenous Fgf8 cis-regulatory elements. After confirming that GFP expression accurately reflects the expression of Fgf8, we successfully obtained both embryonic and neonatal IHCs with high purity, highlighting the power of Fgf8^GFP/+. Furthermore, our fate-mapping analysis revealed, unexpectedly, that IHCs are also derived from inner ear progenitors expressing Insm1, which is currently regarded as an OHC marker. Thus, besides serving as a highly favorable tool for sorting early IHCs, Fgf8^GFP/+ will facilitate the isolation of pure early OHCs by excluding IHCs from the entire hair cell pool.
Animals ; Mice ; Hair Cells, Auditory, Inner ; Cochlea/metabolism* ; Hair Cells, Auditory, Outer/metabolism* ; Disease Models, Animal ; Fibroblast Growth Factor 8/metabolism*

Humans ; Finasteride/pharmacology* ; Dutasteride/pharmacology* ; 5-alpha Reductase Inhibitors/pharmacology* ; Testosterone/metabolism* ; Hair Follicle/metabolism* ; Transcriptome ; Hair/metabolism*

Oxidative stress plays an important role in the pathogenesis of aminoglycoside-induced hearing loss and represents a promising target for treatment. We tested the potential effect of apigenin, a natural flavonoid with anticancer, anti-inflammatory, and antioxidant activities, on neomycin-induced ototoxicity in cochlear hair cells in vitro. Results showed that apigenin significantly ameliorated the loss of hair cells and the accumulation of reactive oxygen species upon neomycin injury. Further evidence suggested that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was activated by apigenin treatment. Disruption of the Nrf2 axis abolished the effects of apigenin on the alleviation of oxidative stress and subsequent apoptosis of hair cells. This study provided evidence of the protective effect of apigenin on cochlear hair cells and its underlying mechanism.
Apigenin/pharmacology* ; Apoptosis ; Hair Cells, Auditory/metabolism* ; Humans ; NF-E2-Related Factor 2/pharmacology* ; Neomycin ; Oxidative Stress ; Reactive Oxygen Species/metabolism* ; Signal Transduction

In mammals, the piezoelectric protein, Prestin, endows the outer hair cells (OHCs) with electromotility (eM), which confers the capacity to change cellular length in response to alterations in membrane potential. Together with basilar membrane resonance and possible stereociliary motility, Prestin-based OHC eM lays the foundation for enhancing cochlear sensitivity and frequency selectivity. However, it remains debatable whether Prestin contributes to ultrahigh-frequency hearing due to the intrinsic nature of the cell's low-pass features. The low-pass property of mouse OHC eM is based on the finding that eM magnitude dissipates within the frequency bandwidth of human speech. In this study, we examined the role of Prestin in sensing broad-range frequencies (4-80 kHz) in mice that use ultrasonic hearing and vocalization (to >100 kHz) for social communication. The audiometric measurements in mice showed that ablation of Prestin did not abolish hearing at frequencies >40 kHz. Acoustic associative behavior tests confirmed that Prestin-knockout mice can learn ultrahigh-frequency sound-coupled tasks, similar to control mice. Ex vivo cochlear Ca²⁺ imaging experiments demonstrated that without Prestin, the OHCs still exhibit ultrahigh-frequency transduction, which in contrast, can be abolished by a universal cation channel blocker, Gadolinium. In vivo salicylate treatment disrupts hearing at frequencies <40 kHz but not ultrahigh-frequency hearing. By pharmacogenetic manipulation, we showed that specific ablation of the OHCs largely abolished hearing at frequencies >40 kHz. These findings demonstrate that cochlear OHCs are the target cells that support ultrahigh-frequency transduction, which does not require Prestin.
Animals ; Cochlea/metabolism* ; Hair Cells, Auditory, Outer/metabolism* ; Hearing ; Humans ; Mammals/metabolism* ; Mice ; Mice, Knockout ; Molecular Motor Proteins/metabolism*

Recent studies have revealed great functional and structural heterogeneity in the ribbon-type synapses at the basolateral pole of the isopotential inner hair cell (IHC). This feature is believed to be critical for audition over a wide dynamic range, but whether the spatial gradient of ribbon morphology is fine-tuned in each IHC and how the mitochondrial network is organized to meet local energy demands of synaptic transmission remain unclear. By means of three-dimensional electron microscopy and artificial intelligence-based algorithms, we demonstrated the cell-wide structural quantification of ribbons and mitochondria in mature mid-cochlear IHCs of mice. We found that adjacent IHCs in staggered pairs differ substantially in cell body shape and ribbon morphology gradient as well as mitochondrial organization. Moreover, our analysis argues for a location-specific arrangement of correlated ribbon and mitochondrial function at the basolateral IHC pole.
Animals ; Artificial Intelligence ; Cochlea/metabolism* ; Hair Cells, Auditory, Inner ; Mice ; Mitochondria ; Synapses/metabolism*

Objective: The aim of this study was to explore the ototoxicity of toluene in the early development of zebrafish embryos/larvae. Methods: Zebrafish were utilized to explore the ototoxicity of toluene. Locomotion analysis, immunofluorescence, and qPCR were used to understand the phenotypes and molecular mechanisms of toluene ototoxicity. Results: The results demonstrated that at 2 mmol/L, toluene induced zebrafish larvae death at 120 hours post fertilization (hpf) at a rate of 25.79% and inhibited the rate of hatching at 72 hpf. Furthermore, toluene exposure inhibited the distance travelled and average swimming velocity of zebrafish larvae while increasing the frequency of movements. As shown by fluorescence staining of hair cells, toluene inhibited the formation of lateral line neuromasts and middle line 1 (Ml Conclusion This study indicated that toluene may affect the development of both the inner ear and lateral line systems in zebrafish, while the lateral line system may be more sensitive to toluene than the inner ear.
Animals ; Ear, Inner/growth & development* ; Embryo, Nonmammalian/drug effects* ; Gene Expression Regulation, Developmental/drug effects* ; Hair Cells, Auditory/metabolism* ; Lateral Line System/growth & development* ; Locomotion/drug effects* ; Ototoxicity/physiopathology* ; Toluene/toxicity* ; Zebrafish

OBJECTIVE: To explore the protective effect of NANOG against hydrogen peroxide (H2O2) -induced cell damage in the human hair follicle mesenchymal stem cells (hHF-MSCs). METHODS: NANOG was expressed from a lentiviral vector, pLVX-IRES-ZsGreen. NANOG hHF-MSCs and vector hHF-MSCs were treated with 400 μmol/L hydrogen peroxide (H2O2) for 2 h, the cell survival rate, cell morphology, ROS production, apoptosis and expression of AKT, ERK, and p21 were determined and compared. RESULTS: Our results showed that NANOG could activate AKT and upregulate the expression of p-AKT, but not p-ERK. When treated with 400 μmol/L H2O2, NANOG hHF-MSCs showed higher cell survival rate, lower ROS production and apoptosis, higher expression of p-AKT, higher ratio of p-AKT/AKT. CONCLUSION Our results suggest that NANOG could protect hHF-MSCs against cell damage caused by H2O2 through activating AKT signaling pathway.
Cell Survival ; Drug Evaluation, Preclinical ; Hair Follicle ; cytology ; Humans ; Hydrogen Peroxide ; Lentivirus ; Mesenchymal Stem Cells ; drug effects ; metabolism ; Nanog Homeobox Protein ; metabolism ; pharmacology ; Oxidative Stress ; drug effects ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction

BACKGROUND: Menkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with progressive neurodegeneration, some connective tissue abnormalities, and characteristic “kinky” hair. In addition, various types of urological complications are frequent in MD because of underlying connective tissue abnormalities. In this study, we studied the clinical features and outcomes of MD, focusing on urological complications. METHODS: A total of 14 unrelated Korean pediatric patients (13 boys and 1 girl) with MD were recruited, and their phenotypes and genotypes were analyzed by retrospective review of their medical records. RESULTS: All the patients had early-onset neurological deficit, including developmental delay, seizures, and hypotonia. The girl patient showed normal serum copper and ceruloplasmin levels as well as milder symptoms. Mutational analysis of the ATP7A gene revealed 11 different mutations in 12 patients. Bladder diverticula was the most frequent urological complication: 8 (57.1%) in the 14 patients or 8 (72.7%) in the 11 patients who underwent urological evaluation. Urological imaging studies were performed essentially for the evaluation of accompanying urinary tract infections. Four patients had stage II chronic kidney disease at the last follow-up. CONCLUSION: Urologic problems occurred frequently in MD, with bladder diverticula being the most common. Therefore, urological imaging studies and appropriate management of urological complications, which may prevent or reduce the development of urinary tract infections and renal parenchymal damage, are required in all patients with MD.
Ceruloplasmin ; Connective Tissue ; Copper ; Diverticulum ; Female ; Follow-Up Studies ; Genotype ; Hair ; Humans ; Medical Records ; Menkes Kinky Hair Syndrome* ; Metabolism ; Muscle Hypotonia ; Phenotype ; Renal Insufficiency, Chronic ; Retrospective Studies ; Seizures ; Urinary Bladder ; Urinary Tract Infections